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Section of Endocrine Neoplasia & Hormonal Disorders (H.M.K., K.E.F.) and the Department of Neurosurgery (I.E.M.), The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; and Medical Department M (Diabetes and Endocrinology) (A.F.), Aarhus Kommunehospital, Aarhus, DK-8000 Denmark
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Abstract |
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 Top Abstract I. IntroductionII. Overview: IGF Physiology...III. Potential Therapeutic...IV. Central Nervous System...V. Gastrointestinal NeoplasmsVI. Head, Neck, and...VII. Female Reproductive...VIII. Male Reproductive...IX. Genitourinary NeoplasmsX. Bone NeoplasmsXI. Skin NeoplasmsXII. Hematological MalignanciesXIII. SummaryReferences |
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I. Introduction |
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TopAbstractI. IntroductionII. Overview: IGF Physiology...III. Potential Therapeutic...IV. Central Nervous System...V. Gastrointestinal NeoplasmsVI. Head, Neck, and...VII. Female Reproductive...VIII. Male Reproductive...IX. Genitourinary NeoplasmsX. Bone NeoplasmsXI. Skin NeoplasmsXII. Hematological MalignanciesXIII. SummaryReferences |
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II. Overview: IGF Physiology and Gene Regulation |
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TopAbstractI. IntroductionII. Overview: IGF Physiology...III. Potential Therapeutic...IV. Central Nervous System...V. Gastrointestinal NeoplasmsVI. Head, Neck, and...VII. Female Reproductive...VIII. Male Reproductive...IX. Genitourinary NeoplasmsX. Bone NeoplasmsXI. Skin NeoplasmsXII. Hematological MalignanciesXIII. SummaryReferences |
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The IGFs are present in the circulation in combination with high- and
low-affinity binders, which form the IGF-binding protein (IGFBP)
superfamily. A total of six high-affinity binding proteins have been
identified, IGFBP-1 through IGFBP-6 (4, 5, 6, 7). Although the majority
of the circulating IGFBPs are synthesized in the liver, many other
organs are capable of production of IGFBPs. IGFBP-3 is the most
abundant binding protein in the serum. It forms a ternary complex with
IGF-I and an acid-labile subunit. The IGFBPs have higher affinities for
IGFs (kd 
10-10
M) than do the type I IGF receptors
(kd 10-8
M). The IGF/IGFBP complex is acted upon by proteases at the
target organ, whereby IGF is released and is available for biological
actions. The IGFBPs have stimulatory and/or inhibitory actions on cell
proliferation, and these effects may be dependent or independent of
IGF. Chen et al. (8) in 1994 demonstrated that addition of
exogenous IGFBP-2 and -3 increased IGF-I stimulated
[3H]thymidine incorporation in the estrogen
receptor-positive cell line, MCF-7. This was thought to be due to
a conformational change in the IGFBP-3 as a result of cell surface
association, leading to reduced affinity and increased
bioavailability of IGF-I and -II.
In addition to the high-affinity IGFBPs, several low-affinity binding proteins, termed IGFBP-related proteins (IGFBP-rP), have been described. The IGFBP-rPs are cysteine rich, have structural similarities to the N terminus of the IGFBPs, and bind to IGFs with a 100-fold lower affinity compared with the IGFBPs. The IGFBP-rPs have actions that are predominantly independent of IGFs.
The IGF-I receptor is a transmembrane heterotetramer consisting of two
- and two ß-subunits. There is approximately 60% sequence
homology between the IGF-I receptor and the insulin receptor. The IGF-I
receptor, like the insulin receptor, possesses tyrosine kinase
activity. The postreceptor signal transduction events include
phosphorylation of insulin receptor substrate-1 (IRS-1) and activation
of phosphatidylinositol-3 (PI-3) and mitogen-activated
protein kinases. IGF-II and insulin also bind to the IGF-I
receptor but with 2- to 15- and 1,000-fold lower affinity, respectively
(9). The IGF-I receptor has been shown to protect cells from apoptosis
in vitro and in vivo. Resnicoff et al.
(10) demonstrated that for a number of different cell lines, including
a human melanoma cell line, decreasing the number of IGF-I receptors by
antisense oligodeoxynucleotides was associated with decreased cell
growth in vitro and in vivo. The number of
apoptotic cells was significantly increased in these cell lines as
measured by various techniques. Valentinis et al. (11) in
1999 suggested that the paradoxical ability of IGF-I to cause
unregulated cell growth, on one hand, or lead to terminal
differentiation, on the other, may depend on the balance between
various intracellular substrates. In their study using murine
hemopoietic cells (32D), which lack IRS-1, exogenous IGF-I induced
differentiation of these cells along the granulocytic pathway after
interleukin-3 withdrawal. The IGF-I-induced differentiation in the
absence of IRS-1 required the C terminus of the IGF-I receptor.
Expression of IRS-1 in these cells was associated with loss of
differentiation and caused unregulated growth, and the degree of
inhibition of differentiation correlated with IRS-1 expression. The
authors also suggested that overexpression of Shc, another substrate of
IGF-I receptor, potentiated 32D cell differentiation while a dominant
negative mutant of Shc partially inhibited differentiation.
The IGF-II/cation-independent mannose-6-phosphate (IGF-II/ Man-6-P) receptor is a monomeric receptor that binds IGF-II with a 500-fold increased affinity over IGF-I. The IGF-II receptor does not bind insulin. Most of the biological actions of IGF-II are thought to be mediated via the IGF-I receptor (12, 13). Four classes of ligands are currently known to bind to the extracytoplasmic receptor domain. They include mannose 6-phosphate-containing lysosomal enzymes, IGF-II, retinoic acid, and urokinase-type plasminogen activator receptor. The IGF-II receptor is thought to function primarily as a scavenger receptor, regulating the internalization and degradation of extracellular IGF-II, thus regulating the circulating IGF-II levels. IGF-II receptor mutant animals have been demonstrated to have increased circulating and serum levels of IGF-II along with an increased birth weight, organomegaly, and perinatal mortality. The IGF-II receptor also regulates intracellular trafficking of lysosomal enzymes including cathepsin, which serves as an IGFBP proteolytic enzyme. Recently, O’Gorman et al. (14) described enhanced tumor growth in a choriocarcinoma cell line, JEG-3, after IGF-II receptor expression was decreased by antisense IGF-II cDNA constructs. The resultant decrease in cathepsin degradation, yielding an increase in IGFBP proteolysis and bioavailable IGFs, may account for this enhanced tumor growth. Although most of the mitogenic/metabolic effects of IGF-II signaling are mediated via the IGF-I receptor, some effects, including Na+/H+ exchange and production of inositol triphosphate in renal tubular cells, stimulation of Ca+ influx, and DNA synthesis in BALB/c 3T3 cells, may be mediated by binding of IGF-II to its receptor (12, 13).
A. IGF-I gene expression
The prepro-IGF-I gene consists of six exons in most mammalian
species and is located on chromosome 12 in humans. The majority of
circulating IGF-I is produced in the liver, and hepatic production is
principally regulated by GH. Although the liver-specific deletion of
the IGF-I gene using the Cre/loxP recombination system
reduced circulating IGF-I concentration by approximately 80% in mice,
the growth rates of these transgenic animals was not significantly
different when compared with the wild-type animals. This was
demonstrated by Yakar et al. (15) and suggests the
importance of extrahepatic, autocrine/paracrine production of IGF-I in
growth regulation. In some tissues, IGF-I gene expression is
predominantly under the control of other hormones: estradiol in the
endometrium, gonadotropins in the gonadal tissue, TSH in the thyroid,
etc. (16, 17, 18). IGF-I mRNA levels have been also demonstrated to be
altered by nutritional state and developmental stage. For instance,
fasting reduces serum IGF-I concentrations as much as 75% and negates
the effects of GH stimulation. Refeeding rapidly restores parameters to
normal (19).
The coding region of prepro-IGF-I is flanked by complex 5'- and 3'-untranslated regions that result in considerable heterogeneity in mature IGF-I transcripts. For instance, in the rat it has been demonstrated that there are separate start sites present in both exons 1 and 2. In exon 1, transcription can be initiated from several different sites over a several hundred base pair region. This broad range of sites exists because there are no core promoter elements such as TATA and CAAT box motifs in exon 1. TATA and CAAT box motifs elements, however, are present upstream of the cluster of start sites present in exon 2. Nevertheless, in most tissues, the majority of transcripts arise from sites in exon 1. As a result of different start sites and alternative splicing, there are a variety of different 5'-untranslated regions that can be present in the mature mRNA transcript. Translation of prepro-IGF-I can be initiated from codons in exons 1, 2, or 3. Alternate polyadenylation sites in the 3'-untranslated region of the molecule also contribute to differences in transcript size. On Northern analysis, IGF-I transcripts ranging from <1 kb to approximately 7.5 kb are observed (20).
B. IGF-II gene expression
The human prepro-IGF-II gene consists of nine exons and is located
on chromosome 11. The first six exons are noncoding. There are four
promoters present (P1–4). There is one promoter each in the regions
upstream of exons 1, 4, 5, and 6. During fetal development, IGF-II
expression is much higher than in the postnatal period or in the adult.
A distinct pattern of promoter use correlates with expression levels
during development. In the fetus, promoters P2–4 are active in the
liver. After birth, the use of these three promoters declines and P1
becomes dominant. There is some degree of tissue-specific regulation
(21). The IGF-II gene is one of the few genes known to have parental
allele-specific expression. As such, it is referred to as an imprinted
gene. In normal cells, IGF-II is maternally imprinted in that it is
expressed only from the paternal copy of the gene. The IGF-II gene is
located on chromosome 11p15.5 close to H19, a paternally imprinted
gene. The imprinting process is an early event, taking place at
the time of gametogenesis. Loss of IGF-II imprinting has been reported
in a variety of tumors, including Wilms’ tumors, gastric
adenocarcinomas, lung cancers, gliomas, hepatoblastomas,
leiomyosarcomas, cervical cancer, prostate cancer, choriocarcinomas,
rhabdomyosarcomas, seminomas, and ovarian carcinomas (22, 23, 24). When
loss of imprinting occurs, biallelic expression of IGF-II results,
ultimately leading to overexpression of this potent growth factor. The
precise role of loss of IGF-II imprinting in tumorigenesis and tumor
growth is unknown at this time. In some neoplasms, such as Wilms’
tumor, loss of imprinting is an event that occurs early in
carcinogenesis. In others, such as cervical carcinoma, it is not an
early event. The precise relationship with H19, which may have tumor
suppressor function, is also not completely known. In Wilms’ tumor,
the loss of imprinting is often linked with a reduced expression of
H19. This reciprocal relationship, however, has not been commonly
detected in other tumor types, such as hepatoblastomas, gliomas,
testicular tumors, and cervical cancers.
C. IGF-I receptor gene expression
The highest levels of IGF-I receptor mRNA expression occur during
fetal development and in the early postnatal period. Although IGF-I
receptor expression is significantly down-regulated in the adult, it is
present in most types of tissue. Its expression is up-regulated to some
degree by fasting; up-regulation has been reported in the kidney in an
experimental diabetes model (25). IGF-I decreases IGF-I receptor
expression in a dose-dependent manner in FRTL-5, IM-9, and endothelial
cells (26, 27).
The IGF-I receptor gene promoter lacks both TATA and CAAT box motifs. The 5'-untranslated region is very GC-rich and contains multiple Sp1 consensus-binding sequences. Accordingly, Sp1 has been demonstrated to potently activate IGF-I receptor gene transcription (28). Transcription is initiated from a single start site. Basic fibroblastic growth factor (bFGF) has also been demonstrated to increase IGF-I receptor mRNA levels and activate the IGF-I receptor promoter. The effects of bFGF have been localized to a region of the IGF-I promoter located between nucleotides -476 and -188 (29). Transfection experiments have demonstrated that the tumor suppressor p53 inhibits activity of the IGF-I receptor promoter. Mutant versions of p53, frequently present in malignant states, result in increased IGF-I receptor gene activation (30). The increased level of IGF-I receptor expression present in some malignant tumors may enhance response to autocrine, paracrine, or circulating IGFs.
D. IGF-II receptor gene expression
The IGF-II receptor binds IGF-II and ligands containing a mannose
6-phosphate recognition marker (lysosomal enzymes). Unlike the IGF-I
receptor gene, this receptor is a large single-chain peptide that has
no intrinsic tyrosine kinase activity (31). Its primary function seems
to be transport of its ligands to liposomes, resulting in either their
activation or degradation. The majority of IGF-II receptors are located
on intracellular membranes. Most of the physiological actions of IGF-II
are thought to be mediated through binding to the IGF-I receptor.
However, binding of IGF-II to its receptor has been demonstrated to
trigger interaction with a membrane-bound GTP-binding protein, Gi-2,
that mediates the influx of calcium into the cell (32).
The mouse IGF-II receptor gene is 93 kb in size and contains 48 exons. The gene contains a strong minimal promoter of 266 bp or less. An extended 54-bp footprint within the proximal promoter containing two E-boxes and probable binding sites for Sp1, nerve growth factor-IA (NGF-IA), and related proteins has also been identified. Deletion of the 54-bp segment resulted in an 8-fold decline in promoter activity. Mutational analyses demonstrated that each E box contributed to more than half of the enhancers activity (33).
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III. Potential Therapeutic Agents |
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TopAbstractI. IntroductionII. Overview: IGF Physiology...III. Potential Therapeutic...IV. Central Nervous System...V. Gastrointestinal NeoplasmsVI. Head, Neck, and...VII. Female Reproductive...VIII. Male Reproductive...IX. Genitourinary NeoplasmsX. Bone NeoplasmsXI. Skin NeoplasmsXII. Hematological MalignanciesXIII. SummaryReferences |
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). The major classes of therapeutic
approaches are summarized in the following section.
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- helical character of the molecule,
have led to the synthesis of GHRH analogs with agonist/antagonistic
activity. The GHRH antagonists inhibit in vitro
GHRH-stimulated GH release in a superfused rat pituitary system and
inhibit basal and hGHRH-stimulated GH release in vivo. By
decreasing pituitary GH release, hepatic IGF-I production is also
reduced. Varga et al. (34), in a study evaluating 22
antagonists of GHRH, demonstrated that some agents potently inhibited
in vivo hGHRH-induced GH release up to at least 60 min after
administration. The GHRH antagonists have also been shown to inhibit autocrine/paracrine production of IGF-I/IGF-II by acting directly on the tumor tissues. In a study by Csernus et al. in 1999, the GHRH antagonists, MZ-4–71 and MZ-5–156, were shown to inhibit autocrine production of IGF-II, reduce IGF-II mRNA expression, and decrease cell proliferation in a number of cell lines including the breast cancer cell lines MDA-MB-468 and ZR-75–1, prostate cancer cell lines PC-3 and DU-145, and the pancreatic cancer cell lines MiaPaCa-2, Capan-2, and SW-1990 (35). Because IGF-II is a potent mitogen for a variety of cell lines, and overexpression of IGF-II mRNA has been demonstrated for some tumors, reduction of IGF-II by GHRH antagonists could be of potential therapeutic use in the management of such tumors.
Thus, the GHRH antagonists could inhibit tumor growth through direct or indirect pathways. The indirect mechanism would be secondary to a reduction in pituitary GH release and subsequent hepatic IGF-I production, leading to a decrease in circulating, "endocrine" IGF-I. The GHRH antagonists may also directly inhibit intratumor IGF-I and/or IGF-II mRNA expression and decrease the autocrine/paracrine production of these growth factors.
B. Somatostatin analogs
Somatostatin is a peptide synthesized as part of a large precursor
molecule that is cleaved and processed to yield several mature
products, two of them being somatostatin-14 and somatostatin-28, the
latter a congener of somatostatin extended at the N terminus.
Somatostatin acts as a neurotransmitter in the central nervous system,
regulates the release of GH and TSH, and has a regulatory role in the
gastrointestinal system and endocrine and exocrine pancreas. The
actions of somatostatin are mediated through somatostatin
receptors, five of which have been characterized. These membrane
receptors are present in multiple organ systems. The receptors are
linked to adenylate cyclase through a coupling mechanism involving
guanine nucleotide-binding (G) protein. As the half-life of
natural somatostatin is very short, longer acting analogs have been
developed, octreotide being the first such analog to come into clinical
use. Other analogs include octreotide-LAR, lanreotide, and vapreotide.
Somatostatin analogs can be expected to reduce circulating IGF-I levels
by 30–50% in nonacromegaly patients (36, 37).
The antineoplastic activity of the somatostatin analogs could result from a reduction of GH and IGF-I secretion, which would, in turn, have an inhibitory effect on cell proliferation. As the somatostatin analogs also inhibit secretion of many gastrointestinal hormones, including gastrin, cholecystokinin (CCK), secretin, and bombesin, which have been implicated as mitogens for a variety of neoplastic cells, modulation of these gastrointestinal hormones may also be responsible for the antineoplastic activity of somatostatin analogs. Furthermore, a more "direct" inhibitory effect of these compounds on cell proliferation has been demonstrated. Somatostatin analogs have been shown to stimulate tyrosine phosphatase activity in certain cell lines, an effect that antagonizes the mitogenic effect of growth factors acting on tyrosine kinase receptors such as epidermal growth factor (EGF), bFGF, and IGF-I (38, 39). This direct mode of action could likely account for the antiproliferative effect of somatostatin analogs observed in vitro.
C. GH receptor antagonists
Pegvisomant (B2036-PEG) is a recombinant protein that is
structurally similar to natural human GH with the exception that it
contains 9 amino acid substitutions. It binds to the GH receptor but
does not initiate signal transduction, thereby functioning as a
competitive antagonist with natural GH (Fig. 2). Although the half-life of natural GH
is only approximately 20 min, pegvisomant has several covalently
attached polyethylene glycol molecules that significantly
prolong its half-life (100 h), allowing it to be administered
subcutaneously on a once-daily basis. Only a limited number of studies
have been performed with pegvisomant in respect to analyzing effects on
tumor growth. Our laboratories, however, have demonstrated that it is
possible to achieve at least a 75% reduction in circulating IGF-I
concentrations when pegvisomant is administered to immunocompromised
mice (Fig. 3).
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The expression of dominant negative mutants of the IGF-I receptor have also been demonstrated to have antitumor effects in vitro and in vivo. Reiss et al. (43) transfected human colon, lung, prostate, kidney, and ovarian cancer cell lines with plasmids expressing the dominant negative mutant of the IGF-I receptor, 486/STOP, which has a frameshift mutation resulting in a stop codon at residue 486. They demonstrated a >75% inhibition in colony formation in soft agar in all transfected clones. The in vivo tumorigenicity of the cells expressing the negative mutant of the IGF-I receptor was also significantly decreased when compared with the wild-type cells. Furthermore, when the transfected cells were coinjected with a tumor forming cell line, there was significant inhibition of tumor growth, which suggested that the dominant negative mutant has a bystander effect.
A monoclonal antibody to the IGF-I receptor (IR3) was developed in
1983 (44). This antibody binds to the ligand-binding domain on the
IGF-I receptor and inhibits IGF-I-mediated effects. This antibody acts
as a competitive inhibitor and does not have a direct cytotoxic effect
as its inhibitory effect can be overcome by increasing IGF-I
concentration. Because IGF-II and insulin also bind to the IGF-I
receptor, the use of this antibody has also been shown to inhibit cell
growth in response to these growth factors.
IGF-I peptide analogs that inhibit IGF-I receptor autophosphorylation have been developed (45, 46). Blakesley et al. (47) in 1996 reported a significant reduction in tumor growth in mice injected with fibroblasts which expressed mutations at the tyrosine residue of the carboxy terminus of the IGF-I receptor.
E. IGFBPs
As reviewed previously, the IGFs circulate in combination
with six high-affinity binding proteins, IGFBP 1–6. The mammalian
IGFBPs contain three distinct domains of roughly equivalent sizes: the
N-terminal, the midregion, and the C-terminal. The N- and C-terminal
domains are conserved, and the midregion is highly variable. The human
IGFBPs share approximately 36% similarity. The C-terminal domain is
responsible primarily for high-affinity binding, whereas the N-terminal
and perhaps the midregion are involved in low-affinity binding. The
high-affinity IGFBPs modulate IGF bioavailability by undergoing
proteolysis and generating fragments with reduced or no affinity for
the IGFs. In the case of human IGFBP-1, posttranslational
phosphorylation has been demonstrated to enhance IGF binding (7). In
addition to modulating IGF bioavailability and thus IGF-dependent
functions, the IGFBPs also have functions that are unrelated to IGFs
and thus are IGF independent. The C-terminal domain and the midregion
seem to be involved in IGF-independent actions. In addition to the
IGFBPs, the IGFBP-rPs can have actions that are independent of IGFs on
cell growth. Recombinant forms of these proteins, therefore, are
potential therapeutic tools.
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IV. Central Nervous System Neoplasms |
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TopAbstractI. IntroductionII. Overview: IGF Physiology...III. Potential Therapeutic...IV. Central Nervous System...V. Gastrointestinal NeoplasmsVI. Head, Neck, and...VII. Female Reproductive...VIII. Male Reproductive...IX. Genitourinary NeoplasmsX. Bone NeoplasmsXI. Skin NeoplasmsXII. Hematological MalignanciesXIII. SummaryReferences |
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Sandberg-Nordqvist et al. (52) in 1993 demonstrated IGF-I
immunoreactivity in 6/9 gliomas and suggested that there appeared to be
a positive correlation between IGF-I immunoreactivity and the
histopathological grade of the tumor. In a study of 39 astrocytomas
(World Health Organization grades II-IV), Hirano et al. (53)
in 1999 demonstrated that there is indeed a positive correlation
between IGF-I immunoreactivity and histopathological grade (Table 1). They also determined that there was a
positive correlation between IGF-I and cell proliferation rates by
examining the relationship between IGF-I and Ki-67 (MIB-1) labeling
indices. Additional findings of note include the observation that in
the high-grade tumors, IGF-I immunoreactivity was greatest in
perivascular areas. Proliferating microvessels exhibited more intense
staining than nonproliferative vessels. Reactive astrocytes at the
margins of tumor infiltration also demonstrated high levels of IGF-I
expression.
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2. IGF-II expression. Sandberg et al. (48) in 1988 demonstrated that IGF-II mRNA is abundantly expressed in fetal brain but only minimally detectable in normal adult brain. Northern analysis identified approximately a 5- to 50-fold increase in IGF-II mRNA levels in 4/4 human glial tumors as compared with fetal brain. Glick et al. (50) in 1991 identified IGF-II in cyst fluid aspirated intraoperatively in 3/5 glial tumors. The concentration in the cyst fluid in the IGF-II positive tumors ranged from 3.9–131 µg/liter. IGF-II concentrations were 3.3 and 564 µg/liter in cerebrospinal fluid and serum, respectively. In a later study, Glick et al. (51) identified IGF-II in the conditioned media in 4/12 glioma primary cultures. Lichtor et al. (55) in 1993, using Northern blot analysis, did not identify IGF-II mRNA expression in two intermediate grade astrocytomas, three anaplastic astrocytomas, or two glioblastomas. No significant IGF-II mRNA expression was found in the two glioma cell lines, U-87 MG and T-98 G. Hultberg et al. (56) in 1993, also by Northern blot analysis, were unable to detect IGF-II mRNA expression in any of the 9 glial tumors studied. In contrast, Antoniades et al. (49) using in situ hybridization demonstrated the presence of IGF-II mRNA in 10 human glial tumors.
3. IGF receptor expression. Using [125I]-labeled
ligand, Sara et al. (57) in 1986 identified IGF-I
specific binding in plasma membrane preparations from both normal brain
tissue and glioblastomas. No statistically significant binding
differences were observed between the two groups, each of which were
comprised of 6 specimens. Gammeltoft et al. (58) in
1988, also using a competitive ligand binding assay, identified IGF-I
binding in 6/6 human glioma cell lines. Glick et al.
(59) in 1989 also confirmed IGF-I receptor expression in human glioma
specimen by [125I]-labeled IGF-I binding studies. Merrill
and Edwards (60) in 1990 studied 18 glioma specimens for IGF-I receptor
expression and found an increase in IGF-I binding sites in some of the
gliomas. The mean number of IGF-I binding sites was 68 (20–133) pmol/g
in normal brain tissue and 195 (60–356) pmol/g in the glioma
specimens. No difference was detected in affinity characteristics.
Cross-linking studies demonstrated that glial tumors expressed the same
lower molecular mass (
118 kDa) -subunit as is expressed in
normal brain tissue. In the cell lines derived from the glioma
specimens, however, a larger ( 133 kDa) -subunit was present.
Using [125I] -labeled IGF-II binding studies, Sara et al. (57) also demonstrated an approximately 2-fold increase in IGF-II binding as compared with normal brain tissue. Gammeltoft et al. (58) found 2 to 5 times more type II IGF binding sites than type I sites. Type II sites bind IGF-II with 10 times greater affinity than IGF-I; type 1 binding sites bind IGF-I and IGF-II with approximately equal affinity.
4. IGF effects on tumor growth. The mitogenic effect of exogenous IGF-I on human glioma cell lines was studied by Merrill and Edwards (60). Using [3H]thymidine incorporation as a tumor growth marker, they reported that 9/10 glioma cell lines responded to IGF-I with increases in [3H]thymidine incorporation that ranged from 1.3 to 4 times the control value. A dose-dependent response to IGF-I was observed. The effect of IGF-I receptor expression on the in vitro and in vivo growth of glioma cell lines has been analyzed by many investigators (61, 62, 63, 64, 65). Resnicoff et al. (66) in 1994 reported complete inhibition of IGF-I-stimulated growth in vitro in C6 rat glioblastoma cells incubated with antisense oligodeoxynucleotides to the IGF-I receptor mRNA. Cells stably transfected with a plasmid expressing an antisense IGF-I receptor mRNA also demonstrated near-complete inhibition of IGF-I- and IGF-II-stimulated growth. This was associated with a reduction in IGF-I receptor phosphorylation and correlated with approximately 50% reduction in IGF-I binding sites. BD-IX rats injected with C6 glioma cells stably transfected with the antisense IGF-I receptor plasmids did not develop tumors, whereas all animals injected with wild-type or sense cells developed tumors within a week. They also demonstrated inhibition of tumor formation when IGF-I receptor antisense C6 cells were injected 3 weeks before wild-type cells, whereas prior injection of sense C6 cells provided no protection against subsequent tumor development. Furthermore, complete regression of established wild-type tumors was seen within 2 weeks of injecting IGF-I receptor antisense cells in the opposite flank.
5. Summary. Many studies have demonstrated that most gliomas express the necessary receptors to respond to IGF stimulation and do so in a wide variety of in vitro and in vivo models. The recent study by Hirano et al. (53), demonstrating that there is a correlation between endogenous IGF-I expression and histopathological grade, is important confirmation of earlier studies suggesting that autocrine IGF production is of functional significance in the clinical setting. Animal studies targeting the IGF-I receptor, such as those by Resnicoff et al. (66), have been sufficiently promising that clinical trials using this strategy have been initiated. How effectively the beneficial effects observed in animals translate into patients should therefore be at least partially answered as the results of these trials become known.
B. Meningiomas
1. IGF-I expression. Glick et al. (50) in 1991
measured IGF-I by RIA in the cystic fluid aspirated from two
meningiomas, obtaining concentrations of 216 and 32 ng/ml,
respectively. In a subsequent study, IGF-I concentrations, indicative
of autocrine production, were measurable in the conditioned media of
5/12 human meningioma primary cell cultures (51). Antoniades et
al. (49) detected IGF-I mRNA and IGF-I protein expression in three
meningioma specimens and one control human meninges specimen. IGF-I
immunoreactivity was detected in 6/12 human meningioma specimens by
Lichtor et al. (55) in 1993.
2. IGF-II expression. Lichtor et al. (67) in 1991 demonstrated IGF-II mRNA using Northern blot analysis in 2/2 human meningioma specimens. Glick et al. (50) did not detect IGF-II in cyst fluid aspirated intraoperatively from two meningiomas. In a subsequent in vitro study using human meningioma cell lines, they detected IGF-II in the culture media of 6/11 tumors (51). Antoniades et al. (49) demonstrated IGF-II mRNA expression in three meningiomas and one control meningeal specimen using in situ hybridization. Hultberg et al. (56) demonstrated IGF-II mRNA in all four meningioma specimens by Northern blot analysis and in 3/4 specimens by RIA. In the IGF-II-positive tumors, the levels measured by RIA were 40, 144, and 160 ng/g. Sandberg- Nordqvist et al. (68) in 1997, studied the expression of IGF-II mRNA and IGFBP-2 mRNA. In all of the anaplastic or atypical meningiomas, there was a high ratio of IGF-II to IGFBP-2 mRNA levels. In a 5-yr follow up period of the 8 patients with a high IGF-II to IGFBP-2 ratio, 4 died from complications of the tumor, 2 had recurrence, and 2 were lost to follow-up. Of the 14 patients with a low IGF-II to IGFBP-2 ratio, no tumor-associated deaths or recurrences were observed, leading the authors to postulate that a high IGF-II to IGFBP-2 mRNA ratio is a sign of biologically aggressive behavior in meningiomas.
3. IGF receptor expression. Kurihara et al. (69) in 1989, using [125I]-labeled ligand, demonstrated the presence of high- affinity IGF-I binding sites in 8/8 of the meningioma specimens examined. Antoniades et al. (49) identified IGF-I and IGF-II receptor mRNA in 3 meningioma specimens using in situ hybridization. Lichtor et al. (55) demonstrated IGF-I receptor immunoreactivity in 4/12 meningiomas.
4. IGF effects on tumor growth. Kurihara et al. (69) demonstrated that IGF-I increased [3H]thymidine incorporation in primary meningioma cultures in a dose-dependent manner. A maximal response of approximately 350% of control was observed at an IGF-I concentration of 10-8 M in serum free conditions. Tsutsumi et al. (70) in 1994 also confirmed that IGF-I was a mitogen for meningiomas. [3H]thymidine incorporation was increased 200-225% over control by IGF-I in a dose-dependent manner. Friend et al. (71) in 1999 analyzed the mitogenic effect of IGF-I on primary cultures of 14 human meningioma specimens. [3H]thymidine incorporation was increased by 21, 43, and 176% of control in response to IGF-I doses of 1, 5, and 10 µg/liter, respectively. The GH receptor antagonist, B2036-PEG (pegvisomant), decreased [3H]thymidine incorporation in vitro. Friend et al. (72) in 1999 reported that the GH receptor antagonist, pegvisomant, decreased meningioma xenograft growth in nude mice. After 8 weeks of treatment, the tumor volume in the pegvisomant group had decreased by 38% of the initial volume, whereas the tumor volume in the vehicle-treated group increased by 23%. The serum IGF-I concentration in the pegvisomant group decreased by 20%.
5. Summary. As with gliomas, a number of studies have demonstrated that meningiomas express the necessary receptors to respond to IGF stimulation; the GH receptor also appears to be ubiquitously expressed. Accordingly, activation of these receptors, particularly the IGF-I receptor, has been demonstrated to stimulate mitogenesis. Endogenous IGF-II production by meningiomas, specifically in association with low IGFBP-2, appears to be an accurate predictor of aggressive behavior and increased risk of mortality. This observation, made by Sandberg-Nordqvist et al. (68) in 1997, is likely an illustration of the importance of autocrine IGF-II production in propagating rapid tumor growth. High levels of IGFBP-2 production would appear to ameliorate the stimulatory actions of IGF-II, suggesting that the binding protein environment is perhaps as critical a factor as the IGF production itself.
In vivo attempts to influence tumor growth by modulating GH or the IGFs have been limited, until recently, by the relative lack of reliable animal models. Using a model developed by Jensen et al. (73), in which primary cultures of human tumors are xenografted into the flank of immunocompromised mice, the authors have demonstrated that the GH receptor antagonist, pegvisomant, significantly inhibits tumor growth (72). A newly developed meningioma model, in which human tumors are implanted orthotopically, should permit more extensive analysis concerning the efficacy of targeting GH and the IGFs in these tumors (74).
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V. Gastrointestinal Neoplasms |
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TopAbstractI. IntroductionII. Overview: IGF Physiology...III. Potential Therapeutic...IV. Central Nervous System...V. Gastrointestinal NeoplasmsVI. Head, Neck, and...VII. Female Reproductive...VIII. Male Reproductive...IX. Genitourinary NeoplasmsX. Bone NeoplasmsXI. Skin NeoplasmsXII. Hematological MalignanciesXIII. SummaryReferences |
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2. IGF-II expression. Tricoli et al. (75) demonstrated the presence of IGF-II mRNA by Northern blot analysis in normal colonic epithelium and colon cancer. In approximately 40% of colon cancer specimens, the IGF-II mRNA was increased 10- to 50-fold compared with the normal colonic mucosa. This increase in IGF-II mRNA levels was limited to cancers involving the rectum and rectosigmoid with 60% of rectal and 50% of rectosigmoid cancers overexpressing IGF-II. None of the tumors of cecal or sigmoid origin demonstrated enhanced IGF-II mRNA expression. Among the IGF-II- expressing cancers, the Dukes C tumors possessed higher IGF-II levels as compared with Dukes B tumors, leading the authors to suggest that increased IGF-II mRNA expression may be a marker for aggressive distal colon cancers. Lambert et al. (77) in 1990 examined 21 surgical specimens and found that, compared with the normal colonic epithelium, 30% of colon cancer specimen had IGF-II mRNA overexpression. The amount of overexpression ranged from 2–800 times that seen in normal tissue. No correlation between overexpression of IGF-II mRNA and the site of the tumor was observed in this study.
Zarrilli et al. (78) in 1994 demonstrated the presence of
IGF-II mRNA in human colon cancer cell line CaCo-2 by Northern blot
analysis. IGF-II levels were high in proliferating cells and decreased
more than 10-fold when the cells stopped proliferating and
differentiated. IGF-II concentrations in the conditioned medium
demonstrated a similar pattern in regard to proliferating and
differentiated cells. Guo et al. (79) in 1995 identified
IGF-II mRNA expression in six human colon cancer cell lines, HCT 116,
COLO 205, COLO 320DM, LoVo, DLD-1, and HT 29. They also demonstrated
autocrine production of IGF-II by a specific RRA in the conditioned
medium of COLO 205 and HCT 116 cells. Kawamoto et al. (80)
in 1998 performed IGF-II immunohistochemical staining on 92 colon
cancer surgical specimens and 38 normal colon specimens. They found
that 74% of cancer specimens stained for IGF-II compared with 11% of
normal. There was a positive correlation between IGF-II staining and
size, depth of tumor invasion, and proliferative cell nuclear
antigen staining. IGF-II-negative tumors were also associated
with a statistically significant increased chance of survival (Fig. 4). Kawamoto et al. (81) in
1999, using in situ hybridization and immunohistochemical
staining, demonstrated that normal liver tissue at the invasive margins
of metastases overexpresses IGF-II. This finding led them to suggest
that hepatic IGF-II might be an important paracrine factor in
propagating the growth of hepatic metastases. Freier et al.
(82) in 1999, using a RNase protection assay, reported that IGF-II mRNA
was increased 40-fold in six human colon cancer specimens compared with
adjacent normal colonic mucosa, while protein levels were twice as
abundant.
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4. IGFBPs. Michell et al. (88) in 1997 analyzed the effect of IGFBPs on [3H]thymidine incorporation in the human colon cancer cell lines, COLO205, HT29, and SW620. In fresh medium, IGF-I was more potent in stimulating DNA synthesis than its analog des(1, 3)IGF. This analog differs from IGF-I primarily in respect to its having a much lower affinity for the IGFBPs. In the 24-h cell-conditioned media, however, IGF-I was much less potent when compared with its analog. When the conditioned medium was analyzed for the presence of binding proteins by Western blot, it was demonstrated that all the cell lines secreted IGFBP-4 and COLO205, and SW620 secreted IGFBP-2 as well. The authors suggested that the binding proteins in the culture media formed complexes with IGF-I and therefore reduced the amount of free IGF-I available, thus decreasing IGF-I-mediated DNA synthesis. As the des(1, 3)IGF-I has reduced affinity for the binding proteins, no significant change was seen in des(1, 3)IGF-I-induced DNA synthesis. Singh et al. (89) in 1994 reported that antibody to IGFBP-4 increased both basal and IGF-I-stimulated growth in the colon cancer cell line HT-29. They also demonstrated that cells transfected with an antisense vector to IGFBP-4 cDNA had a higher basal and IGF-I stimulated growth rate when compared with cells transfected with the sense or control vectors. Transfection with the sense vector to IGFBP-4 cDNA was associated with a 5- to 10-fold increase in IGFBP-4 expression; however, it was not associated with a further inhibition of basal and IGF-I stimulated cell growth. The observation that exogenous IGF-I was unable to overcome the inhibitory effect of IGFBP-4 overexpression led the authors to suggest that the effect of IGFBP-4 on inhibition of cell growth may be IGF-I independent.
Macdonald et al. (90) in 1999 demonstrated that the human colon carcinoma cell line, Caco-2, which was stably transfected with an IGFBP-3 expression construct, grew more slowly in vitro than the cells transfected with a control vector.
5. IGF effects on tumor growth. The effect of IGF-I on the
growth of two mouse colon cancer cell lines was studied by Koenuma
et al. in 1989 (91). IGF-I, added to serum-free media at a
concentration of 10 µg/liter, increased the growth of two variants of
mouse colon adenocarcinoma 26. The growth of a highly metastatic
variant (NL-17) was increased to 490% of control while a variant with
lower metastatic potential (NL-44) was increased to 279% of control.
The number of binding sites, 1.37 x
105/cell (NL-17) and 1.26 x
105/cell (NL-44) was similar between the two cell
lines. Lahm et al. (92) in 1992 studied the effects of IGF-I
and IGF-II on eight human colon cancer cell lines. IGF-I and IGF-II
were roughly equipotent in stimulating tumor growth; half-maximal
responses were observed in the responsive cell lines at IGF
concentrations ranging from 1.9–6.5 µg/liter. In a follow-up study,
Lahm et al. (93) in 1994 demonstrated that a neutralizing
monoclonal antibody against the human IGF-I receptor (IR3) decreased
the growth of 7/12 cell lines. As some responsive lines expressed only
IGF-II, not IGF-I, the authors concluded that autocrine IGF-II, by
binding to and activating the IGF-I receptor, was propagating tumor
growth. Accordingly, the growth-inhibitory effects of IR3 could be
overcome by adding either exogenous IGF-I or IGF-II to the culture
media.
Smith and Solomon (94) in 1988 studied the effect of somatostatin on the growth of human colon cancer cell lines in vivo. Nude mice bearing xenografts of the human colon cancer cell line CX1 developed significantly smaller tumors when treated with 100–300 µg/kg of somatostatin 14 twice daily. In 1991, Qin et al. (95) studied the effects of the somatostatin analog RC-160 (vapreotide) on in vivo growth of the rat colon cancer cell line, DHD/K12, using a syngeneic model. In the RC-160-treated rats (100 µg/kg/day), the final tumor volume was approximately 36% of control. Protein and DNA concentration in the tumors of the treatment group were decreased to 70% and 69%, respectively, of the control values. The percent of bromodeoxyuridine-labeled cells in the treatment group was 35% lower than that in the control group. No similar inhibitory effect was observed on tumor growth in vitro, leading the authors to propose that indirect mechanisms, such as effects of the somatostatin analog on GH/IGF-I, CCK, or gastrin, were mediating the antitumor effects. The in vivo effect of another somatostatin analog, octreotide (SMS 201–995), was studied in mice implanted with the colon cancer cell line CT 26 by Alonso et al. (96) in 1992. Tumor volume, tumor weight, and DNA content were significantly reduced in the mice who received the somatostatin analog. Tumor growth was inhibited by 40% and was accompanied by a prolonged survival (42.5 vs. 48.5 days).
The effect of vapreotide (25 µg/twice daily) on the growth of hepatic metastases of the human colon cancer cell lines, 320 DM and WidR, was studied by Qin et al. in 1992 (97). The mice were randomized to receive either RC-160 or vehicle after intrasplenic tumor injection. There was a decrease in the incidence (25% vs. 38%) and mean number (60 vs. 177 in 320 DM; 77 vs. 135 in WidR) of hepatic metastases and a corresponding increase in survival times (7 days vs. 20 days) in the mice receiving RC-160. When the same cell lines were implanted subcutaneously into the flank, similar beneficial effects on tumor volumes in the treatment groups were observed. In 1992 Dy et al. (98) studied the effects of octreotide (50 µg/kg/day) on the growth of LIM 2412 and LIM 2405 cells implanted subcutaneously in mice. Octreotide inhibited tumor growth by approximately 50%. As inhibitory effects were also observed in in vitro studies, direct effects of octreotide on the tumor, independent of the GH/IGF-I axis, were considered potential mechanisms of action. Duan et al. (99) in 1999 analyzed the effect of pegvisomant on human colon cancer cell line, COLO 205, xenografted in nude mice. After treatment for 16 days, they reported a 39% reduction in tumor volume and a 44% reduction in tumor weight in the pegvisomant group along with reductions in circulating IGF-I and IGFBP-3 levels.
6. Clinical studies. Glass et al. in 1994 measured IGF-I levels in more than 300 healthy people scheduled for a colonoscopy for occult gastrointestinal (GI) bleeding (100). No significant difference in the serum IGF-I concentrations were observed between the group with a normal colonoscopy and the group with colonic polyps or colon cancer. Ma et al. (101) reported the results of a case-control study, nested in the physicians’ health study in 1999. IGF-I and IGFBP-3 levels were measured in more than 14,000 subjects at the beginning of the study. The 193 patients who subsequently developed colon cancer, some up to 15 yr later, had significantly higher baseline IGF-I levels and lower IGFBP-3 levels than age- and weight-matched controls from the same cohort.
Iftikhar et al. (102) studied the effects of the somatostatin analog octreotide on tumor kinetic measurements in 12 patients with primary rectal cancer. Four of the 12 patients who received octreotide had a lower Ki67 immunostaining in the posttreatment biopsy compared with the pretreatment biopsy. None of the six untreated control patients had a lower Ki67 index at the time of the second biopsy. In a randomized trial by Cascinu et al. (103) in 1995, 107 patients with advanced colon cancer refractory to chemotherapy were randomized to receive octreotide 200 µg three times per day 5 days/week or best supportive care. The patients in the octreotide group had a median survival time of 20 weeks compared with 11 weeks in the supportive care group. Although there were no objective responses, 45% of the patients randomized to octreotide had stable disease compared with 15% in the supportive care group. Goldberg et al. (104) in 1995 reported the results of an Eastern Cooperative Oncology Group randomized trial in which 260 patients with advanced colon cancer received either octreotide 150 µg subcutaneously three times per day or placebo/no treatment. No significant difference was observed in time to progression or survival between the two groups.
In neither the 1995 Cascinu study or the Goldberg studies were serum IGF-I levels measured. Cascinu et al., however, in a follow-up study in 1997 (105), did measure IGF-I concentrations. They randomized 75 patients with newly diagnosed colon cancer to receive either octreotide, 200 µg subcutaneously three times per day, or placebo for 2 weeks before surgery. There was approximately a 50% reduction in circulating IGF-I levels in the octreotide-treated group (179 vs. 86). They also studied effects of octreotide treatment on tumor cell kinetics. [3H]thymidine labeling and flow cytometry were used to assess S-phase fraction in the tissue obtained from the baseline endoscopic biopsy specimen and the tissue obtained at the time of surgery. The percentage of cells in the S-phase fraction, as measured by [3H]thymidine incorporation, decreased from 18% to 3% in the octreotide group whereas no difference was observed in the placebo group. By flow cytometry, the decrease in S-phase fraction in the octreotide group was decreased from 27 to 22%. Again, no change was observed in the placebo group.
7. Summary. The increased risk of colonic polyps and colon cancer in the acromegalic population is well known. The recent epidemiological study by Ma et al. (101) suggests that even within the normal population, a high IGF-I/IGFBP-3 ratio may increase the risk of colon cancer development. Once tumors develop, the overexpression of IGF-II that occurs in a substantial subset, originally described by Tricoli et al. (75) and subsequently confirmed by Lambert et al. (77), has been clearly demonstrated by Kawamoto et al. (80) to correlate with an aggressive phenotype. Attempts to understand the utility of agents that modulate GH or the IGFs should be analyzed with respect to whether or not the tumors express high levels of IGF endogenously. Tumors without high autocrine IGF production may be the most responsive to agents that only modify circulating or paracrine IGF production. IGF-II-overexpressing tumors, which appear to be more aggressive, will likely require strategies that decrease tumor IGF production, bioavailability, or action at the receptor level.
B. Gastric cancer
1. IGF-I and IGF-II expression. Thompson et al.
(106) in 1990 reported the detection of autocrine IGF-II production in
the human gastric carcinoma cell line, LIM-1839. IGF-II mRNA was
present and IGF-II was measurable in the conditioned medium of cells
grown to confluence. No IGF-I mRNA was detectable. Chung and Antoniades
(107) in 1992 demonstrated the presence of IGF-I mRNA by in
situ hybridization in three human gastric cancer surgical
specimens. Expression was also observed in the adjacent normal
epithelium. Guo et al. (108) demonstrated IGF-II mRNA in AGS
and SIIA gastric cancer cell lines in 1993 by Northern analysis. No
IGF-I mRNA was detected in either cell line.
2. IGF receptor expression. Thompson et al. (106) demonstrated the presence of IGF-I and IGF-II receptors by affinity cross-linking and competitive binding studies in LIM-1839 gastric carcinoma cells. Durrant et al. (109) demonstrated the presence of IGF-I receptors by competitive binding in the gastric cancer cell lines, St16, St42, and MKN45. The number of receptors per cell were 250,190 and 310, respectively. Chung and Antoniades (107) demonstrated the presence of IGF-I receptor mRNA by in situ hybridization in human gastric cancer specimens.
3. IGF effects on tumor growth. The mitogenic effect of
exogenous IGF-I and IGF-II on human gastric cancer cell line LIM-1839
was reported by Thompson et al. (106). These growth factors
increased cell growth 1.6- to 2.0-fold when added to serum-free medium
at 20 and 50 ng/ml. The growth-promoting effect was inhibited by
IR3, indicating that both IGF-I and IGF-II stimulate growth via the
IGF-I receptor. Durrant et al. (109) also demonstrated that
IGF-I has mitogenic effects on the St16, St42, and MKN45 gastric cancer
cell lines.
C. Pancreatic cancer
1. IGF-I and IGF-II expression. Ohmura et al. (110)
in 1990 demonstrated the autocrine production of IGF-I in MIA-PaCa 2
cells, a human pancreatic cancer line, by measuring IGF-I by RIA in
conditioned culture medium. Bergmann et al. (111) did not
detect IGF-I mRNA by Northern analysis in four human pancreatic cell
lines, including ASPC-1, COLO 357, T3 M4, and PANC-1 cells. In 12
pancreatic surgical specimens, a 32-fold increase was present as
compared with the low levels observed in the normal pancreas.
2. IGF receptor expression. Ohmura et al. (110) demonstrated 125I-labeled IGF-I binding in the human pancreatic cancer cell line, MIA-PaCa 29. Ishiwata et al. (112) in 1997 reported the presence of IGF-II receptor mRNA in six human pancreatic cancer cell lines by Northern analysis (ASPC-1, CAPAN-1, COLO 357, MIA-PaCa-2, PANC-1, and T3 M4). They also found that 7 of 12 pancreatic cancer surgical specimens overexpressed IGF-II receptor mRNA (5.6-fold) in comparison to normal pancreatic tissue.
3. IGF effects on tumor growth. Bergmann et al.
(111) demonstrated that IGF-I stimulated cell growth in human
pancreatic cell lines, ASPC-1 and COLO 357. For the ASPC-1 cells, the
one-half maximal and maximal stimulation occurred at 1.8 and 5
nM, respectively. In the COLO 357 cells, the
corresponding values were 0.3 and 1.3 nM. They
also observed inhibition of IGF-I stimulated growth by IR3. An
antisense oligonucleotide to the IGF-I receptor inhibited the growth of
ASPC-1 and COLO-357 by 34% and 35%, respectively.
D. Other (esophageal, hepatocellular)
a. Esophageal cancer. Oku et al. (113) in 1991
demonstrated that both IGF-I and IGF-II were potent mitogens for the
human squamous esophageal cancer cell line TE-3-OS. Both IGF-I and
IGF-II increased [3H]thymidine uptake by
approximately 300% in a dose-dependent manner with maximal effects
being observed at 100 µg/liter concentrations of both peptides. The
anti-IGF-I receptor antibody, IR3, inhibited growth stimulated by
both IGF-I and IGF-II. Chen et al. (114) in 1991
demonstrated IGF-I mRNA by Northern analysis in the human esophageal
cancer cell line CE48T/VGH. IGF-I increased cell growth in serum-free
media about 3.5-fold, with maximal stimulation being observed at
10- 9 M.
[125I]-IGF-I binding studies demonstrated
2.5 x 105 receptors per cell.
b. Hepatocellular carcinoma.
1. IGF-I expression.
Tsai et al. (115) demonstrated
the presence of IGF-I mRNA by Northern analysis in 10 of 10 human
hepatoma cell lines in 1988. Su et al. (116) analyzed 7
human hepatoma surgical specimen for the presence of IGF-I mRNA in
1989. Compared with nontumorous hepatic tissue from an adjacent area,
the tumors expressed relatively low levels of IGF-I mRNA. Because the
expression of GH receptor mRNA in the tumors was also low on a relative
basis, the authors proposed that IGF-I mRNA was low as a result of
reduced GH stimulation of transcription.
2. IGF-II expression.
Cariani et al. (117) in 1988
observed a 40- to 100-fold increase in IGF-II mRNA expression in 9 of
40 liver cancer surgical specimens as compared with normal adult liver.
They reported that many liver cancers expressed fetal transcripts (6.0
and 5.0 kb) instead of the 5.3-kb transcript present in the normal
adult. Su et al. (116) in 1989 also reported that 4 of 7
human liver cancer surgical specimens had expression of IGF-II fetal
transcripts (5.6 and 4.5 kb). The authors suggested the presence of the
fetal transcript of IGF-II mRNA was reflective of cellular
dedifferentiation. The amount of IGF-II mRNA expression in the tumors
was highly variable. Lamas et al. (118) in 1991, using
in situ hybridization and immunohistochemistry, demonstrated
an overexpression of IGF-II mRNA and protein in malignant cells as
compared with surrounding nontumorous cells.
D’Errico et al. (119) in 1994 studied IGF-II immunoreactivity in liver sections from 54 patients with hepatocellular carcinoma. IGF-II immunoreactivity was detected in 60% (9 of 15) of the specimens from hepatitis B virus-positive patients and in 26% (10 of 39) of the specimens obtained from hepatitis B virus-negative patients. Rogler et al. (120) in 1994 analyzed the effects of IGF-II overexpression by constructing transgenic mice in which human prepro-IGF-II cDNA was placed under control of the major urinary protein promoter. This led to an increase of up to 30-fold in serum IGF-II concentration in the transgenic animals compared with controls. Over the course of 18 months, the transgenic mice developed an increased number of tumors in general and hepatocellular carcinoma in particular when compared with control animals. Scharf et al. (121) in 1998 using a Northern blot technique could not detect IGF-II mRNA in the human hepatoma cell line PLC. Ng et al. (122) in 1998 reported repression of the expression of the normal adult IGF-II transcript in 93% (28 of 30) of human hepatoma surgical specimens. Fetal transcripts, however, were present in 40% of the specimens. The nontumorous hepatocytes expressed the adult IGF-II mRNA transcript in 93% of the cases. The tumors from older patients were more likely to express IGF-II. Sohda et al. (123) in 1997 detected an overexpression of IGF-II mRNA by in situ hybridization and immunohistochemistry in 50% (5 of 10) of human hepatocellular carcinoma specimens. Cells that expressed IGF-II were more likely to express the Ki-67 antigen (expressed during active cellular proliferation), suggesting that IGF-II acts as an autocrine or paracrine growth factor for these tumors.
3. IGF receptor expression.
Tsai et al. (115)
detected the presence of IGF-I receptor mRNA in 10 of 10 human hepatoma
cell lines. Scharf et al. (121) identified IGF-I and IGF-II
receptor mRNA in the hepatoma cell line PLC.
4. IGF effects on tumor growth.
The effects of exogenous IGF-I
and IGF-II on DNA synthesis were also demonstrated by Scharf et
al. (121). Both growth factors increased
[3H]thymidine incorporation in the PLC cell
line in a dose-dependent manner. Lin et al. (124) in 1997
observed that high levels of IGF-II were produced by the human hepatoma
cell lines HuH-7 and HepG2. Antisense oligonucleotides complementary to
IGF-II mRNA led to reduction in IGF-II mRNA and protein content in the
cell lines. There was also a decrease in
[3H]thymidine incorporation and
cell-proliferative activity. The inhibitory effect on cell growth was
not observed in those cell lines that did not overexpress IGF-II.
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VI. Head, Neck, and Pulmonary Neoplasms |
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TopAbstractI. IntroductionII. Overview: IGF Physiology...III. Potential Therapeutic...IV. Central Nervous System...V. Gastrointestinal NeoplasmsVI. Head, Neck, and...VII. Female Reproductive...VIII. Male Reproductive...IX. Genitourinary NeoplasmsX. Bone NeoplasmsXI. Skin NeoplasmsXII. Hematological MalignanciesXIII. SummaryReferences |
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2. IGF receptor expression. Nakanishi et al. (127) reported the presence of two high-affinity specific binding sites for 125I-labeled IGF-I [dissociation constant (Kd) 1.3 and 4.0 nM] in the human SCLC cell line, NCI-H345. Jaques et al. (128) also demonstrated high-affinity IGF-I binding sites in 14 of 14 SCLC cell lines (Kd 0.89–5.21 nM). The maximum binding (Bmax) ranged from 131 to 1,230 fmol/mg protein. Rotsch et al. (131) in 1992 described the presence of high-affinity IGF-I binding sites in a number of SCLC and NSCLC lines. They also demonstrated the presence of IGF-I receptor mRNA by Northern blot analysis in all of the cell lines. Schardt et al. (132) in 1993 reported that 125I-labeled IGF-II binds with high affinity (70–80 pM) to the IGF-I receptor and with low affinity (2–4 nM) to the IGF-II receptor using receptor assays on microsomal and plasma membranes of the SCLC lines, NCI-H841 and NCI-H82. The presence of mannose-6-P enhanced the binding of [125I]IGF-II to the IGF-II receptor. Kaicer et al. (133) in 1993, using a monoclonal antibody, demonstrated the expression of IGF-I receptor in bronchial epithelial cells of normal lung and in 22 of 24 primary lung carcinomas. A total of 17 of 24 of the specimens expressed IGF-II receptor. In this study, 18 of the 24 specimens were squamous cell carcinomas.
3. IGF effects on tumor growth. Jaques
et al. (128) demonstrated that IGF-I increased
[3H]thymidine incorporation in 2 of 7 human SCLC cell
lines. Peak responses were observed at 0.1–1.0 nM. Minuto
et al. (126) reported that IGF-I administration resulted
in a 52% increase in cell number in the human lung cancer cell line,
CALU-6, at concentrations between 10 and 25 µg/liter. Nakanishi
et al. (127) demonstrated an approximately 250%
increase in cell growth in several SCLC cell lines by both IGF-I and
IGF-II. On a molar basis, IGF-I was 10- to 100-fold more potent than
IGF-II or insulin. The growth-promoting properties of both IGF-I and
IGF-II were inhibited by the IGF-I receptor antibody, IR3. Rotsch
et al. (131) in 1992 also observed that IGF-I was a
potent mitogen, stimulating growth 1.6- to 4.2-fold in a panel of SCLC
cell lines and 1.1- to 2.7-fold in a panel of NSCLC cell lines. Zia
et al. (134) in 1996 demonstrated that IGF-I increased
the growth of the NSCLC cell line, NCI-H1299, approximately 7-fold at a
concentration of 100 ng/ml. When the tumors were implanted into nude
mice, IR3 significantly inhibited cell growth (134). The mean tumor
weights in PBS-treated animals was 8.03 ± 0.35 g after 4
weeks. When IR3 was injected intraperitoneally three times weekly at
a concentration of 100 µg, the mean tumor weight decreased to
3.40 ± 0.90 g. Lee et al. (135) in 1996
constructed an adenovirus expressing an antisense version of the first
300 bp of the IGF-I receptor (Ad-IGF-Ir/as). This led to approximately
a 50% reduction in IGF-I receptor expression in the human lung cancer
cell lines, NCI H460 and SCC5. The soft agar clonogenicity of the
transfected NCI H460 cells was reduced by 84%. The intraperitoneal
treatment of nude mice bearing established intraperitoneal NCI H460
cells resulted in prolonged survival compared with that achieved with a
reporter virus. Long et al. (136) in 1998 studied the
effect of IGF-I receptor overexpression on the metastatic behavior of
the Lewis lung carcinoma cell line, M-27. M-27 cells were stably
transfected with a plasmid vector expressing a full-length cDNA for
human IGF-I receptor under the control of the SV-40 promoter. This led
to a 3-fold increase in the number of IGF-I binding sites. In their
in vitro studies, IGF-I was more potent in stimulating
cell growth and [3H]thymidine incorporation in the cell
line overexpressing IGF-I receptor as compared with the wild type.
Intrasplenic injection of the IGF-I receptor-transfected cell line, but
not mock-transfected cells, gave rise to multiple tumor nodules in the
liver.
Taylor et al. (137) in 1988 analyzed the effect of the somatostatin analog BIM-23014C (lanreotide) on in vivo growth of the human SCLC cell line NCI-H69 after xenografting into nude mice. Treatment with this compound (500 µg twice daily) was associated with a prolongation of the lag time for tumor appearance and a significant inhibition of tumor growth rate when compared with control. In 1990, Bodgen et al. (138) evaluated the same compound in vivo against four SCLC cell lines (NCI-H69, NCI-N417, NCI-H345, LX-1) and a NSCLC cell line (H-165). Tumors derived from all cell lines responded, albeit in varying degrees. In some instances, direct infusion around the tumor was superior to injection on the side opposite the tumor. Pinski et al. (139) in 1994 also demonstrated an inhibitory effect of a somatostatin analog RC-160 (vapreotide) on the in vivo growth of an SCLC and an NSCLC cell line in nude mice. A greater than 50% reduction in tumor size was seen with both cell lines.
4. Clinical studies. Macaulay et al. (140) in 1991 reported the results of a small clinical trial of octreotide, 250 µg subcutaneously three times daily, in 20 patients with SCLC. Although serum IGF-I levels were reduced to 62 ± 7% of pretreatment levels, no objective antitumor activity was observed in regard to tumor bulk or serum levels of neuron-specific enolase. Cotto et al. (141) in 1994 treated 18 patients with recurrent and/or nonresponsive SCLC with the somatostatin analog, Somatuline (lanreotide), administered as a continuous infusion in doses ranging from 2–10.5 mg/day. No antitumor activity was seen after 28 days of treatment despite reductions in serum IGF-I levels by up to a mean of 36%. Marschke et al. (142) in 1999 also did not observe significant antitumor activity of 2,000 µg three times daily of a somatostatin analog in a phase II study involving 18 patients with extensive SCLC. The median survival was 106 days.
5. Summary. IGF receptor expression is common in both SCLC and NSCLC. In vivo studies using multiple cell lines have been encouraging. Experiments designed to block IGF action such as those by Lee et al. (135), using an adenovirus expressing an antisense IGF-I receptor vector, have demonstrated potent antitumor activity. Conversely, IGF-I receptor overexpression experiments such as those performed by Long et al. (136) indicate that increasing IGF-I receptor numbers can dramatically increase metastatic potential. The limited clinical studies that have been performed, however, have been disappointing. These studies, which have primarily involved the use of somatostatin analogs in the treatment of SCLC, did not demonstrate a survival benefit. Possible reasons for this include the relatively modest GH/IGF-I inhibition achieved with somatostatin analogs and their inability to affect endogenous IGF production.
B. Thyroid cancer
Tode et al. (143) in 1989 demonstrated autocrine
production of IGF-I by RIA in the conditioned medium of human thyroid
follicular cells in primary culture. Exogenous TSH increased the
secretion of IGF-I in the medium. Minuto et al. (144) in
1989 measured IGF-I by RIA in human thyroid surgical specimens. In
their study, IGF-I levels were higher in nodular and cancerous thyroid
tissue compared with normal thyroid tissue, suggesting that IGF-I may
be involved in goiter/cancer pathogenesis. Onoda et
al. (145) in 1992 demonstrated autocrine production of IGF-I by a
human papillary thyroid cancer cell line. IGF-I immunoreactivity was
present in the conditioned medium of the cell line, and IGF-I mRNA was
detected by a PCR-based methodology.
The presence of receptors for IGF-I on normal as well as malignant human thyroid epithelium was demonstrated in 1989 by Yashiro et al. (146). Using affinity cross-linking, they demonstrated an increase in [125I]IGF-I binding to human surgical thyroid cancer specimens when compared with normal or benign thyroid neoplasms. Tode et al. (143) demonstrated the presence of IGF-I receptor by binding studies on human thyroid follicular cells in primary culture. Yashiro et al. (147) in 1991 demonstrated the presence of IGF-II receptors in human thyroid surgical specimen by [125I]-IGF-II binding studies and reported an overexpression of IGF-II receptors in papillary and follicular carcinoma specimen when compared with nonmalignant thyroid tissue.
Tramontano et al. (148) in 1986 demonstrated the mitogenic
effect of exogenous IGF-I on rat thyroid follicular cell line, FRTL5.
They showed that IGF-I had an additive effect with TSH on cell
proliferation and thymidine incorporation. DNA synthesis was increased
up to 9-fold with IGF-I and up to 30-fold with IGF-I and TSH together.
Onoda et al. (145) demonstrated the mitogenic effect
of IGF-I on a human papillary thyroid cancer cell line. IGF-I increased
growth up to 200% over control. The effect of IGF-I on cell growth was
inhibited by IR3, the IGF-I receptor antibody.
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VII. Female Reproductive Neoplasms |
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TopAbstractI. IntroductionII. Overview: IGF Physiology...III. Potential Therapeutic...IV. Central Nervous System...V. Gastrointestinal NeoplasmsVI. Head, Neck, and...VII. Female Reproductive...VIII. Male Reproductive...IX. Genitourinary NeoplasmsX. Bone NeoplasmsXI. Skin NeoplasmsXII. Hematological MalignanciesXIII. SummaryReferences |
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2. IGF-II expression. In 1989, Osborne et al. (153) studied six breast cancer cell lines (BT20, ZR75–1, MDA-231, MDA-330, T47D, and MCF-7L) for endogenous expression of IGF-II. Only two cell lines, TD47D and MCF-7L, were shown to have mRNA for IGF-II by Northern blot and RNase protection assay and to have significant secretion of IGF-II in the culture medium as measured by RIA and RRA. Paik (151) studied the IGF-II expression of 10 human surgical breast cancer specimen using in situ hybridization. He demonstrated that IGF-II mRNA expression was present in the stromal elements surrounding both normal and malignant breast epithelium. In one case of carcinoma in situ, IGF-II mRNA expression was detected in the malignant epithelium. Gebauer et al. (152) detected IGF-II mRNA in 1 of 7 breast cancer cell lines and in 7 of 11 surgical specimens, leading the authors to conclude that IGF-II, like IGF-I, is produced predominantly in the stromal tissue.
3. IGF receptor expression. Furlanetto et al. (154) in 1984 observed the presence of high-affinity type I IGF binding sites in four human breast cancer cell lines (MCF-7, MDA-231, T47-D, and HBL-100). Myal et al. (155) demonstrated similar high-affinity binding in T47D cells the same year. Pollak et al. (156) and De Leon et al. (157) demonstrated high-affinity binding in a variety of breast cancer cell lines in 1988. Peyrat and Bonneterre (158) demonstrated the presence of IGF-I receptors by competitive binding and cross-linking techniques in 5 breast cancer cell lines (BT-20, MCF-7, T-47D, HBL 100, and MDA-MB-231) in 1992. They also demonstrated IGF-I receptor mRNA by Northern analysis in each of the cell lines. The concentration of IGF-I receptor was higher in the estrogen-dependent cell lines than in the estrogen-independent cell lines. There was also a positive correlation seen between the estrogen, progesterone, and PRL receptors and IGF-I receptor expression. They also demonstrated the presence of IGF-I receptor and IGF-I receptor mRNA in human breast cancer biopsy specimens. IGF-I receptor levels in the breast cancer biopsy specimen were higher. Gebauer et al. (152) demonstrated the presence of IGF-II receptor and IGF-II receptor mRNA in the MCF-7 breast cancer cell line, 6 primary breast cancer cell cultures from metastatic breast cancer patients, and breast cancer surgical specimens from 11 patients.
4. IGFBPs. Clemmons et al. (159) in 1990 measured IGFBP immunoreactivity in the conditioned media of breast cancer cell lines and observed that the estrogen receptor-positive lines secreted predominantly IGFBP-2 while the estrogen receptor-negative lines secreted IGFBP-1 and 3. Pratt and Pollak (160) in 1993 studied the effect of estrogen and the antiestrogens, tamoxifen and ICI 182,780, on cell growth and IGFBP expression in the estrogen-dependent cell line, MCF-7. The antiestrogens caused an increase in IGFBP-3 and a decrease in IGFBP-4 secretion, as measured by Western blot in the culture media of the cell lines, whereas treatment with estrogens had the opposite effect. Furthermore, the antiestrogen ICI 182,780 inhibited IGF-I-stimulated MCF-7 cell proliferation. The authors suggested that the antiestrogen- mediated increase in IGFBP-3 was the cause of decreased cell growth. The same authors (161) in 1994 reported that exogenous IGFBP-3 inhibited estrogen-mediated cell proliferation and [3H]thymidine incorporation in MCF-7 cell line. Huynh et al. (162) in 1996 also confirmed the negative and positive effects, respectively, of estrogens and antiestrogens on IGFBP-3 expression in MCF-7 breast cancer cell line. Exogenous recombinant IGFBP-3 inhibited basal and estrogen-stimulated growth. The antiestrogen, ICI 182,780, along with increasing IGFBP-3 concentration, also decreased basal and estrogen-stimulated growth. When antisense oligodeoxynucleotides to IGFBP-3 were added, the inhibitory effect of the antiestrogens on cell proliferation was attenuated, leading the authors to suggest that a part of the antiproliferative effect of antiestrogens in breast cancer cells may be due to the increase in IGFBP-3 production.
Oh et al. (163) in 1993 demonstrated the secretion of IGFBP-3 in the cultured medium of the estrogen-independent breast cancer line Hs578T using Western blot and immunoprecipitation studies. This particular cell line does not respond to the mitogenic effect of either IGF-I or IGF-II. The presence of IGFBP-3 receptors was also demonstrated by affinity cross-linking studies. Exogenous IGFBP-3 was demonstrated to cause significant decrease in cell proliferation and [3H]thymidine incorporation in serum-free conditions. The inhibitory effect of IGFBP-3 on cell growth was suggested to be IGF independent as IGFs are not mitogenic for this cell line. Furthermore, when exogenous IGF-I or IGF-II was added to the medium, there was an attenuation of IGFBP-3 inhibitory effects on cell growth. However, when analogs of the IGFs with reduced affinity to IGFBP-3 were added, there was no reduction in the inhibitory effect of IGFBP-3. The authors suggested that the IGFs formed complexes with IGFBP-3 and hence made IGFBP-3 unavailable to exert its growth-inhibitory effects whereas the analog, because of its reduced affinity for IGFBP-3, left more free IGFBP-3 to exert its effects.
Nickerson et al. (164) in 1997, however, suggested that the IGF-dependent effects of IGFBP-3 are more important in regulating cell growth. They studied the effects of IGFBP-3 and the antiestrogen ICI 182,780 on apoptosis (measured by cell death enzyme-linked immunosorbent assay) and DNA synthesis (by [3H]thymidine incorporation) in the estrogen-responsive cell line MCF-7. Both ICI 182,780 and IGFBP-3 caused a greater than 3-fold increase in apoptosis along with significant decreases in [3H]thymidine incorporation. They also demonstrated that the antiestrogen increased IGFBP-3 production and the inhibitory effect on cell growth of the antiestrogen was mediated, at least in part, by IGFBP-3. Exogenous IGF-I, in the presence of the antiestrogen and IGFBP-3, increased apoptotic rates whereas the analog of IGF-I with reduced affinity to IGFBP-3, potentially making more "free’ IGF-I available to act on the IGF-I receptor, decreased apoptotic rates. Martin et al. (165) in 1995 analyzed the production of IGFBP-3 and -6 in the estrogen-dependent cell line MCF-7. They reported a significant increase in the secretion of IGFBP-3 and -6 in the conditioned medium after exposure of the cell line to retinoic acid, (Bu)2cAMP, and forskolin (a stimulator of adenylate cyclase). They also demonstrated that MCF-7 cells, after incubation with retinoic acid and forskolin, had an attenuated response to IGF-I-stimulated [3H]thymidine incorporation. They suggested that the 6- and 12-fold increase in IGFBP-3 and -6 production, respectively, after exposure to retinoic acid and forskolin, decreased the bioavailability of IGF-I. Estradiol had differential effects on IGFBP-3 and -6 production in MCF-7 cell line with estradiol decreasing IGFBP-3 production and increasing IGFBP-6 production. Gucev et al. (166) in 1996 reported a 40% reduction in cell proliferation by retinoic acid and TGF-ß2 in the estrogen-independent breast cancer cell line MDA-MB-231. They observed a 3-fold increase in IGFBP-3 production and a 2-fold increase in IGFBP-3 mRNA expression in the cell lines induced by retinoic acid and TGF-ß2. Using antisense oligodeoxynucleotides to IGFBP-3, which decreased retinoic acid and TGF-ß2-stimulated IGFBP-3 production by 90%, they demonstrated up to 40% reduction in retinoic acid and TGF-ß2 inhibitory effects on cell proliferation, indicating that a part of the growth-inhibitory effects of retinoic acid and TGF-ß2 are mediated via IGFBP-3. Gill et al. (167) in 1997 reported that exogenous IGFBP-3 decreased cell proliferation in the basal state and in response to ceramide in the estrogen-independent, IGF-I-independent breast cancer cell line Hs578T. The IGFBP-3-induced increase in metabolically inactive cells was demonstrated to be the result of an increase in apoptotic rates as measured by flow cytometry. They also reported that after the addition of exogenous IGFBP-3 in Hs578T cell media, a number of IGFBP-3 fragments were seen in addition to the intact IGFBP-3 after 24 and 48 h, suggesting that the exogenous IGFBP-3 may be proteolytically cleaved by the Hs578T cells.
Yee et al. (168) in 1994 reported the effects of endogenous IGFBP-1 expression on IGF-I-mediated IGF-I receptor phosphorylation. MCF-7 cells were stably transfected with an IGFBP-1 vector, and IGFBP-1 expression was confirmed in the cells by RNase protection assay and by analyzing IGFBP-1 in the culture medium. In the transfected cells, exogenous IGF-I was unable to cause IGF-I receptor phosphorylation, whereas the analog of IGF-I with reduced affinity for IGFBP-1 caused IGF-I receptor phosphorylation. The authors suggested that IGFBP-1, either exogenous or endogenously produced, binds with IGF-I, thus inhibiting ligand/receptor interaction and subsequent cell growth. Van den Berg et al. (169) in 1997 analyzed the effect of the polyethylene glycol-conjugated IGFBP-1 compounds, WT-BP-1 and PEG-BP-1, on the in vitro and in vivo growth of the breast cancer cell lines, MCF-7, MDA-MB 231, and MDA-MB-435A. The colony growth of MCF-7 and MDA-MB-435A cells was significantly inhibited by both the IGFBP-1 compounds, whereas growth of MDA-MB-231 was stimulated by WT-BP-1. In the in vivo studies, PEG-BP-1 decreased tumor volume in mice bearing MDA-MB-231 but not in MCF-7-bearing mice. The in vitro effects on MDA-MB-231 tumor growth were hypothesized to occur because of effects on host IGF production.
5. IGF effects on tumor growth. Furlanetto et al.
(154) studied the effect of IGF-I on DNA synthesis on breast cancer
cell lines. In each of the four cancer cell lines studied (MCF-7, T47D,
MDA-MB-231, and HBL-100), IGF-I stimulated DNA synthesis as measured by
[3H]thymidine incorporation. The concentration
of IGF-I required for half-maximal stimulation varied from a minimum of
0.03 nM in the MCF-7 cells to a maximum of 0.6
nM in the T47-D cells. The effects of the
monoclonal antibody IR3, which blocks IGF binding to the IGF-I
receptor, were studied by Rohlik et al. (170) in 1987. Using
the estrogen-responsive cell line, MCF-7, they demonstrated that IR3
decreased cell growth both in the presence and absence of exogenous
estrogen. The cells were propagated in 5% calf serum supplemented with
5 ng/ml of insulin. Karey and Sirbasku (171) in 1988 demonstrated that
both IGF-I and IGF-II stimulated cell growth in MCF-7 and T47-D cells.
IGF-I was the most potent growth factor of the panel analyzed (EGF,
aFGF, bFGF, TGF, TGFß, PDGF, IGF-II, insulin).
Arteaga and Osborne (172) described the mitogenic effect of exogenous
IGF-I and IGF-II on a panel of estrogen receptor-positive (MCF-7,
ZR75–1, T47D) and estrogen receptor- negative (MDA 231, HS578T) cell
lines in 1989. Both growth factors increased in vitro DNA
synthesis in all cell lines studied. They also demonstrated that IR3
inhibited IGF-I- and IGF-II-stimulated growth, suggesting that both
these growth factors act via the IGF-I receptor. IR3, however, did
not abolish estrogen-stimulated growth in the estrogen
receptor-positive cell lines. In a separate study published in 1989,
Arteaga et al. (173) demonstrated that exogenous IGF-I
increased the proliferation of MCF-7 and MDA-231 cells, and this
increase in proliferation was inhibited in a dose-dependent manner by
the addition of IR3. In serum-free medium, IR3 was able to
inhibit growth only after exogenous administration of IGF-I, suggesting
no autocrine IGF production.
Osborne et al. (153) demonstrated a mitogenic effect of
IGF-II in 5 of 5 of the breast cancer cell lines examined. The addition
of IR3 inhibited the IGF-II-mediated increase in DNA synthesis.
Stewart et al. (174) in 1990 observed that in MCF-7 cells,
IGF-I and IGF-II increased cell proliferation only in the presence of
estradiol. They also demonstrated that estradiol induced an increase in
IGF-I receptor mRNA (6.5-fold) and in
[125I]IGF-I binding (7.0-fold) in the MCF-7
cell line. In an estrogen receptor-negative cell line, MDA MB-231,
IGF-I stimulated growth of the cell line in a manner that was
unaffected by the presence or absence of estrogen in the medium. De
Leon et al. (175) in 1992 studied the in vitro
effects of IGF-I and IGF-II and their receptor antibodies on growth of
the MCF-7 breast cancer cell line. Both growth factors stimulated cell
proliferation (3- to 5-fold). When IR3 was added, it inhibited IGF-I
induced cell growth approximately 50%. It did not inhibit
IGF-II-induced cell growth. Two different IGF-II receptor antibodies
and an insulin receptor antibody also failed to significantly block
IGF-II-stimulated growth.
Arteaga and Osborne (172) in 1989 studied the in vivo effect
of IR3 on growth of breast cancer cell lines xenografted into nude
mice. Three-week-old athymic mice were inoculated with either MCF-7 or
MDA-231 cells. There was a greater than 80% reduction in tumor volume
at 35 days in those animals that received 500 µg of the antibody via
intraperitoneal injection on a twice weekly basis. This inhibitory
effect was not observed with the MCF-7 xenografts. Weckbecker et
al. (176) in 1994 reported that treatment with the somatostatin
analog, octreotide, potentiated the antineoplastic activity of
tamoxifen and ovariectomy in 7,12-dimethylbenz(a)anthracene
(DMBA)-induced rat mammary carcinomas. Yang et al. (177) in
1996 xenografted MCF-7 cells in control mice and scid mice homozygous
for the lit mutation. This missense mutation leads to loss
of function of the GH-releasing hormone receptor and causes marked
reductions of GH and IGF-I concentrations. The tumors in the
lit/lit mice were approximately 50% smaller than the tumors
implanted in the control mice. Huynh and Pollak (178) in 1994 reported
that the inhibitory effect of tamoxifen on IGF-I was potentiated by the
somatostatin analog octreotide. Combined therapy decreased serum IGF-I
concentrations in rats to 49 ± 10% of control values and hepatic
IGF-I gene expression to 12 ± 9% of control.
6. Clinical studies. Peyrat et al. (179) in 1993 demonstrated that preoperative circulating IGF-I levels in 47 patients with breast cancer were elevated when compared with controls (152 µg/liter vs. 115 µg/liter) and suggested that a positive correlation between IGF-I concentrations and breast cancer risk might exist. A positive correlation between serum IGF-I levels and the risk of premenopausal breast cancer was suggested by the study of Hankinson et al. (180) in 1998. As a nested case control study within the nurses’ health study cohort (>30,000 women), baseline IGF-I levels were measured in women who developed breast cancer (397 women) and case controls (620 women). The relative risk for premenopausal breast cancer was 4.58 (top tertile vs. bottom tertile) with a P value of 0.02. The relative risk for developing postmenopausal breast cancer was 2.33 with a P value of 0.08.
Pollak et al. (181) in 1990 reported that breast cancer patients treated with tamoxifen for 3 months had lower IGF-I concentrations compared with a placebo-treated group (1.4 U/ml vs. 0.9 U/ml). The authors suggested that part of the antitumor effect of tamoxifen in breast cancer may be due to reduction in circulating IGF-I concentrations. The effect of octreotide in 14 patients with advanced breast cancer was reported by Vennin et al. (182) in 1989. At a dose of 100 µg sc twice/day there was no objective response seen in any of the patients. In 1995, Di Leo et al. (183) reported the results of lanreotide administration (30 mg ip every 2 weeks) in 10 patients with breast cancer (predominantly estrogen receptor-positive patients). No significant responses were observed. In the analysis of serum IGF-I levels, however, lanreotide treatment did not significantly decrease circulating IGF-I concentrations. Canobbio et al. (184) in 1995 studied tamoxifen treatment combined with the somatostatin analog Somatuline. A total of 33 postmenopausal patients with breast cancer were treated. Half of the patients achieved at least a partial response. Although the IGF-I levels declined significantly in the cohort, there was no significant difference in the IGF-I levels between those that responded and those that did not. O’Byrne et al. (185) in 1999 administered the somatostatin analog RC-160 by continuous subcutaneous infusion to 14 patients with estrogen receptor-positive breast cancer. No objective responses were observed despite decreases in circulating IGF-I levels of almost 50%. In a randomized trial by Ingle et al. (186) in 1999, 135 postmenopausal women with predominantly estrogen receptor-positive breast cancer were randomized to receive tamoxifen alone or a combination of tamoxifen and octreotide (150 µg sc three times per day). There was no statistically significant difference in time to progression between the tamoxifen only group (14.2 months) and the combination therapy (10.3 months). The serum IGF-I concentrations were decreased 17% in the tamoxifen group and 40% in the combination group.
7. Summary. Early studies by Yee et al. (150),
subsequently confirmed by others, indicate that autocrine IGF-I
production by breast tumors, if it does occur, is a relatively rare
phenomenon. Autocrine IGF-II production occurs in only a minority of
cases. The stromal elements in the breast tissue may secrete both IGF-I
and IGF-II and stimulate growth of the breast epithelial cells in a
paracrine fashion (Fig. 5). IGF-I
receptor expression, however, is ubiquitous or nearly ubiquitous, and
activation of this receptor has been demonstrated by many investigators
to be a potent stimulus for growth. Numerous animal models have
demonstrated the utility of targeting the IGFs or the IGF-I receptor.
The administration of binding proteins or agents that modify tumor
binding protein production also would appear to be a promising
therapeutic strategy. It is worth noting again that at least some of
the antitumor actions of the binding proteins appear to be mediated by
mechanisms that are independent of their ability to modulate IGF
bioavailability. As with most other tumor types, clinical trials to
date have been limited to small numbers of patients receiving
somatostatin analogs. Larger studies, as well as studies employing
agents targeting IGF or binding protein action in ways other than the
somatostatin analogs, are needed to make more definitive statements
about the potential clinical utility of this type of approach.
|
2. IGF receptor expression. Yee et al. (187) identified IGF-I receptor mRNA in 10 of 10 human ovarian cell lines and in 7 of 7 surgical specimens by RNase protection assay. Beck et al. (191) in 1994 demonstrated IGF-I receptor using a RIA in all primary and metastatic ovarian cancer surgical specimens examined.
3. IGFBPs. Yee et al. (187) demonstrated the presence of IGFBP-3 mRNA by Northern blot in the ovarian cancer cell lines, OVCAR-3, CaOV-4, and SK-OV-3. The first two cell lines also expressed IGFBP-2 mRNA. The IGFBP-2 and -3 peptides were also demonstrated by Western blot in the conditioned medium of OVCAR-3. Krywicki et al. (192) in 1993 analyzed the effect of estrogen and on IGFBP expression in the estrogen-responsive ovarian cancer cell line PE04. Estrogen decreased the expression of IGFBP-3 mRNA in the cells and also decreased IGFBP-3 peptide levels in the conditioned medium. IGFBP-5 mRNA levels were increased after estrogen treatment. They did not observe a significant estrogen-induced modulation of the other IGFBPs. Karasik et al. (189) in 1994 reported that IGFBP-2 levels were significantly higher in cyst fluid from invasive malignant than from benign epithelial ovarian neoplasms. Kanety et al. (193) in 1996 reported that IGFBP-2 levels were significantly higher in the protein extracts prepared from malignant ovarian surgical specimen compared with benign ovarian tumors. They also observed an increase in IGFBP-2 mRNA expression, from 2- to 30-fold, in the malignant ovarian tumors and found an association between IGFBP-2 mRNA expression and invasiveness of the tumor. Flyvbjerg et al. (194) in 1997 reported that serum IGFBP-2 levels in patients with malignant ovarian tumors were 253% (RIA) and 105% (WLB) of serum IGFBP-2 levels in control patients and in patients with benign ovarian disease. They also observed a positive correlation between serum IGFBP-2 levels and the tumor marker, cancer antigen 125 (CA 125). The serum IGF-I and IGFBP-3 levels were lower, and IGFBP-3 proteolytic activity higher, in patients with malignant ovarian tumors compared with the other groups. The serum IGF-I, IGFBP-3, and IGFBP-3 proteolytic activity did not correlate with CA 125.
4. IGF effects on tumor growth. Yee et al. (187)
demonstrated that exogenous IGF-I (5 nM)
increased cell growth in the ovarian cancer cell line OVCAR-3 in a
manner equivalent to 10% FCS. Resnicoff et al. (188)
reported that IGF-I (10 ng/ml) increased OVCAR-3 and CaOV-3 cell growth
approximately 50%. Antisense oligodeoxynucleotides to IGF-I receptor
RNA inhibited cell growth in serum-free medium as well as in the
presence of exogenous IGF-I. In 1998, Muller et al. (195)
demonstrated that an antisense oligodeoxynucleotide targeted against
the translation initiation site of the IGF-I receptor mRNA was
associated with a decrease in IGF-I receptor mRNA and protein. These
antisense oligonucleotides resulted in inhibition of basal and IGF-I
stimulated growth of the human ovarian cancer cell line NIH:OVCAR-3.
Coppola et al. (196) in 1999 transfected rabbit ovarian
mesothelial cells with the human IGF-I receptor gene and observed
increased basal (8-fold) and IGF-I stimulated (20-fold) growth
compared with nontransfected cells. The addition of antisense
oligonucleotides against the IGF-I receptor mRNA decreased basal and
IGF-I-stimulated growth significantly in the transfected cells. When
compared with the nontransfected cells, the transfected clone (OMIR)
demonstrated fewer apoptotic cells and reduced expression of Fas-R, a
cell membrane protein implicated in the apoptosis signaling pathway.
The OMIR clone was also demonstrated to be tumorigenic in
vivo.
C. Other (endometrial, vaginal, cervical)
a. Endometrial carcinoma.
1. IGF expression.
Klienman et al. (197) in 1993
demonstrated, using RIA, the presence of IGF-II but not IGF-I in the
conditioned medium of Ishikawa cells, a human endometrial cancer cell
line. Hana and Murphy (198) in 1994 demonstrated the presence of IGF-I
and IGF-II mRNA using a PCR-based methodology in Ishikawa cells.
Northern analysis was not sensitive enough to detect the IGF
messages. Estradiol (10-7
M) increased IGF-I mRNA 366 ± 20%. At the
same concentration, 4-hydroxy tamoxifen increased IGF-I mRNA levels
257 ± 35% above control. Neither estradiol nor 4-
hydroxy tamoxifen had any effect on IGF-II mRNA expression.
Klienman et al. (199) in 1996 reported that in the Ishikawa
cell line, tamoxifen (10-6
M) decreased membrane-bound IGFBPs (3-fold) and
IGFBP-3 mRNA (3.5-fold), thus likely increasing IGF availability.
Tamoxifen did not affect the number or affinity of IGF-I receptors,
although it was associated with increased IGF-I-stimulated
phosphorylation of the IGF-I receptor. Reynolds et
al. (200) also studied the autocrine production of IGF-I in four
human endometrial adenocarcinoma cell lines, Ishikawa, HEC, KLE, and
RL95–2. IGF-I mRNA was detected by a PCR-based methodology in
all four cell lines. IGF-I was also demonstrated by RIA in
conditioned medium of all four cell lines; the basal cell proliferation
in serum-free medium was inhibited by the IGF-I receptor antibody
IR3 in 3 of 4 cell lines, further pointing to the importance of an
autocrine role of IGF-I. Elkas et al. (201) in 1998 also
demonstrated IGF-I expression in normal and malignant human endometrial
specimen by immunohistochemistry. They also reported an increase in
IGF-I (7- to 20-fold) and a decrease in IGFBP-1 expression (32–36%)
in benign endometrial specimen from patients treated with tamoxifen
compared with proliferative or secretory endometrium from untreated
patients.
2. IGF receptor expression.
Talavera et al. (202)
in 1990 demonstrated the presence of IGF-I receptors by
[125I]IGF-I binding studies on human
endometrial biopsy specimens. They also reported a slight increase in
the number of IGF-I receptors on malignant endometrial tissue when
compared with the normal nonneoplastic endometrium.
3. IGFBPs.
Rutanen et al. (203) in 1994 analyzed
the expression of IGFBP 1, 2, 4, 5, and 6 mRNA by RT-PCR in 20 human
endometrial cancer surgical specimens and normal endometrium. IGFBP-1
mRNA expression was either undetectable or as low as in the
proliferative phase of the endometrium. IGFBP-1 mRNA expression
increased in the late secretory phase and early pregnancy decidua.
IGFBP-2, -4, and -5 mRNA expression was detectable in all cancer
specimens, and their expression was not different compared with that in
the cycling endometrium. They observed a cyclic variation in the
expression of IGFBP-6 mRNA in the normal endometrium, and the mean
level of IGFBP-6 mRNA in the endometrial cancer specimen was similar to
that at midcycle. Kleinman et al. (204) in 1995 reported the
down-regulation of IGFBP-3 mRNA and peptide levels in the
estrogen-responsive Ishikawa endometrial cancer cell line after
treatment with estrogen. Estrogen and IGF-I were synergistic in causing
cell proliferation, and the decrease in IGFBP-3 could potentially make
more IGF-I bioavailable.
4. IGF effects on tumor growth.
Pearl et al. (205)
in 1993 analyzed the mitogenic effect of IGF-I (100 µg/liter) and
IGF-II (100 µg/liter) on human endometrial adenocarcinoma cell lines,
HEC1-A and KLE. They reported a 2.1- to 2.7-fold increase in cell
proliferation in the two cell lines. Similar increases in DNA
synthesis, as measured by [3H]thymidine
incorporation, were induced by both growth factors.
b. Cervical cancer. Steller et al. (206) in 1996 reported the presence of IGF-II mRNA but not IGF-I mRNA in human cervical cancer cell lines using a PCR-based methodology. They also demonstrated the presence of IGF-I receptor by [125I]IGF-I binding studies and reported that compared with normal ectocervical cells, IGF-I receptor was overexpressed in cervical cancer cells. Hembree et al. (207) in 1994 reported that IGF-I increased cell growth in the human cervical cancer cell line ECE16–1. EGF decreased IGFBP-3 concentrations in the culture medium and enhanced the growth response to IGF-I.
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VIII. Male Reproductive Neoplasms |
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|
TopAbstractI. IntroductionII. Overview: IGF Physiology...III. Potential Therapeutic...IV. Central Nervous System...V. Gastrointestinal NeoplasmsVI. Head, Neck, and...VII. Female Reproductive...VIII. Male Reproductive...IX. Genitourinary NeoplasmsX. Bone NeoplasmsXI. Skin NeoplasmsXII. Hematological MalignanciesXIII. SummaryReferences |
|---|
2. IGF-II expression. Cohen et al. (208) did not
detect IGF-II in the conditioned medium of normal prostate epithelial
cells in primary culture. Connolly and Rose (212) did not detect IGF-II
in the conditioned medium of DU145 cells. Angelloz-Nicoud and Binoux
(213) observed that PC-3 cells are capable of autocrine IGF-II
production. They also demonstrated that the IGF-I receptor antibody,
IR3, inhibited cell growth, suggesting that the IGF-II was important
in propagating growth and that its effects were mediated via the IGF-I
receptor. Tennant et al. (215) in 1996, using in
situ hybridization, observed that IGF-II mRNA was 30% more
abundant in prostate adenocarcinoma than in benign epithelial cells.
Lamharzi et al. (216) in 1998 detected IGF-II mRNA but not
IGF-I mRNA in DU-145 cells using a PCR-based methodology. Using similar
methodology, Csernus et al. (35) in 1999 demonstrated IGF-II
mRNA in PC-3 cells. They also reported that treatment of PC-3 cells in
culture with the GHRH antagonists, MZ-4–71 or MZ-5–156, at
concentrations of 3 µM, decreased autocrine
IGF-II mRNA to 70 and 77% of control, respectively.
[3H]thymidine incorporation was also decreased
by both agents. Kaplan et al. (214) observed a 75–95%
reduction in IGF-II mRNA expression in the prostate of the TRAMP mice
compared with the nontransgenic mice.
3. IGF receptor expression. The presence of type IGF-I receptors on normal prostate epithelial cells was demonstrated by Cohen et al. (208) using [125I]-IGF-I binding studies. No IGF-II receptors were detected. High-affinity IGF-I binding sites with dissociation constants between 0.23–0.39 nM were detected on PC-3, DU-45, and LNCaP cells by Iwamura et al. (211) in 1993. Pietrzkowski et al. (210) identified IGF-I receptor mRNA in three human prostate cancer cell lines. In two, PC-3 and DU-45 cells, IGF-I receptor mRNA was overexpressed. Kaplan et al. (214) observed a significant reduction in IGF-I and IGF-II receptor mRNA expression in tumors from castrated TRAMP mice and in metastatic lesions when compared with nontransgenic mice. The authors suggested that loss of IGF-I receptor expression may be associated with the loss of differentiation and increased tumorigenicity.
4. IGFBPs. Figueroa et al. (217) in 1995 reported that recombinant IGFBP-1 inhibited basal and IGF-II stimulated growth of the androgen-independent prostate cancer cell line, DU145. This inhibitory effect of IGFBP-1 was reversed by adding an analog of IGF-I that does not bind to the IGFBPs. The authors suggested that the IGFBP-1 inhibited cell growth by binding to and thus making unavailable the autocrine growth factor(s). Damon et al. (218) in 1998 analyzed the effects of IGFBP-4 overexpression in the human prostate cancer cell line, M12 (218). IGFBP-4 mRNA and peptide levels were increased in the transfected cells. The cell line overexpressing the IGFBP-4 proliferated slower than the control cells both in the absence and presence of exogenous IGF-II. Cells overexpressing IGFBP-4 also demonstrated slower anchorage-independent growth compared with control cells. This inhibitory effect, however, was not seen after treatment of the cells with an IGF-I analog without affinity for the IGFBPs, suggesting that IGFBP-4 overexpression inhibited cell growth via an IGF-dependent mechanism. When the cell lines were implanted in nude mice, there was an initial transient lower take rate in the mice implanted with the IGFBP-4 overexpressing cell line compared to the control cell line. This inhibitory effect, however, was lost after 10 weeks, and both the transfected and the control cell lines demonstrated similar growth.
Nickerson et al. (219) in 1999 analyzed the effect of castration-induced tumor regression and IGFBP-5 mRNA expression in the androgen-dependent Shionogi prostate carcinoma. They reported a 90% reduction in Shionogi tumors 10 days post castration, which was accompanied with up to a 120-fold increase in IGFBP-5 mRNA expression. The authors suggested a functional role of IGFBP-5 in androgen deprivation-mediated apoptosis in androgen-dependent prostate cancer.
5. IGF effects on tumor growth. Pietrzkowski et al. (210) reported that IGF-I is a potent mitogen for the prostate cancer cell lines, LNCaP, PC-3, and DU-145. The proliferation of each cell line in serum-free medium was inhibited by an antisense oligodeoxynucleotide complementary to IGF-I receptor mRNA. Peptide analogs of IGF-I that compete with IGF-I for binding to its receptor also inhibited growth. Iwamura et al. (211) observed that IGF-I administration stimulated DNA synthesis in the androgen-independent cell lines, PC-3 and DU-145. The growth-promoting effects of IGF-I were not dependent upon the presence of dihydrotestosterone (DHT) in the medium. In the androgen-dependent cell line, LNCaP, IGF-I was able to stimulate DNA synthesis only in the presence of DHT.
Schally and Redding (220) in 1987 analyzed the effects of a LH-releasing hormone (LHRH) agonist and the somatostatin analog RC-121 (5 µg/day), alone and in combination, on rats bearing the androgen-dependent Dunning R-3327H rat prostate adenocarcinomas. Although the LHRH agonist was more effective than RC-121, the combined treatment was superior to either treatment alone. The combination treatment reduced tumor weight to 16% and tumor volume to 23% of control. In the rats that received RC-121 treatment alone, there was a 58% reduction in tumor weight and a 55% reduction in volume compared with control. Murphy et al. (221) in 1987 observed that rats bearing R-3327 prostate cancers treated with the somatostatin analog, DC-13–167, developed tumors that were 41% smaller than vehicle-treated controls. Yano et al. (222) in 1992, also using Dunning R-3327H prostate tumors, observed that there was a synergistic effect when the somatostatin analog RC-160 (vapreotide) was administered in combination with a LHRH antagonist. Pinski et al. (223) in 1993 studied the effects of the somatostatin analog RC-160 (vapreotide), alone or in combination with the bombesin/gastrin-releasing peptide antagonist (RC-3095), on growth of the androgen-independent prostate cancer cell line PC-3 implanted into nude mice. Treatment with either agent resulted in approximately a 40% reduction in tumor weight and volume, but no additive benefit was observed when the agents were administered together. The inhibitory effects on tumor growth were lost when treatment was initiated with the tumors measuring 90 mm3 rather than 10 mm3. Pinski et al. (224) in 1993 also reported approximately a 50% reduction in tumor volume and weight with RC-160 (vapreotide) treatment (100 µg/day sc) of nude mice bearing the androgen-independent DU-145 human prostate cancer.
Burfeind et al. (225) in 1996 stably transfected PA-III cells (rat prostate adenocarcinoma) with an IGF-I receptor antisense construct. As a result, IGF-I mRNA levels were reduced several fold. Mice injected with IGF-I receptor antisense-transfected PA-III cells developed tumors that were approximately 90% smaller than controls. Jungwirth et al. (226) in 1997 reported the effects of treatment with the GHRH antagonist, MZ-4–71, on tumor growth in nude mice implanted with the human cell lines, DU-145 and PC-3 (40 µg/day), and the rat prostate cancer cell line, Dunning R-3327 AT-1 (100 µg/day). Treated groups had significantly smaller tumors as follows: DU-145 (81% of control), PC-3 (70% of control), and Dunning R-3327 AT-1 (44% of control). Tumor IGF-I and IGF-II levels, which were 146 ± 25 and 190 ± 32 pg/100 µg protein in the control group, respectively, decreased to undetectable levels in the treatment group. The antitumor effects of MZ-4–71 were also studied by Lamharzi et al. (216) in 1998 using DU-145 xenografts. A 71% decrease in tumor volume was observed in the GHRH-treated mice. A 77% reduction in IGF-II protein concentrations and a 58% reduction in tumor IGF-II mRNA was also seen. Although serum IGF-I concentrations were decreased by 21%, there were no significant differences observed in terms of tumor content of IGF-I.
6. Clinical studies. Mantzoros et al. (227) in 1997 reported that serum IGF-I levels in 52 patients with histologically confirmed prostate cancer were significantly higher than age- and weight-matched normal controls, 160.3 vs. 124.4 µg/liter. Chan et al. (228) in 1998 reported the results of a nested case-control study within the Physicians Health Study. Of the 14,916 participants, the serum IGF-I concentrations of the 152 patients who developed prostate cancer were significantly higher than a group of matched controls (269.4 vs. 248.9 µg/liter). A correlation between serum IGF-I levels and prostate cancer was also suggested by Wolk et al. (229) in 1998. The IGF-I mean concentration in 210 newly diagnosed, untreated prostate cancer patients was 158.4 µg/liter compared with 147.4 µg/liter in matched controls.
Parmar et al. (230) performed an open-label clinical trial of the somatostatin analog, BIM 32014 (lanreotide), in 25 patients with progressive metastatic prostate cancer. Two patients achieved a partial remission, one of which was maintained at 30 months. Figg et al. (231), in a Phase I dose escalation study of the somatostatin analog Somatuline, did not find any objective response after 28 days of treatment in 25 patients with metastatic prostate cancer. Circulating IGF-I concentrations were reduced by 39% from baseline values. Maulard et al. (232) in 1995 reported the effects of lanreotide 30 mg ip injections administered weekly for 3 months in patients with hormone-refractory prostate cancer. Prostate-specific antigen levels decreased at least 50% in 20% of the patients. A significant improvement in bone pain (35% of patients) and performance status (40% of patients) was also reported. In one patient, the bone scan normalized.
7. Summary. The case-control study by Chan et al. (228), demonstrating that men with elevated IGF-I concentrations are at increased risk for developing prostate cancer, indicates that IGF may have a role in tumorigenesis or, at least, is a marker of early, subclinical disease. Interestingly, the recently developed TRAMP model of prostate cancer is also associated with an early rise in serum IGF concentrations. The IGF-I receptor appears to be abundantly expressed in most prostate cancer cell lines, but some studies have suggested that levels are significantly reduced as the disease becomes androgen-independent. Although IGF-II autocrine production by some prostate cell lines is significantly elevated, the recent study by Csernus et al. (35) demonstrating that GHRH antagonists markedly decrease autocrine IGF-II production in PC-3 cells is an important finding. It indicates that IGF overexpression, which provides some tumor cells with a critical growth advantage, is a phenomenon that can be down-regulated. This could have significant clinical ramifications. Additionally, several IGFBPs have been demonstrated to have marked antitumor effects on prostate cancer viability and growth rates, indicating that recombinant binding proteins or agents that modify endogenous production may be of significant clinical utility as well.
B. Testicular cancer
Biddle et al. (233) in 1988 demonstrated the presence
of IGF-I and IGF-II receptors by binding studies on human teratoma cell
line, Tera-2. Weima et al. (234) in 1989 also
demonstrated IGF-I receptor on human embryonal carcinoma cell line Tera
2 by [125I]IGF-I binding studies and affinity
cross-linking. Biddle et al. (233) demonstrated that both
IGF-I and IGF-II increased [3H]thymidine
incorporation and cell proliferation in the Tera-2 cells.
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TopAbstractI. IntroductionII. Overview: IGF Physiology...III. Potential Therapeutic...IV. Central Nervous System...V. Gastrointestinal NeoplasmsVI. Head, Neck, and...VII. Female Reproductive...VIII. Male Reproductive...IX. Genitourinary NeoplasmsX. Bone NeoplasmsXI. Skin NeoplasmsXII. Hematological MalignanciesXIII. SummaryReferences |
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B. Bladder cancer
Dunn et al. (236) in 1997 studied the effects of diet
restriction (DR) on the effect of a bladder carcinogen,
p-cresidine, in heterozygous p53-deficient mice. In their
previous study, 40% DR reduced serum IGF-I concentration by 50%
(237). The mice were initially fed an ad libitum (AL) diet
for 15 weeks, after which they were divided into 3 groups of 10 as
follows: one group continued the AL diet, one group was placed on a
20% DR diet, and the third group was on a 20% DR diet but received
IGF-I (IGF-I/DR) via a miniosmotic pump to restore the serum IGF-I
concentration to match the AL group. All three groups received
p-cresidine in their diet for 15 weeks until randomization.
When the mice were killed, 4 of 10 mice in the AL group, 6 of 10 in the
IGF-I/DR, and 2 of 10 in the DR group had developed transitional cell
carcinoma (TCC) of the bladder. A total of 3 of 10 tumors in the
IGF-I/DR group, 1 of 10 in the AL group, and 0 of 10 in the DR group
were multiple. Furthermore, the tumors in the AL and IGF-I/DR groups
tended to be of a higher histopathological grade than the DR group.
Serum IGF-I concentrations were reduced 26% in the DR group compared
with the AL group. By measuring BrdUrd labeling as a marker for cell
proliferation, the IGF-I/DR and the AL groups had a 6-fold increase in
cell proliferation compared with the AL group. The mice in the IGF-I/DR
and the AL group had a 10-fold reduction in apoptosis compared with the
DR group. These findings indicated that the differences in the cell
proliferation and apoptosis rates between the groups could be explained
primarily by the modest differences in the serum IGF-I concentrations.
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TopAbstractI. IntroductionII. Overview: IGF Physiology...III. Potential Therapeutic...IV. Central Nervous System...V. Gastrointestinal NeoplasmsVI. Head, Neck, and...VII. Female Reproductive...VIII. Male Reproductive...IX. Genitourinary NeoplasmsX. Bone NeoplasmsXI. Skin NeoplasmsXII. Hematological MalignanciesXIII. SummaryReferences |
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2. IGF-receptor expression. In 1990 Pollak et al. (240) demonstrated the presence of IGF-I receptors on membranes prepared from MG-63 immortalized human osteosarcoma cells and primary human osteosarcoma cells by competitive binding assays and affinity-labeling experiments. Scatchard analysis revealed that the MG-63 cells and primary osteosarcoma cells had Kd values of 2.9 and 2.5 nM, respectively. The calculated binding capacity was 0.17 pmol/mg for the primary cells and 0.21 pmol/mg for the MG-63 cells. Raile et al. (238) demonstrated IGF-I and IGF-II receptors by affinity cross-linking and identified their respective mRNAs by Northern analysis in U-2 OS cells. A total of 4.5 x 104 and 10.0 x 104 binding sites were observed for IGF-I and IGF-II, respectively. The corresponding apparent affinity constants were 0.7 x 10-9 and 11.2 x 10-9 M. Kappel et al. (241) in 1994 demonstrated IGF-I receptors in five osteosarcoma cell lines (G292, HOS, MG-63, SaOS, U-2) using a ligand-binding assay.
3. IGF effects on tumor growth. Pollak et al. (240)
demonstrated a dose-dependent proliferative effect of IGF-I on MG-63
osteosarcoma cells, an effect that was blocked by the anti-IGF-I
receptor antibody, IR3. IGF-I was effective at concentrations as low
as 10-10 M. Raile et
al. (238) also demonstrated an in vitro mitogenic
effect of exogenous IGF-I and IGF-II on the human osteosarcoma cell
line U-2 OS and suggested that both act via the IGF-I receptor as
IR3 inhibited the stimulatory effect of both IGFs. Kappel et
al. (241) demonstrated that the in vitro survival of
some osteosarcoma cell lines is dependent upon the addition of IGF-I to
serum-free media. They also observed that the mitogenic effect of
exogenous IGF-I in some cell lines was blocked by IR3 or antisense
oligonucleotides complementary to the IGF-I receptor.
In 1992 Pollak et al. (242) reported on the results of xenografting the human osteosarcoma cell line MGH-OGS into hypophysectomized mice. The mean serum IGF-I concentration in the control mice was 195 ± 8 µg/liter; this was reduced to 29 ± 6 µg/liter in the hypophysectomized animals. The tumors in the hypophysectomized animals grew significantly slower and developed significantly fewer lung metastases than the tumors in the control animals (mean number of metastases, 16 vs. <1). Pinski et al. in 1995 analyzed the effects of the GH-releasing hormone antagonist MZ-4–71 on the treatment of nude mice bearing tumors from the human osteosarcoma cell lines MNNG/HOS and SK-ES-1 (243). MZ-4–71 was administered via osmotic pump at a dose of 40 µg/day or via sc injection, 25 µg/twice daily. The treated mice, either with osmotic pump or subcutaneous injection, had a significantly lower tumor weight and volume. Serum IGF-I levels were decreased by 62 (MNNG/HOS) and 42% (SK-ES-1) below control in the subcutaneous injection experiments. MZ-4–71, at a concentration of 10-5 M, decreased thymidine incorporation by 28% in SK-ES-1 cells and 85% in MNNG/HOS cells. This finding indicated that there was a direct, pituitary-independent effect of MZ-4–71 on cell growth. Pinski et al. (244) in 1996 reported that somatostatin analog, RC-160 (vapreotide), has antitumor effects in vitro and in vivo on the growth of human osteosarcoma cell lines, SK-ES-1 and MNNG/HOS. In the in vitro studies, RC-160 was able to inhibit cell growth in the somatostatin receptor-positive cell line MNNG/HOS, but not in the somatostatin receptor negative line SK-ES-1. This suggested that the antiproliferative effect of the somatostatin receptor analogs might be related to the presence or absence of membrane somatostatin receptors. However, in their in vivo study, both cell line-derived tumors were inhibited by RC-160 (100 µg administered subcutaneously on a daily basis), highlighting the probable importance of indirect GH/IGF-I effects.
B. Other (chondrosarcoma/fibrosarcoma)
a. Chondrosarcoma.Foley et al. (245) in 1982
demonstrated the presence of high-affinity
[125I]IGF-I and
[125I]IGF-II binding on Swarm rat
chondrosarcoma chondrocytes. IGF-I and IGF-II were able to stimulate
glycosaminoglycan synthesis as evidenced by increased
[35S]sulfate incorporation into macromolecules
from the medium and cell matrix of the chondrosarcoma chondrocytes.
Takigawa et al. (246) in 1997 demonstrated the presence of
IGF-I and IGF-II mRNA by Northern analysis in a human
chondrosarcoma-derived chondrocyte cell line HCS-2/8. Conditioned
medium from their cell culture also demonstrated the presence of IGF-I
and IGF-II by RIA. IGF-I and IGF-II receptor mRNA was also detected
using Northern analysis. Seong et al. (247) in 1994 also
demonstrated a mitogenic effect of IGF-I on DNA and glycosaminoglycan
synthesis as measured by [3H]thymidine
incorporation and [35S]sulfate incorporation,
respectively, in rat chondrosarcoma chondrocytes in culture. The
stimulatory effects of IGF-I on [3H]thymidine
incorporation and [35S]sulfate incorporation
were inhibited by 29 and 25%, respectively, by IR3.
b. Fibrosarcoma. Butler et al. in 1998 analyzed the
effect of IGF-I expression and development of fibrosarcomas in mice
(248). Tumors arising from NIH3T3 lines expressing different numbers of
the IGF-I receptor were studied. The NWTc43 line expressed 1.9 x
105 receptors/cell while the pNeo1 line expressed
1.6 x 104. Nude mice transplanted with the
NWTc43 cells and treated with an IGF-I infusion (4 or 10 mg/kg
administered subcutaneously daily) developed palpable tumors more
quickly than those animals treated with vehicle or IGF-I
concentrations 
1 mg/kg/day. Once palpable, the tumors grew more
quickly with the higher IGF-I doses. Identically treated animals with
the pNeo1 grafts did not demonstrate the same stimulatory response to
IGF-I administration.
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XI. Skin Neoplasms |
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TopAbstractI. IntroductionII. Overview: IGF Physiology...III. Potential Therapeutic...IV. Central Nervous System...V. Gastrointestinal NeoplasmsVI. Head, Neck, and...VII. Female Reproductive...VIII. Male Reproductive...IX. Genitourinary NeoplasmsX. Bone NeoplasmsXI. Skin NeoplasmsXII. Hematological MalignanciesXIII. SummaryReferences |
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IR3. Furlanetto et al. (250) in 1993 demonstrated that
IGF-I was a mitogen for two human melanoma cell lines in
vitro, WM 373 and WM 852, whereas it did not have an effect on two
other human melanoma lines, WM 239-A and WM 266–4. IR3 inhibited
IGF-I stimulated cell growth in vitro in the responsive cell
lines. In in vivo studies, IR3 (500 µg ip twice weekly)
significantly inhibited tumor growth in the mice bearing WM 373 and WM
852 xenografts but had no effect on mice implanted with the other cell
lines. The effect of IGF-I on melanoma cell cultures was also analyzed
by Resnicoff et al. in 1994 (251). They observed that the
FO-1 human melanoma cell line, after being stably transfected with a
plasmid expressing an antisense RNA to IGF-I receptor, expressed 70%
fewer IGF-I receptors (49 x 104
receptors/cell vs. 14.7 x 104
receptors per cell). When 107 cells were
implanted into nude mice, the latent period for tumor development was
28 days compared with 4 days for those animals with tumors transfected
with an expression vector for the sense RNA or not transfected at all.
Pretreatment with antisense oligonucleotides to the IGF-I receptor had
a similar inhibitory effect on tumorigenesis.
B. Basal/squamous
Neely et al. (252) in 1991 demonstrated the presence of
IGF-I receptors by affinity cross-linking on normal adult human
keratinocytes in culture and on a skin-derived squamous cell carcinoma
cell line, SCL-1. At the maximum dose of 100 µg/liter, both IGF-I and
IGF-II administration resulted in a 2.3-fold increase in normal
keratinocyte cell number. In SCL-1 cells, IGF-I and IGF-II
administration at 333 µg/liter both resulted in a 4.7-fold increase
in [3H]-thymidine incorporation. Bol et
al. (253) in 1997 developed transgenic mice in which expression of
a human IGF-I cDNA was targeted to the interfollicular epidermis using
a human keratin 1 promoter construct (HK1). The transgenic mice
(HK1.IGF-I) showed evidence of epidermal hyperplasia, and 60%
developed papillomas by 20 weeks in response to
12-O-tetradecanoylphorbol-13-acetate, whereas none of the
nontransgenic mice developed tumors. Wilker et al. (254) in
1999 determined that HK1.IGF-I mice were more sensitive to a wide
variety of tumor promoters such as chrysarobin, okadaic acid, and
benzoyl peroxide when compared with nontransgenic mice.
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XII. Hematological Malignancies |
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TopAbstractI. IntroductionII. Overview: IGF Physiology...III. Potential Therapeutic...IV. Central Nervous System...V. Gastrointestinal NeoplasmsVI. Head, Neck, and...VII. Female Reproductive...VIII. Male Reproductive...IX. Genitourinary NeoplasmsX. Bone NeoplasmsXI. Skin NeoplasmsXII. Hematological MalignanciesXIII. SummaryReferences |
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2. IGF effects on tumor growth.Vetter et al. (255)
demonstrated that IGF-I increased [3H]thymidine
incorporation in a Burkitt type ALL line (X308) and a Hodgkin’s
disease-derived cell line (L 428 KSA) in a dose-dependent manner.
Maximal stimulation was observed at an IGF-I concentration of 50
µg/liter, which resulted in values about 170% of control in both
cell lines. IGF-II was less potent as 50 µg/liter concentrations
resulted in [3H]thymidine incorporation values
equal to only 130% of control in each of the two cell lines. Sinclair
et al. (258) demonstrated that IGF-I increased
[3H]thymidine incorporation in HL60 cells up to
250% over control (100 µg/liter for 48 h) but had no effect on
Namalwa cells. The increase in [3H]thymidine
incorporation in HL60 cells was inhibited by IR3. Estrov et
al. (259) in 1991 observed that IGF-I has a dose-dependent effect
on HL60 and Burkitts lymphoma cell lines. IGF-I also had a mitogenic
effect on freshly obtained marrow cells from 4 of 5 patients with acute
lymphoblastic leukemia (ALL) of childhood and 4 of 4 with acute
myeloblastic leukemia (AML). Stimulatory effects were observed at IGF-I
concentrations ranging from 0.05 µg/liter to 0.5 µg/liter. Maximum
stimulation for the ALL and AML specimens were 105 and 65%,
respectively.
Hursting et al. (237) in 1993 compared the growth of mononuclear cell leukemia (MNCL) cells in DR rats to control rats fed AL. DR reduced serum GH and IGF-I levels to 30 and 44% of the AL rats, respectively. The incidence of MNCL in DR rats was lower than in the AL rats (54% vs. 77%), and the DR rats also had an increased latency period (57 ± 2 vs. 52 ± 1 days), a lower histological grade of the tumor, and a lower splenic weight (10.7 ± 1.3 vs. 15.3 ± 1 g). In vitro, serum from DR rats induced less cell proliferation in CRNK-16 cells than serum from AL-treated rats. When the DR-treated rats were infused with rat GH (resulting in serum concentrations of 5.0 µg/liter), their serum then induced a similar degree of proliferation in CRNK-16 cells as observed with the serum obtained from AL animals. They also studied the effect of DR on cell proliferation in situ by using implanted diffusion chambers filled with CRNK-16 cells. The in situ proliferation index (ISPI), which is the diffusion chamber cell count, was significantly lower in the DR rats than in the AL animals, suggesting that DR-sensitive endogenous factors modulate the in situ growth of MNCL cells. When the DR rats were treated with GH (6.25 µg/h x 5 days) or IGF-I (10 µg/h x 5 days), the ISPI increased to that seen with the AL rats.
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XIII. Summary |
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TopAbstractI. IntroductionII. Overview: IGF Physiology...III. Potential Therapeutic...IV. Central Nervous System...V. Gastrointestinal NeoplasmsVI. Head, Neck, and...VII. Female Reproductive...VIII. Male Reproductive...IX. Genitourinary NeoplasmsX. Bone NeoplasmsXI. Skin NeoplasmsXII. Hematological MalignanciesXIII. SummaryReferences |
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GHRH antagonists such as MZ-5–156 also decrease circulating IGF-I concentrations. A reduction of approximately 23% was observed in a recently reported manuscript (35). GH receptor antagonists such as pegvisomant appear to decrease serum IGF-I concentrations more effectively than the currently available somatostatin or GHRH antagonists. Reductions of up to 75–80% are achievable with pegvisomant and occur in a dose-dependent manner, as would be expected with this competitive antagonist compound. Because escalating doses of pegvisomant above those necessary to achieve an 80% reduction do not result in additional decreases in circulating IGF-I concentrations, it would seem that about 20% of the IGF-I in the circulation is produced in a GH-independent manner. Although the pegvisomant dose- response studies were performed in mice, the circulating levels of IGF-I in GH-deficient patients suggest that a 70–80% reduction would probably be the maximum achievable in humans as well. The increased potency of the GH receptor antagonists, at least as measured by reduction in serum IGF-I concentrations, probably exists because of its mechanism of action. By blocking GH binding to its receptor, pegvisomant is essentially producing complete GH deficiency, a phenomenon that, at best, could be equaled by combining a somatostatin analog with a GHRH antagonist.
One of the most interesting aspects of the GHRH antagonists is their ability to decrease intratumor IGF-II production. This is an important phenomenon because it indicates that these compounds can act to diminish a fundamental growth advantage possessed by many types of tumors. For instance, MZ-4–71 administration to animals bearing DU-145 human prostate carcinoma xenografts was associated with a decrease in intratumor IGF-II concentrations from 1,486 pg/100 µg of tissue to 304 pg/100 µg of tissue. Accordingly, a marked antitumor effect was observed in the treatment group. Although the IGF-II assay used in these experiments was not species-specific, this profound decrease in IGF-II production almost certainly reflects tumor production as the serum IGF-II concentrations were not significantly different between the animals that received MZ-4–71 and those that did not. The precise mechanism of the down-regulation of tumor autocrine IGF-II production by the GHRH antagonists is unknown, but it has been observed in both in vitro and in vivo experiments, indicating that it is at least partially mediated by direct actions at the cellular level. Although less extensively studied, the GH receptor antagonist pegvisomant has been demonstrated to also reduce intratumor IGF production (99). The ability to down-regulate endogenous IGF production is likely to be a critical component, if not the most critical component, in mediating the antitumor effects of the GH and GHRH antagonist compounds. In addition to blocking an autocrine growth loop, decreasing endogenous IGF production may also make tumors more responsive to traditional agents such as cytotoxic chemotherapy or radiation.
Modifying the IGFBP environment, whether through agents that modify tumor IGFBP production or simply by the exogenous administration of recombinant proteins, offers significant therapeutic opportunities. The antiestrogens, tamoxifen and ICI 182,780, are excellent examples of agents that modify tumor IGFBP production. For instance, both have been demonstrated to increase IGFBP-3 production in MCF-7 cells, an estrogen-responsive breast cancer cell line. This alteration in IGFBP-3, at least in certain instances, appears to be able to inhibit IGF-I-stimulated cell proliferation. Many examples of the ability of exogenous IGFBP administration to inhibit tumor growth were detailed in the preceding text. Because IGF-II also circulates in complex with the IGFBPs, changes in the binding protein milieu should influence both IGF-I and IGF-II actions. It is important to remember, however, that the effects of all binding proteins are not always uniformly inhibitory. Additionally, at least some of their actions appear to be mediated in a manner that is independent of their actions on IGF bioavailability. Nevertheless, the IGFPBs are an important component of the natural physiological regulation of IGF actions and, as such, are promising candidates for therapeutic intervention.
Agents that block IGF action at the receptor level are also excellent
therapeutic candidates. For instance, IGF-I receptor blocking
antibodies, such as IR3, should be capable of inhibiting the
stimulatory actions of all IGF-I, not just the 75–80% that is
regulated by GH. Additionally, because most of the growth-promoting
actions of IGF-II appear to be mediated by the IGF-I receptor,
therapeutic strategies that block the IGF-I receptor would also inhibit
the actions of IGF-II. Any direct actions of GH, however, would not be
attenuated with this approach. However, as the IGFs are important to
many normal physiological activities in virtually every tissue, there
has to be some concern about the ramifications of blocking the actions
with systemic agents such as an IGF-I receptor antibody. Therefore,
this type of approach may be most useful for those tumors that clearly
overexpress IGF-I receptor and are therefore disproportionately
susceptible to receptor blockade. The use of gene therapy approaches,
such as antisense IGF-I receptor vectors that are targeted to the tumor
only (either by direct injection or the use of a tissue-specific
promoter), offers the possibility of circumventing the problems of
agents that would have systemic actions. They would, however, suffer
from the same limitations of other gene therapy vectors, namely that it
is difficult to achieve a high enough transfection efficiency to
generate clinically meaningful outcomes. Advances in this arena,
however, would make this approach even more attractive.
In summary, a new generation of potential therapeutic agents that target the IGFs is currently under investigation. These new agents are capable of modulating the IGFs and their receptors in ways not previously possible. Endocrine, paracrine, and even autocrine production of the IGFs can be down-regulated. IGF action at the receptor level, and even receptor expression itself, can be blocked. Additionally, the action of GH can be completely blocked as well. The increased potency and alternate mechanisms of actions of these new approaches suggests that some of the promising findings observed in in vitro studies and animals models may eventually come to be realized in the clinical setting. Experimental design that builds upon the vast body of knowledge accumulated over the past several decades, much of which has been reviewed in this manuscript, will have the greatest opportunity for success.
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Footnotes |
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References |
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TopAbstractI. IntroductionII. Overview: IGF Physiology...III. Potential Therapeutic...IV. Central Nervous System...V. Gastrointestinal NeoplasmsVI. Head, Neck, and...VII. Female Reproductive...VIII. Male Reproductive...IX. Genitourinary NeoplasmsX. Bone NeoplasmsXI. Skin NeoplasmsXII. Hematological MalignanciesXIII. SummaryReferences |
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messenger RNA and their respective
receptor messenger RNA in primary human gastric carcinomas: in
vivo studies with in situ hybridization and
Immunocytochemistry. Cancer Res 52:3453–3459 and insulin-like growth factor-I.
Br J Cancer 63:67–70[Medline]
as autocrine growth factors in human
pancreatic cancer cell growth. Cancer Res 50:103–107IR3 inhibits non-small cell
lung cancer growth in vitro and in vivo. J
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and insulin-like growth factor-I, but not epidermal
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S. Kaulfuss, P. Burfeind, J. Gaedcke, and J.-G. Scharf Dual silencing of insulin-like growth factor-I receptor and epidermal growth factor receptor in colorectal cancer cells is associated with decreased proliferation and enhanced apoptosis Mol. Cancer Ther., April 1, 2009; 8(4): 821 - 833. [Abstract] [Full Text] [PDF]
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B. GIRI, A. GOMES, R. SENGUPTA, S. BANERJEE, J. NAUTIYAL, F. H. SARKAR, and A. P.N. MAJUMDAR Curcumin Synergizes the Growth Inhibitory Properties of Indian Toad (Bufo melanostictus Schneider) Skin-derived Factor (BM-ANF1) in HCT-116 Colon Cancer Cells Anticancer Res, January 1, 2009; 29(1): 395 - 401. [Abstract] [Full Text] [PDF]
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C. S. Fuchs, R. M. Goldberg, D. J. Sargent, J. A. Meyerhardt, B. M. Wolpin, E. M. Green, H. C. Pitot, and M. Pollak Plasma Insulin-like Growth Factors, Insulin-like Binding Protein-3, and Outcome in Metastatic Colorectal Cancer: Results from Intergroup Trial N9741 Clin. Cancer Res., December 15, 2008; 14(24): 8263 - 8269. [Abstract] [Full Text] [PDF]
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A. Vrieling, M. A. Rookus, E. Kampman, J. M.G. Bonfrer, A. Bosma, A. Cats, J. van Doorn, C. M. Korse, B. J.M. Witteman, F. E. van Leeuwen, et al. No Effect of Red Clover-Derived Isoflavone Intervention on the Insulin-Like Growth Factor System in Women at Increased Risk of Colorectal Cancer Cancer Epidemiol. Biomarkers Prev., October 1, 2008; 17(10): 2585 - 2593. [Abstract] [Full Text] [PDF]
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S. H. Siahpush, T. L. Vaughan, J. N. Lampe, R. Freeman, S. Lewis, R. D. Odze, P. L. Blount, K. Ayub, P. S. Rabinovitch, B. J. Reid, et al. Longitudinal Study of Insulin-like Growth Factor, Insulin-like Growth Factor Binding Protein-3, and their Polymorphisms: Risk of Neoplastic Progression in Barrett's Esophagus Cancer Epidemiol. Biomarkers Prev., November 1, 2007; 16(11): 2387 - 2395. [Abstract] [Full Text] [PDF]
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J. Chi-Hang Li and R. Li RAV12 Accelerates the Desensitization of Akt/PKB Pathway of Insulin-like Growth Factor I Receptor Signaling in COLO205 Cancer Res., September 15, 2007; 67(18): 8856 - 8864. [Abstract] [Full Text] [PDF]
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S. Feng, I. U. Agoulnik, N. V. Bogatcheva, A. A. Kamat, B. Kwabi-Addo, R. Li, G. Ayala, M. M. Ittmann, and A. I. Agoulnik Relaxin Promotes Prostate Cancer Progression Clin. Cancer Res., March 15, 2007; 13(6): 1695 - 1702. [Abstract] [Full Text] [PDF]
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A. Lukanova and R. Kaaks Endogenous Hormones and Ovarian Cancer: Epidemiology and Current Hypotheses Cancer Epidemiol. Biomarkers Prev., January 1, 2005; 14(1): 98 - 107. [Abstract] [Full Text] [PDF]
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M. Terzolo, G. Reimondo, M. Gasperi, R. Cozzi, R. Pivonello, G. Vitale, A. Scillitani, R. Attanasio, E. Cecconi, F. Daffara, et al. Colonoscopic Screening and Follow-Up in Patients with Acromegaly: A Multicenter Study in Italy J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 84 - 90. [Abstract] [Full Text] [PDF]
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B. Liao, M. Patel, Y. Hu, S. Charles, D. J. Herrick, and G. Brewer Targeted Knockdown of the RNA-binding Protein CRD-BP Promotes Cell Proliferation via an Insulin-like Growth Factor II-dependent Pathway in Human K562 Leukemia Cells J. Biol. Chem., November 19, 2004; 279(47): 48716 - 48724. [Abstract] [Full Text] [PDF]
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J. Svensson, B.-A. Bengtsson, T. Rosen, A. Oden, and G. Johannsson Malignant Disease and Cardiovascular Morbidity in Hypopituitary Adults with or without Growth Hormone Replacement Therapy J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3306 - 3312. [Abstract] [Full Text] [PDF]
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M. Neid, K. Datta, S. Stephan, I. Khanna, S. Pal, L. Shaw, M. White, and D. Mukhopadhyay Role of Insulin Receptor Substrates and Protein Kinase C-{zeta} in Vascular Permeability Factor/Vascular Endothelial Growth Factor Expression in Pancreatic Cancer Cells J. Biol. Chem., February 6, 2004; 279(6): 3941 - 3948. [Abstract] [Full Text] [PDF]
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M. S. Sandhu, J. M. Gibson, A. H. Heald, D. B. Dunger, and N. J. Wareham Association between Insulin-Like Growth Factor-I: Insulin-Like Growth Factor-Binding Protein-1 Ratio and Metabolic and Anthropometric Factors in Men and Women Cancer Epidemiol. Biomarkers Prev., January 1, 2004; 13(1): 166 - 170. [Abstract] [Full Text] [PDF]
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C. A. Kanashiro, A. V. Schally, K. Groot, P. Armatis, A. L. F. Bernardino, and J. L. Varga Inhibition of mutant p53 expression and growth of DMS-153 small cell lung carcinoma by antagonists of growth hormone-releasing hormone and bombesin PNAS, December 23, 2003; 100(26): 15836 - 15841. [Abstract] [Full Text] [PDF]
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 J. M. Harper, A. T. Galecki, D. T. Burke, S. L. Pinkosky, and R. A. Miller Quantitative trait loci for insulin-like growth factor I, leptin, thyroxine, and corticosterone in genetically heterogeneous mice Physiol Genomics, September 29, 2003; 15(1): 44 - 51. [Abstract] [Full Text] [PDF]
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Y. Mao, S. Pan, S. W. Wen, and K. C. Johnson Physical Activity and the Risk of Lung Cancer in Canada Am. J. Epidemiol., September 15, 2003; 158(6): 564 - 575. [Abstract] [Full Text] [PDF]
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A. M. Y. Nomura, G. N. Stemmermann, J. Lee, and M. N. Pollak Serum Insulin-like Growth Factor I and Subsequent Risk of Colorectal Cancer among Japanese-American Men Am. J. Epidemiol., September 1, 2003; 158(5): 424 - 431. [Abstract] [Full Text] [PDF]
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E. K. Maloney, J. L. McLaughlin, N. E. Dagdigian, L. M. Garrett, K. M. Connors, X.-M. Zhou, W. A. Blattler, T. Chittenden, and R. Singh An Anti-Insulin-like Growth Factor I Receptor Antibody That Is a Potent Inhibitor of Cancer Cell Proliferation Cancer Res., August 15, 2003; 63(16): 5073 - 5083. [Abstract] [Full Text] [PDF]
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L. Richiardi, J. Askling, F. Granath, and O. Akre Body Size at Birth and Adulthood and the Risk for Germ-cell Testicular Cancer Cancer Epidemiol. Biomarkers Prev., July 1, 2003; 12(7): 669 - 673. [Abstract] [Full Text] [PDF]
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 J.-W. Chen, T. Ledet, H. Orskov, N. Jessen, S. Lund, J. Whittaker, P. De Meyts, M. B. Larsen, J. S. Christiansen, and J. Frystyk A highly sensitive and specific assay for determination of IGF-I bioactivity in human serum Am J Physiol Endocrinol Metab, June 1, 2003; 284(6): E1149 - E1155. [Abstract] [Full Text] [PDF]
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B.-e. Wang, J. Shou, S. Ross, H. Koeppen, F. J. de Sauvage, and W.-Q. Gao Inhibition of Epithelial Ductal Branching in the Prostate by Sonic Hedgehog Is Indirectly Mediated by Stromal Cells J. Biol. Chem., May 9, 2003; 278(20): 18506 - 18513. [Abstract] [Full Text] [PDF]
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 T.-T. Phan, I. J. Lim, B. H. Bay, R. Qi, M. T. Longaker, S.-T. Lee, and H. Huynh Role of IGF system of mitogens in the induction of fibroblast proliferation by keloid-derived keratinocytes in vitro Am J Physiol Cell Physiol, April 1, 2003; 284(4): C860 - C869. [Abstract] [Full Text] [PDF]
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 S. Yakar and C. J. Rosen From Mouse to Man: Redefining the Role of Insulin-Like Growth Factor-I in the Acquisition of Bone Mass Experimental Biology and Medicine, March 1, 2003; 228(3): 245 - 252. [Abstract] [Full Text] [PDF]
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 K. D. Burroughs, J. Oh, J. C. Barrett, and R. P. DiAugustine Phosphatidylinositol 3-Kinase and Mek1/2 Are Necessary for Insulin-Like Growth Factor-I-Induced Vascular Endothelial Growth Factor Synthesis in Prostate Epithelial Cells: A Role for Hypoxia-Inducible Factor-1? Mol. Cancer Res., February 1, 2003; 1(4): 312 - 322. [Abstract] [Full Text] [PDF]
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R. A. Krajcik, N. D. Borofsky, S. Massardo, and N. Orentreich Insulin-like Growth Factor I (IGF-I), IGF-binding Proteins, and Breast Cancer Cancer Epidemiol. Biomarkers Prev., December 1, 2002; 11(12): 1566 - 1573. [Abstract] [Full Text] [PDF]
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 E. Chaum and H. Yang Transgenic Expression of IGF-1 Modifies the Proliferative Potential of Human Retinal Pigment Epithelial Cells Invest. Ophthalmol. Vis. Sci., December 1, 2002; 43(12): 3758 - 3764. [Abstract] [Full Text] [PDF]
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S. Garrone, G. Radetti, M. Sidoti, M. Bozzola, F. Minuto, and A. Barreca Increased Insulin-Like Growth Factor (IGF)-II and IGF/IGF-Binding Protein Ratio in Prepubertal Constitutionally Tall Children J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5455 - 5460. [Abstract] [Full Text] [PDF]
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K. J. Hunt, P. Toniolo, A. Akhmedkhanov, A. Lukanova, H. Dechaud, S. Rinaldi, A. Zeleniuch-Jacquotte, R. E. Shore, E. Riboli, and R. Kaaks Insulin-like Growth Factor II and Colorectal Cancer Risk in Women Cancer Epidemiol. Biomarkers Prev., September 1, 2002; 11(9): 901 - 905. [Abstract] [Full Text] [PDF]
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H. Yu, F. Jin, X.-O. Shu, B. D. L. Li, Q. Dai, J.-R. Cheng, H. J. Berkel, and W. Zheng Insulin-like Growth Factors and Breast Cancer Risk in Chinese Women Cancer Epidemiol. Biomarkers Prev., August 1, 2002; 11(8): 705 - 712. [Abstract] [Full Text] [PDF]
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 M. S. Sandhu, D. B. Dunger, and E. L. Giovannucci Insulin, Insulin-Like Growth Factor-I (IGF-I), IGF Binding Proteins, Their Biologic Interactions, and Colorectal Cancer J Natl Cancer Inst, July 3, 2002; 94(13): 972 - 980. [Abstract] [Full Text] [PDF]
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C. A. Sklar, A. C. Mertens, P. Mitby, G. Occhiogrosso, J. Qin, G. Heller, Y. Yasui, and L. L. Robison Risk of Disease Recurrence and Second Neoplasms in Survivors of Childhood Cancer Treated with Growth Hormone: A Report from the Childhood Cancer Survivor Study J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3136 - 3141. |
