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The Effects of Insulin-Like Growth Factors on Tumorigenesis and Neoplastic Growth

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

Several decades of basic and clinical research have demonstrated that there is an association between the insulin-like growth factors (IGFs) and neoplasia. We begin with a brief discussion of the function and regulation of expression of the IGFs, their receptors and the IGF-binding proteins (IGFBPs). A number of investigational interventional strategies targeting the GH or IGFs are then reviewed. Finally, we have assembled the available scientific knowledge about this relationship for each of the major tumor types. The tumors have been grouped together by organ system and for each of the major tumors, various key elements of the relationship between IGFs and tumor growth are discussed. Specifically these include the presence or absence of autocrine IGF-I and IGF-II production; presence or absence of IGF-I and IGF-II receptor expression; the expression and functions of the IGFBPs; in vitro and in vivo experiments involving therapeutic interventions; and available results from clinical trials evaluating the effect of GH/IGF axis down-regulation in various malignancies.

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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]

				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]

				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]

				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]

				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]

				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 Exp Biol Med, March 1, 2003; 228(3): 245 - 252. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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. [Abstract] [Full Text] [PDF]

				G. O. Hellawell, G. D. H. Turner, D. R. Davies, R. Poulsom, S. F. Brewster, and V. M. Macaulay Expression of the Type 1 Insulin-like Growth Factor Receptor Is Up-Regulated in Primary Prostate Cancer and Commonly Persists in Metastatic Disease Cancer Res., May 1, 2002; 62(10): 2942 - 2950. [Abstract] [Full Text] [PDF]

				H. Huynh, P. K. H. Chow, L. L. P. Ooi, and K.-C. Soo A Possible Role for Insulin-like Growth Factor-binding Protein-3 Autocrine/Paracrine Loops in Controlling Hepatocellular Carcinoma Cell Proliferation Cell Growth Differ., March 1, 2002; 13(3): 115 - 122. [Abstract] [Full Text] [PDF]

				D. Hoelzer, N. Gokbuget, O. Ottmann, C.-H. Pui, M. V. Relling, F. R. Appelbaum, J. J.M. van Dongen, and T. Szczepanski Acute Lymphoblastic Leukemia Hematology, January 1, 2002; 2002(1): 162 - 192. [Abstract] [Full Text] [PDF]

				Y. Lu, X. Zi, Y. Zhao, D. Mascarenhas, and M. Pollak Insulin-Like Growth Factor-I Receptor Signaling and Resistance to Trastuzumab (Herceptin) J Natl Cancer Inst, December 19, 2001; 93(24): 1852 - 1857. [Abstract] [Full Text] [PDF]

				J. Whittaker, A. V. Groth, D. C. Mynarcik, L. Pluzek, V. L. Gadsboll, and L. J. Whittaker Alanine Scanning Mutagenesis of a Type 1 Insulin-like Growth Factor Receptor Ligand Binding Site J. Biol. Chem., November 16, 2001; 276(47): 43980 - 43986. [Abstract] [Full Text] [PDF]

				K. Szepeshazi, A. V. Schally, P. Armatis, K. Groot, F. Hebert, A. Feil, J. L. Varga, and G. Halmos Antagonists of GHRH Decrease Production of GH and IGF-I in MXT Mouse Mammary Cancers and Inhibit Tumor Growth Endocrinology, October 1, 2001; 142(10): 4371 - 4378. [Abstract] [Full Text] [PDF]

				S. L. Leng, K. S. Leeding, P. R. Gibson, and L. A. Bach Insulin-like growth factor-II renders LIM 2405 human colon cancer cells resistant to butyrate-induced apoptosis: a potential mechanism for colon cancer cell survival in vivo Carcinogenesis, October 1, 2001; 22(10): 1625 - 1631. [Abstract] [Full Text] [PDF]

				R. D. Kineman, L. T. Teixeira, G. V. Amargo, K. T. Coschigano, J. J. Kopchick, and L. A. Frohman The Effect of GHRH on Somatotrope Hyperplasia and Tumor Formation in the Presence and Absence of GH Signaling Endocrinology, September 1, 2001; 142(9): 3764 - 3773. [Abstract] [Full Text] [PDF]

				C. Gicquel, X. Bertagna, V. Gaston, J. Coste, A. Louvel, E. Baudin, J. Bertherat, Y. Chapuis, J.-M. Duclos, M. Schlumberger, et al. Molecular Markers and Long-Term Recurrences in a Large Cohort of Patients with Sporadic Adrenocortical Tumors Cancer Res., September 1, 2001; 61(18): 6762 - 6767. [Abstract] [Full Text] [PDF]

				T. W. Chan, M. Pollak, and H. Huynh Inhibition of Insulin-like Growth Factor Signaling Pathways in Mammary Gland by Pure Antiestrogen ICI 182,780 Clin. Cancer Res., August 1, 2001; 7(8): 2545 - 2554. [Abstract] [Full Text] [PDF]