The Role of the IGF System in Cancer Growth and Metastasis: Overview and Recent Insights
Amir Abbas Samani,
Shoshana Yakar,
Derek LeRoith and
Pnina Brodt
Departments of Medicine (A.A.S., P.B.), Surgery (P.B.), and Oncology (P.B.), McGill University Health Centre, Royal Victoria Hospital, Montreal, Québec, Canada H3A 1A1; and Division of Endocrinology, Diabetes and Bone Disease (S.Y., D.L.), Mount Sinai School of Medicine, New York, New York 10029-6574
Correspondence: Address all correspondence and requests for reprints to: Pnina Brodt, Department of Surgery, McGill University Health Center, Surgical Labs, Royal Victoria Hospital, Room H6.25687, Pine Avenue West, Montreal, Québec, Canada H3A 1A1. E-mail: pnina.brodt{at}muhc.mcgill.ca
IGF-I receptor (IGF-IR) signaling and functions are mediatedthrough the activities of a complex molecular network of positive(e.g., type I IGF) and negative (e.g., the type II IGF receptor,IGF-IIR) effectors. Under normal physiological conditions, thebalance between the expression and activities of these moleculesis tightly controlled. Changes in this delicate balance (e.g.,overexpression of one effector) may trigger a cascade of molecularevents that can ultimately lead to malignancy. In recent years,evidence has been mounting that the IGF axis may be involvedin human cancer progression and can be targeted for therapeuticintervention. Here we review old and more recent evidence onthe role the IGF system in malignancy and highlight experimentaland clinical studies that provide novel insights into the complexmechanisms that contribute to its oncogenic potential. Controversiesarising from conflicting evidence on the relevance of IGF-IRand its ligands to human cancer are discussed. Our review highlightsthe importance of viewing the IGF axis as a complex multifactorialsystem and shows that changes in the expression levels of anyone component of the axis, in a given malignancy, should beinterpreted with caution and viewed in a wider context thattakes into account the expression levels, state of activation,accessibility, and functionality of other interacting components.Because IGF targeting for anticancer therapy is rapidly becominga clinical reality, an understanding of this complexity is timelybecause it is likely to have an impact on the design, mode ofaction, and clinical outcomes of newly developed drugs.
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