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Review
. 2012 Jun;41(2):335-50, vi.
doi: 10.1016/j.ecl.2012.04.014.

The insulin-like growth factor system in cancer

S John Weroha  1 , Paul Haluska
Affiliations
Review

The insulin-like growth factor system in cancer

S John Weroha et al. Endocrinol Metab Clin North Am. 2012 Jun.

Abstract

Insulin-like growth factor (IGF) plays an important role in tissue growth and development. Several studies have demonstrated the association between circulating levels of IGF-1 and -2 and cancer risk, and the IGF system has been implicated in the oncogenesis of essentially all solid and hematologic malignancies. The optimal strategy for targeting IGF signaling in patients with cancer is not clear. The modest benefits reported thus far underscore the need for a better understanding of IGF signaling, which would enable clinicians to identify the subset of patients with the greatest likelihood of attaining benefit from this targeted approach.

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Conflict of interest statement

Authors’ Disclosure of Potential Conflicts of Interests:

P.H. receives research funds from BMS, Roche, ImClone, GSK, Pfizer, Merck and MedImmune and is an unpaid consultant for BMS, Roche, Merck and MedImmune.

Figures

Figure 1
Figure 1
Circulating IGF-1/2 is bound to IGF binding proteins and released at the IGF-1R, which is comprised of an alpha and beta tetrameric receptor. This leads to the activation of Ras and AKT with subsequent upregulation of genes involved in cell proliferation, survival, invasion, and angiogenesis. AKT is also an upstream regulator of mTORC1 and downstream effector of mTORC2. Both mTOR complexes play an important role in positive and negative feedback on the IGF/AKT signaling pathway. Legend: Insulin like growth factor (IGF), IGF receptor 1 (IGF-1R), Hybrid receptors (Hybrid-Rs), insulin receptor substrate 1 (IRS1), mammalian target of rapamycin complex (mTORC), p70 S6 kinase (S6K1).
Figure 2
Figure 2
IGF-1R and EGFR/HER2crosstalk occurs by two main mechanisms. Since both pathways share a common signal transduction mediator, IRS1, resistance to inhibition of one receptor pathway can result from activation of IRS1 by the alternate receptor pathway. In addition, the formation of IGF-1R and EGFR/HER2 heterodimers increases the functional pool of receptors capable of binding IGF or EGFR/HER2 ligands, thus conferring resistance to single-agent targeted therapy. Legend: Insulin like growth factor (IGF), IGF receptor 1 (IGF-1R), Hybrid receptors (Hybrid-Rs), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), insulin receptor substrate 1 (IRS1), phosphatidylinositol 3-kinase (PI3K)
See this image and copyright information in PMC

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