Thursday, January 20, 2011

The Importance of IGF-1 in Cancer

Background of the IGF-1 Axis

The insulin like growth factor (IGF) axis is composed of multiple parts, including ligands, binding proteins as well as receptors.  Three ligands (IGF-1, IGF-2, Insulin) complex with six binding proteins (IGFBP 1-6) and interact with either the IGF receptors (IGF-1R, IGF-2R) or the Insulin receptors (IR-A, IR-B, and the orphan insulin receptor related receptor) 1.   

IGF-1, also known as somatomedin C, is a hormone similar in structure to insulin, and plays an important role in both childhood growth as well as adult anabolic activity.  It is secreted primarily by the liver as a result of stimulation by human growth hormone (GH), but can also be produced locally in tissues including muscle, bone, and tumor2.  IGF-2 is not dependent on GH and is expressed in a variety of tissues.   Six binding proteins associate with these IGF ligands in serum to stabilize these growth factors and modulate their ability to associate with IGF-1R.  As a result, only 2% of IGF ligands exist in free form in serum2.

There are a number of factors that can cause variation in the levels of IGF-1 in the circulation, including genetic make-up, age, sex, and pubertal stage.  In an individual, levels do not fluctuate greatly throughout the day3,4.
Upon ligand binding, IGF-1R undergoes a conformational change, activating its tyrosine kinase activity and allowing for autophosphorylation of a series of tyrosine residues within its cytoplasmic domain as well as one or more adaptor proteins, such as insulin receptor substrate -1 (IRS-1), that initiate signal transduction from the IGF-1R.  The principal pathways for transduction of the IGF signal are the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways.  The MAPK pathway is primarily responsible for the mitogenic signal elicited following insulin-like growth factor (IGF) stimulation, but may also play a role in cell survival.  IGF-dependent signaling through PI3K elicits survival processes including the phosphorylation and activation of the anti-apoptotic protein Akt and, as a result, has been shown to protect cells from damage-induced apoptosis. 5
The IGF-2R binds IGF-2 but does not transduce signals, as it lacks tyrosine kinase activity (in essence, serving as a sink for IGF-2).  Loss of functional IGF-2R may enhance interaction of IGF-2 with IGF-1R.2 

The Importance of the IGF axis in Cancer

Increases in serum IGF-1, serum IGF1/IGFBP3 ratio, as well as tissue IGF-IR expression has been implicated in the development and progression of a number of cancers6-11. Higher serum expression of both IGF ligands, as well as tissue expression of IGF-IR has been associated with tumor metastatic potential. 12-14 

IGF-1 serves as a ligand for IGF-1R, and causes direct changes in the expression of genes strongly associated with cell proliferation, metabolism, and DNA repair15. The upregulation of IGF-1 expression, rather than the amplification of IGF-1R, is considered the primary mechanism for receptor activation in cancer development and progression16 

Increased expression of tissue IGF-1R leads to increased mitogenesis and decreased apoptotic potential, mediated by an adaptor protein called insulin receptor substrate (IRS-1), which then phosphorylates and activates anti-apoptotic protein Akt1,17.

The pharmaceutical industry has also recognized the importance of the IGF axis, as evidenced by the surging interest in selective IGF-1R receptor blockers, some of which are entering phase III clinical trials18.

1.            Sachdev D, Yee D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther. 2007 Jan;6(1):1-12.
2.            Moschos SJ, Mantzoros CS. The role of the IGF system in cancer: from basic to clinical studies and clinical applications. Oncology. 2002;63(4):317-32.
3.            Rosario PW. Normal values of serum IGF-1 in adults: results from a Brazilian population. Arq Bras Endocrinol Metabol.54(5):477-81.
4.            Elmlinger MW, Kuhnel W, Weber MM, Ranke MB. Reference ranges for two automated chemiluminescent assays for serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3). Clin Chem Lab Med. 2004;42(6):654-64.
5.            Wang Y, Sun Y. Insulin-like growth factor receptor-1 as an anti-cancer target: blocking transformation and inducing apoptosis. Curr Cancer Drug Targets. 2002 Sep;2(3):191-207.
6.            Pollak M. Insulin, insulin-like growth factors and neoplasia. Best Pract Res Clin Endocrinol Metab. 2008 Aug;22(4):625-38.
7.            Wolpin BM, Meyerhardt JA, Chan AT, et al. Insulin, the insulin-like growth factor axis, and mortality in patients with nonmetastatic colorectal cancer. J Clin Oncol. 2009 Jan 10;27(2):176-85.
8.            Reinmuth N, Fan F, Liu W, et al. Impact of insulin-like growth factor receptor-I function on angiogenesis, growth, and metastasis of colon cancer. Lab Invest. 2002 Oct;82(10):1377-89.
9.            Lonning PE, Helle SI. IGF-1 and breast cancer. Novartis Found Symp. 2004;262:205-12; discussion 12-4, 65-8.
10.          Pollak M. Insulin-like growth factor physiology and cancer risk. Eur J Cancer. 2000 Jun;36(10):1224-8.
11.          Wu X, Zhao H, Do KA, et al. Serum levels of insulin growth factor (IGF-I) and IGF-binding protein predict risk of second primary tumors in patients with head and neck cancer. Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):3988-95.
12.          Zeng H, Datta K, Neid M, Li J, Parangi S, Mukhopadhyay D. Requirement of different signaling pathways mediated by insulin-like growth factor-I receptor for proliferation, invasion, and VPF/VEGF expression in a pancreatic carcinoma cell line. Biochem Biophys Res Commun. 2003 Feb 28;302(1):46-55.
13.          Zhang X, Lin M, van Golen KL, Yoshioka K, Itoh K, Yee D. Multiple signaling pathways are activated during insulin-like growth factor-I (IGF-I) stimulated breast cancer cell migration. Breast Cancer Res Treat. 2005 Sep;93(2):159-68.
14.          Mitsiades CS, Mitsiades N. Treatment of hematologic malignancies and solid tumors by inhibiting IGF receptor signaling. Expert Rev Anticancer Ther. 2005 Jun;5(3):487-99.
15.          Creighton CJ, Casa A, Lazard Z, et al. Insulin-like growth factor-I activates gene transcription programs strongly associated with poor breast cancer prognosis. J Clin Oncol. 2008 Sep 1;26(25):4078-85.
16.          Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004 Jul;4(7):505-18.
17.          Baserga R. Customizing the targeting of IGF-1 receptor. Future Oncol. 2009 Feb;5(1):43-50.
18.          Osborne R. Commercial interest waxes for IGF-1 blockers. Nat Biotechnol. 2008 Jul;26(7):719-20.

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