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.
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