Signaling mechanisms of endogenous angiogenesis inhibitors derived from type IV collagen

Abstract

Vascular basement membrane (VBM) derived molecules are regulators of certain biological activities such as cell growth, differentiation and angiogenesis. Angiogenesis is regulated by a systematic controlled balance between VBM derived antiangiogenic factors and proangiogenic growth factors. In the normal physiological state, equilibrium is maintained between the antiangiogenic and proangiogenic factors. The antiangiogenic factors (molecules), which are generated by the proteolytic cleavage of the VBM, include; alpha1 chain non-collagenous (NC1) domain of type XVIII collagen (endostatin) and the NC1 domains from the alpha chains of Type IV collagen considered as endogenous angiogenesis inhibitors. These collagen derived NC1 domains have a pivotal role in the regulation of tumor angiogenesis, thus making them attractive alternate candidates for cancer therapies. In this review we illustrate a comprehensive overview of the knowledge gained from the signaling mechanisms of Type IV collagen derived endogenous inhibitors in angiogenesis.

Figure 1

Schematic illustration of signaling pathway mediated by α1(IV)NC1. α1(IV)NC1 binds to α1β1 integrin and cross talk with growth factor receptors, and inhibit phosphorylation of FAK. Inhibition of FAK activation leads to inhibition of Raf/MEK/ERK1/2/p38 MAP kinase pathways that leads to inhibition of HIF-1α and VEGF expression which in turn results in inhibition of endothelial cell migration, proliferation and tube formation in proliferating endothelial cells.

Figure 2

Schematic illustration of distinct signaling pathways induced by α2(IV)NC1. α2(IV)NC1 binds to αVβ3 and αVβ5 integrins on endothelial and tumor cells, and initiates two distinct signaling pathways. (1) Inhibition of phosphorylation of FAK/PI-3K/eIF4E/4E-BP1. (2) Activation of caspase-8 and -9 leading to activation of caspase-3. α2(IV)NC1 activates pro-caspase-8 and -9 directly through inhibition of FAK/PI3K/Akt/mTOR pathway. α2(IV)NC1 also indirectly enhances the mitochondrial pathway through Fas dependent caspase-8 activation, which results in inhibition of protein synthesis, DNA damage and cell death.

Figure 3

Schematic illustration of different signaling pathway mediated by α3(IV)NC1. α3(IV)NC1 binds to αVβ3 and α3β1 integrins, and inhibits phosphorylation of FAK. Inhibition of FAK activation leads to inhibition of FAK/PI-3K/eIF4E/4E-BP1 cap dependent translation. In addition α3(IV)NC1 inhibits NFκB mediated signaling in hypoxic conditions leading to inhibition of COX-2/VEGF/bFGF expression, resulting in inhibition of hypoxic tumor angiogenesis.