The interplay of integrin, VE-cadherin, and β-catenin signaling triad in angiogenesis: regulation by Wnt antagonist, secreted frizzled related protein 4 in the tumor angiogenic loop.

Abstract

Angiogenesis is the physiological process by which blood vessels form to provide oxygen and nutrients to cells. While angiogenesis can contribute to the therapy of certain ailments, it can also be involved in the pathology of diseases such as cancer. Angiogenesis is performed by endothelial cells (ECs), the innermost layer of blood vessels and the process is dependent on the expression of pro-angiogenic growth factors, cell adhesion proteins, and signaling pathways. Several pathways influence and regulate different stages of blood vessel formation, including EC proliferation, differentiation, migration, polarity, and survival. In tumors, these pathways are dysfunctional, leading to uncontrolled cellular attributes, including deregulated angiogenesis. Specifically, Wnt-β-catenin signaling, a vital cell proliferation pathway, anomalously enhances the expression of pro-angiogenic genes such as vascular endothelial growth factor VEGF, fibronectin and other factors. This review elucidates the role of angiogenic factors and highlights the interplay among VEGF, β-catenin, VE-cadherin, and integrin, all of which are associated with the Wnt-β-catenin pathway. Secreted frizzled related protein 4 (SFRP4) is a well-established Wnt antagonist proven to have anti-tumorigenic, anti-angiogenic, and pro-apoptotic roles. This review proposes a novel role of interaction between SFRP4 and integrin which could disrupt Wnt signaling and inhibit angiogenesis by SFRP4 mediated inhibition of integrin signaling.