Research / Clinical Summary

Judith Varner, PhD Professor, Medicine Tumor Growth, Invasion & Metastasis Program Contact by Email

Project: Study of the molecular mechanism regulating tumor angiogenesis and metastasis

Tumor angiogenesis depends on growth factors and on cell adhesion receptors called integrins that interact with matrix proteins such as fibronectin, fibrinogen and proteolytically cleaved collagen. Endothelial cell migration and angiogenesis depend upon the interaction of these matrix proteins with a subset of integrin receptors, such as a5b1 and avb3. This interaction is required to suppress activation of protein kinase A, which, when activated, blocks endothelial cell migration, induces endothelial cell apoptosis and inhibits angiogenesis. Protein kinase A activation perturbs normal cycling of small GTPases Rho and Rac and blocks activation of critical focal adhesion regulatory proteins such as FAK and paxillin, leading to inhibition of cell migration. Activation of protein kinase A can also inhibit tumor cell migration and metastasis. We are investigating the potential of gene therapy based on these observations as novel therapiea for cancer and other diseases.

Importantly, some ECM proteins, the 'angiomatrix proteins', can induce angiogenesis by binding to resting cell integrins such as avb5. This interaction induces the expression the proangiogenic homeobox gene Hox D3, which converts the endothelium from the resting to the angiogenic state by inducing expression of proangiogenic molecules such as integrin avb3 and a5b1. In fact, Hox D3 promotes vascular proliferation and functions downstream of integrin avb5 but upstream of avb3 and a5b1. Thus, ECM proteins and their integrin receptors play multiple essential roles in the important biological process of angiogenesis.

Keywords: integrin, angiogenesis, endothelial cell, protein kinases, cAMP dependent kinase (PKA), integrin alpha 5 beta 1, extracellular matrix, signal transduction, solid tumor cancer, Rho A

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