Modulation of VEGF Bioavailability in Breast Tumors by Direct MMP Cleavage
Abstract
VEGF-A is one of the most relevant mediators of capillary morphogenesis during development and a key stimulator of tumor-induced angiogenesis. hVEGF-A exists in five forms, VEGF(exp 121), VEGF(exp 145), VEGF165, VEGF(exp 189), and VEGF(exp 205), as a result of alternative splicing from a single gene. These various isoforms differ in their affinity for extracellular matrix (ECM) proteins(all except for VEGF(exp 121) bind to ECM components upon secretion) and regulate vascular density and patterning of vessels in vivo. ECM-binding mVEGF(exp 188) promotes ectopic filopodia extension and excess branching, while soluble mVEGF(exp 120) mouse embryo shows a reduction in vascular branching. We previously found that several MMPs cleave VEGF(exp 164), releasing bioactive VEGF fragment(mVEGF exp 113). To further explore the relevance of this processing event, we generated an uncleavable form of mVEGF(exp 164)(mVEGFDDP). Xenografts tumors of T47D cells expressing mVEGF(exp 113) and mVEGF showed different tumor growth kinetics and differential tumor vessel formation mVEGF(exp DDP) tumors grew faster and bigger than wild-type VEGF tumors, followed by mVEGF exp 113) tumors. Also, mVEGF(exp DDP) tumors showed excessive sprouting with long and thin vessels, while mVEGF(exp 113) tumors showed reduced vessel branching and density. Overall the data imply that VEGF may be processed extracellulary and this proteolysis might offer an important mode for extracelluar regulation in addition to splicing events.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2004
- Accession Number
- ADA426154
Entities
People
- Luisa Iruela-arispe
- Sunyoung Lee
Organizations
- University of California, Los Angeles