Accession Number:

ADA426154

Title:

Modulation of VEGF Bioavailability in Breast Tumors by Direct MMP Cleavage

Descriptive Note:

Annual Summary rept. 16 Apr 2003-15 Apr 2004

Corporate Author:

CALIFORNIA UNIV LOS ANGELES

Personal Author(s):

Report Date:

2004-05-01

Pagination or Media Count:

11.0

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, VEGFexp 121, VEGFexp 145, VEGF165, VEGFexp 189, and VEGFexp 205, as a result of alternative splicing from a single gene. These various isoforms differ in their affinity for extracellular matrix ECM proteinsall except for VEGFexp 121 bind to ECM components upon secretion and regulate vascular density and patterning of vessels in vivo. ECM-binding mVEGFexp 188 promotes ectopic filopodia extension and excess branching, while soluble mVEGFexp 120 mouse embryo shows a reduction in vascular branching. We previously found that several MMPs cleave VEGFexp 164, releasing bioactive VEGF fragmentmVEGF exp 113. To further explore the relevance of this processing event, we generated an uncleavable form of mVEGFexp 164mVEGFDDP. Xenografts tumors of T47D cells expressing mVEGFexp 113 and mVEGF showed different tumor growth kinetics and differential tumor vessel formation mVEGFexp DDP tumors grew faster and bigger than wild-type VEGF tumors, followed by mVEGF exp 113 tumors. Also, mVEGFexp DDP tumors showed excessive sprouting with long and thin vessels, while mVEGFexp 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.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE