Mechanisms of VEGF Availability in Prostate Cancer
Abstract
Vascular endothelial growth factor is a critical mediator of angiogenesis. Levels of this cytokine are under exquisite transcriptional and translational control and alterations in can have devastating effects in development. In this study, we demonstrated that VEGF is also regulated extracellularly by matrix metalloproteases. Specifically, MMP3 is capable to cleave the three main splice forms of this growth factor releasing bioactive fragments with equal ability to induce VEGFR2 phosphorylation in vitro. We have mapped the regions of MMP3 processing and generated recombinant forms that mimic MMP3-cleaved VEGF and MMP3-resistant VEGF to explore the biological relevance of this processing event. We found that cleavage of VEGF impacts vessel size, vascular density, and vascular branching. MMP-cleaved VEGF is less able to support tumor growth than MMP-resistant VEGF. MMP-cleaved VEGF induces capillary hyperplasia in existent vessels, but induces a poor angiogenic response. In contrast, MMP-resistant VEGF supports robust growth of thin vessels with frequent branching points. In addition, this form is conducive to metastatic events in cell lines that normally do not metastasize. These findings reveal a novel mode of regulation of VEGF that impacts all spliced forms and have modulatory effects in tumor growth and vessel morphogenesis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2004
- Accession Number
- ADA428040
Entities
People
- Arnaud Monvoisin
Organizations
- University of California, Los Angeles