Identification of Genes Regulating Angiogenesis and Targeted Reduction of Antisense Therapy
Abstract
Angiogenesis, the formation of new blood vessels from existing vessels, is a process critical to many normal physiologic processes However, uncontrolled capillary growth can have dramatic consequences, as seen in the rapid growth of well-vascularized tumors such as breast carcinoma. Indeed, failure to induce a new blood supply limits the size of a tumor dramatically. It is clear that controlling angiogenesis could have a major impact on treatment of breast cancer, the most common cancer in American women. Using a PCR-based screen (Representational Difference Analysis) we have identified several genes that are involved in formation of new blood vessels and that are upregulated in cultured capillary endothelial cells (EC) forming tubes (neo-capillaries) in collagen gels, but not in EC growing in monolayers. ESM-l is a secreted molecule that may be related to chondroitin sulfates. It is highly expressed in several tumors and appears to be regulated by the vascular endothelial growth factor, VEGF. Beta-ig-H3 is an extracellular matrix molecule involved in cross-linking of collagen fibers. Reducing its expression using antisense molecules blocks in vitro capillary formation. NrCAM is a "neural" adhesion molecule and is highly upregulated on tube-forming EC. We speculate that it may have a role in guidance of new vessels. HESR1 is a bHLH transcription factor that appears to control the switch from quiescence to migration and proliferation. It is downstream of the notch receptor and can suppress transcription of the VEGF receptor gene VEGFR2. Blocking HESRl induction with antisense blocks tube formation. By identifying genes differentially expressed during angiogenesis, and designing effective molecular therapies that reduce their expression and thereby reduce capillary growth, we hope to identify future targets for specific therapy aimed at blocking growth of solid tumors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2001
- Accession Number
- ADA404650
Entities
People
- Christopher C. Huges
Organizations
- University of California, Irvine