Molecular Disruption of Breast Tumor Angiogenesis
Abstract
Endothelial cells must express plasminogen activator inhibitor type-1 (PAI-1) in order to undergo and angiogenic switch during tumorigenesis. The PAI-l gene has emerged, therefore, as an important candidate target for gene therapy of human breast cancer. In year 03, we conducted studies to confirm that targeted ablation of endothelial cell PAI-l gene expression resulted in a marked inability to migrate and an inability to from angiogenic networks on Matrigel. Addition of recombinant active PAI-l restored migratory of these genetically-engineered PAI-l-deficient cells to approximate that of wild-type endothelial cells. Confirmatory results were obtained with human microvessel endothelial (HMEC-l) cells which validates these findings within the context of human endothelial cells and human endothelial tubulogenic differentiation. Capillary network integrity (i.e., angiogenic structures for by T2 and HMEC-l cells) on Matigel surfaces was disrupted by addition of neutralizing PAI-l antibodies. This suggests that continued PAI-l synthesis and/or activity, even in mature tubes, was required for network stability. These results support the "balanced proteolysis" concept of angiogenesis and support our hypothesis that the PAI-l gene is a anti-angiogenic target for breast cancer therapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2003
- Accession Number
- ADA419337
Entities
People
- Paul J. Higgins
Organizations
- Albany Medical College