Molecular Disruption of Breast Tumor Angiogenesis
Abstract
Endothelial cells must express plasminogen activator inhibitor type-1 (PAI-1) in order to undergo an angiogenic switch during tumor progression. The PAI-1 gene, therefore, has emerged as an important candidate target for gene therapy of human breast cancer. During the period of this grant, we carried out studies to confirm that targeted ablation of PAI-1 gene expression resulted in a marked attenuation of endothelial cell migration as well as an inability to form and maintain capillary network structures on Matrigel-coated surfaces. Addition of PAI-1 protein or transfection of PAI-1 expression vectors rescued the migratory phenotype. Confirmatory results were obtained with human microvessel endothelial cells. Breast cancer-derived factors (TGF-beta, EGF)were found to be important contributors of continued PAI-1 expression and long-term maintenance of capillary structures. PAI-1 synthesis and/or protease inhibitory activity, even in mature tubular networks, was required for a invasive growth and a stabilized angiogenic response. The work carried out under this award support the "balanced proteolysis" concept of angiogenesis, identified critical molecular mechanisms underlying the angiogenic response and support our hypothesis that the PAI-1 gene is an accessible anti-angiogenic target.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2004
- Accession Number
- ADA430673
Entities
People
- Paul J. Higgins
Organizations
- Albany Medical College