Molecular Disruption of Breast Tumor Angiogenesis
Abstract
Findings in mice genetically-engineered to be deficient in the expression of genes that comprise the plasmin activation cascade confirmed the importance of plasminogen activator inhibitor type-1 (PAI-1) in tumor-induced angiogenesis. We found that endothelial cells must express PAI-1 to undergo angiogenesis upon co-culture with human breast tumor cells. PAI-1, thus, is an important candidate target for gene therapy of human cancers. Year 01 work determined the effects of expression vector-driven PAI-1 synthesis in endothelial cells (in which the endogenous PAI-1 gene was molecularly disrupted) on Natrigel-induced angiogenesis. This provided an assessment of the threshold level of PAI-1 required for the "angiogenic switch". A vector construct in which PAI-1 cDNA expression was driven by a CMV promoter was used to assess the consequences of varying levels of PAI-1 synthesis on induced angiogenesis. A panel of endothelial transfectant cell lines was created that varied (over 40-fold) in PAI-1 mRNA expression. While PAI-1 null parental cells, and transfectants expressing high levels of PAI-1, were incapable of forming angiogenic neworks when cultured on Matrigel, cells that produced low to moderate levels of PAI-1 were highly angiogenic. This expression window" provides a target for directed therapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2001
- Accession Number
- ADA396437
Entities
People
- Paul J. Higgins
Organizations
- Albany Medical College