Abnormalities in angiogenesis contribute to the pathogenesis of a variety of diseases including tumor growth and metastases, diabetic retinopathy, arthritis, psoriasis, and atherosclerosis. Angiostatin is a recently-discovered inhibitor of angiogenesis that has been shown to prevent the growth and metastasis of experimental tumors. The goal of this proposal is to understand the molecular mechanisms by which angiostatin inhibits cellular growth and migration. Based on its striking homology with hepatocyte growth factor (HGF), a known inducer of angiogenesis, it is hypothesized that angiostatin may act as a competitive inhibitor of HGF, perhaps by binding, but not activating the c-met receptor. This hypothesis will be tested in cell proliferation and migration assays and with competitive cellular binding studies. Another potential mechanism of action of angiostatin involves its ability to displace plasminogen and thereby inhibit plasmin-mediated pericellular proteolytic activities, including the activation of procollagenases and the conversion of latent TGF-B to the active form. A final mechanism that to be examined is the potential ability of angiostatin to inhibit vitronectin-mediated haptotaxis, by disrupting urokinase receptor (UPAR) or integrin-mediated adherence of cells to this extracellular matrix protein. Recombinant vitronectin (wild and mutant forms) will be used to evaluate angiostatin's effect on VN-supported haptotaxis. Preliminary studies demonstrate that HGF (like angiostatin) binds to vitronectin. Domain deletion mutants of VN will be used to determine the VN binding site of HGF. The ability of angiostatin and HGF to compete for the same binding site on VN will also be examined using ELISA-based assays. By virtue of its ability to mediate haptotaxis and also approximate either pro or anti-angiogenic factors close to the cell, VN may modulate angiogenesis. These studies will lead to a better understanding of the mechanisms of angiogenesis inhibition by angiostatin.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA081233-01
Application #
2832454
Study Section
Pathology A Study Section (PTHA)
Program Officer
Freeman, Colette S
Project Start
1998-09-30
Project End
2003-07-31
Budget Start
1998-09-30
Budget End
1999-07-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041418799
City
Winston-Salem
State
NC
Country
United States
Zip Code
27106