Accession Number:

ADB233109

Title:

Regulation of Breast Carcinoma Growth and Neovascularization by Novel Peptide Sequences in Thromospondin

Descriptive Note:

Annual rept. 30 Sep 1996-29 Sep 1997

Corporate Author:

NATIONAL INSTITUTES OF HEALTH BETHESDA MD

Personal Author(s):

Report Date:

1997-10-01

Pagination or Media Count:

77.0

Abstract:

Thrombospondin-1 TSP is an extracellular matrix glycoprotein that modulates endothelial cell growth, motility, and adhesion. Its role in regulating angiogenesis of breast tumors was examined using site specific mutagenesis, recombinant fragments, and peptide mimetics based on TSP. Peptides from the type I repeats of TSP reproduced the growth inhibitory activity of the intact protein and specifically interact with heparin, heparan sulfate proteoglycans, fibronectin, and TGFbeta. Stable analogues of the L- forward peptides and of D-reverse or retro-inverso peptide mimetics were prepared that inhibited endothelial cell proliferation stimulated by FGF-2 and selectively induced apoptosis of endothelial cells. Over expression of TSP in breast carcinoma cells suppresses tumorigenesis and angiogenesis in murine xenografts. The role of the TGFbeta-activating and FGF2 antagonist type I repeat sequences in this activity was examined using site-directed mutagenesis of phenylalanine and tryptophan residues required for activity of peptides derived from TSP. Stably transfected breast carcinoma cell lines expressing these mutants were characterized for tumorigenic potential in vivo and behavior in vitro.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE