Regulation of Breast Carcinoma Growth and Neovascularization by Novel Peptide Sequences in Thrombospondin
Annual rept. 29 Aug 1997-28 Aug 1998
NATIONAL INSTITUTES OF HEALTH BETHESDA MD
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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 reproduce the growth inhibitory activity of the intact protein. Stable analogues of these peptides inhibit tumor growth in vivo, endothelial cell proliferation, and selectively induce apoptosis of endothelial cells. Over-expression of TSP in breast carcinoma cells suppresses tumorigenesis and angiogenesis in murine xenografts. The roles of the TGF beta-activating and FGF2-antagonist sequences in this activity were examined using site-directed mutagenesis of the residues required for activity of the type I repeat peptides. Stable transfected breast carcinoma cell lines expressing these mutant TSPs were characterized for tumorigenic potential in vivo and behavior in vitro. Endothelial cell responses to the mutant TSPs were examined by transient transfection of the mutated expression plasmids. Adhesion and chemotaxis of the breast carcinoma cells to TSP were shown to be mediated by an activation dependent beta 1 integrin.
- Medicine and Medical Research