Regulation of Breast Carcinoma Growth and Neovascularization by Peptide Sequences in Thromospondin
Abstract
Thrombospondin-l (TSPl) 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 TSPl. Peptides from the type I repeats of TSPl reproduced the growth inhibitory activity of the intact protein. 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 basic fibroblast growth factor (FGF-2) and selectively induced apoptosis of endothelial cells, The alpha3beta1 integrin was identified as receptor on breast carcinoma cells that mediates adhesive and migratory responses of the cells to TSPl. Over expression of TSPl 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 TSPl. Stably transfected breast carcinoma cell lines expressing these mutants were characterized for tumorigenic potential in vivo and behavior in Vitro.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 1999
- Accession Number
- ADB258779
Entities
People
- David Roberts
Organizations
- National Institutes of Health