Inhibition of tumor growth by systemic treatment with thrombospondin-1 peptide mimetics
| Autor: | Susan E. Crawford, Fortuna Haviv, Steven C. Campbell, Noel P. Bouck, Jack Henkin, F. Reiher, Colin P.N. Dinney, Olga V. Volpert, Benilde Jiménez |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
CD36 Antigens
Male Cancer Research medicine.medical_specialty Lung Neoplasms Endothelium Angiogenesis CD36 Melanoma Experimental Mice Nude Apoptosis Thrombospondin 1 Mice Proliferating Cell Nuclear Antigen Internal medicine In Situ Nick-End Labeling medicine Animals Humans Thrombospondin Dose-Response Relationship Drug Neovascularization Pathologic biology business.industry Molecular Mimicry Peptide Fragments Mice Inbred C57BL Platelet Endothelial Cell Adhesion Molecule-1 medicine.anatomical_structure Endocrinology Urinary Bladder Neoplasms Oncology Cancer cell Cancer research biology.protein Tumor necrosis factor alpha Endothelium Vascular business Cell Division |
| Zdroj: | International Journal of Cancer. 98:682-689 |
| ISSN: | 1097-0215 0020-7136 |
| DOI: | 10.1002/ijc.10247 |
| Popis: | Many normal human cells produce thrombospondin-1 (TSP-1), a potent antiangiogenic protein that promotes vascular quiescence. In various organ systems, including the brain, breast and bladder and in fibroblasts, TSP-1 secretion is reduced during tumorigenesis, thereby allowing induction of the vigorous neovascularization required for tumor growth and metastasis. Full-length and short TSP-1-derived peptides inhibit angiogenesis by inducing endothelial cell apoptosis and thus disrupting the vasculature of the growing tumor. CD36 expressed on the surface of endothelial cells functions as the primary antiangiogenic receptor for TSP-1. A D-isoleucyl enantiomer of a TSP-1 heptapeptide specifically inhibits the proliferation and migration of capillary endothelial cells. DI-TSP, an approximately 1 kDa capped version of this peptide, is also antiangiogenic in vitro, with a specific activity approaching that of the 450 kDa parental molecule. Here, we show that DI-TSP delivered systemically dose-dependently inhibits the growth of murine melanoma metastases in syngeneic animals and that its more soluble isomer, DI-TSPa, similarly blocks the progression of primary human bladder tumors in an orthotopic model in immune-deficient mice. Like intact TSP-1, these peptide mimetics had no effect on cancer cells growing in vitro but markedly suppressed the growth of endothelial cells by inducing receptor-dependent apoptosis. Antibodies raised against CD36 blocked the ability of peptides to induce apoptosis in endothelial cells but had no effect on tumor necrosis factor-alpha-induced apoptosis. In vivo, the peptide mimetics were associated with a significantly reduced microvessel density and increased apoptotic indices in both the endothelial and tumor cell compartments. Such short peptides targeted to a specific antiangiogenic receptor, potent and easy to synthesize, show great promise as lead compounds in clinical antiangiogenic strategies. |
| Databáze: | OpenAIRE |
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