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- Title
ORIGINAL ARTICLE An N-Terminal 80 kDa Recombinant Fragment of Human Thrombospondin-2 Inhibits Vascular Endothelial Growth Factor Induced Endothelial Cell Migration In Vitro and Tumor Growth and Angiogenesis In Vivo.
- Authors
Yun-Hee Noh, Pierre A.; Matsuda, Kant; Young-Kwon Hong; Kunstfeld, Rainer; Riccardi, Lucia; Koch, Manuel; Oura, Hajimu; Dadras, Soheil S.; Streit, Michael; Detmar, Michael
- Abstract
We have previously shown that stable overexpression of the thrombospondin-2 (TSP-2) gene inhibited the tumor growth and angiogenesis of human squamous cell carcinoma xenotransplants. To investigate the potential antitumoral efficacy of systemic TSP-2 therapy, we expressed a recombinant 80 kDa fragment of human TSP-2 (TSP-2/NTF), encompassing the N-terminal globular region through the three type 1 repeats, in human kidney 293 EBNA cells, using a modified pCEP4 expression vector. Daily intraperitoneal injections of TSP-2/NTF resulted in a significant inhibition of the growth of human A431 squamous cell carcinomas in vivo and in reduced tumor vascularization. To further investigate possible mechanisms of the antiangiogenic activity of TSP-2/NTF, several in vitro angiogenesis assays were performed in human dermal microvascular endothelial cells. TSP-2/NTF inhibited vascular endothelial growth factor induced migration of human dermal microvascular endothelial cells and inhibited tube formation on Matrigel in vitro. TSP-2/NTF also inhibited vascular endothelial growth factor induced angiogenesis in an in vivo Matrigel assay. Moreover, TSP-2/NTF potently induced human dermal microvascular endothelial cell apoptosis in vitro but did not affect A431 tumor cell proliferation or apoptosis. These findings identify TSP-2/NTF as a potent systemic inhibitor of tumor growth and angiogenesis, acting by direct inhibition of several endothelial cell functions involved in neovascularization.
- Subjects
THROMBOSPONDINS; CANCER cells; GROWTH factors; VASCULAR endothelium; NEOVASCULARIZATION
- Publication
Journal of Investigative Dermatology, 2003, Vol 121, Issue 6, p1536
- ISSN
0022-202X
- Publication type
Article
- DOI
10.1046/j.1523-1747.2003.12643.x