REVIEW: Endostatin: Current Concepts about Its Biological Role and Mechanisms of Action

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A. V. Digtyar^1,2*, N. V. Pozdnyakova², N. B. Feldman², S. V. Lutsenko², and S. E. Severin^1,2

¹Department of Biological Chemistry, Medical Faculty, Sechenov Moscow Medical Academy, Trubetskaya ul. 8, Build. 1, 119992 Moscow, Russia; E-mail: digtyar@mail.ru

²Moscow Research Institute of Medical Ecology, Simferopol'skii Bulvar 8, 117638 Moscow, Russia

^* To whom correspondence should be addressed.

Received May 17, 2006; Revision received November 1, 2006

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Endogenous inhibitors of angiogenesis are proved to be a major factor preventing the emergence of clinically manifested stages of human cancer. The protein endostatin, a 20-kD proteolytic fragment of type XVIII collagen, is one of the most active natural inhibitors of angiogenesis. Endostatin specifically inhibits the in vitro and in vivo proliferation of endothelial cells, inducing their apoptosis through inhibition of cyclin D1. On the surface of endothelial cells, endostatin binds with the integrin alpha₅beta₁ that activates the Src-kinase pathway. The binding of endostatin with integrins also down-regulates the activity of RhoA GTPase and inhibits signaling pathways mediated by small kinases of the Ras and Raf families. All these events promote disassembly of the actin cytoskeleton, disorders in cell-matrix interactions, and decrease in endotheliocyte mobility, i.e., promote the suppression of angiogenesis. Endostatin displays a high antitumor activity in vivo: it inhibits the progression of more than 60 types of tumors. This review summarizes results of numerous studies concerning the biological activity and action mechanism of endostatin.

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KEY WORDS: endostatin, collagen XVIII, Knobloch syndrome, angiogenesis inhibitors, extracellular matrix, endothelial cells

DOI: 10.1134/S0006297907030017

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