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The COOH-Terminal Globular Domain of Fibrinogen Chain Suppresses Angiogenesis and Tumor Growth

Departments of ¹ Dermatology and ² Medical Pathology and Laboratory Medicine, University of California-Davis Medical Center, Sacramento, California

Requests for reprints: Yoshikazu Takada, Department of Dermatology, University of California-Davis Medical Center, Research III Suite 3300, 4645 Second Avenue, Sacramento, CA 95817. Phone: 916-734-7443; Fax: 916-734-7505; E-mail: ytakada{at}ucdavis.edu.

Fibrinogen is a major plasma protein (350 kDa) that induces proliferative signals by serving as a scaffold to support the binding of growth factors and to promote the cellular responses of adhesion, proliferation, and migration during wound healing, angiogenesis, and tumor growth. Fibrin(ogen) degradation products generated during fibrinolysis are implicated in tissue injury. The fibrinogen chain has a COOH-terminal globular domain (C, residues 151-411 of the chain, 30 kDa) to which several integrin cell adhesion receptors (e.g., platelet _IIbß₃, endothelial _vß₃, and leukocyte _Mß₂) bind. Integrins play a critical role in signal transduction from fibrin(ogen). We found that C and its truncation mutant (designated C399tr), with a deletion of the COOH-terminal 12 residues, induced apoptosis of endothelial cells and blocked tube formation of endothelial cells. DLD-1 human colon cancer cells that secrete C or C399tr grew at similar levels in vitro but grew much slower in vivo than mock-transfected cells. The recombinant purified C399tr fragment markedly suppressed tumor growth, development of intratumoral vasculature, and tumor metastasis in vivo in the highly metastatic Met-1 breast cancer model. The determinant responsible for binding to endothelial cells is cryptic in native fibrinogen but is exposed in C and C399tr. These results suggest that fibrinogen has a novel cryptic determinant, which can exert apoptosis-inducing activity on endothelial cells when exposed, and polypeptides containing this determinant have therapeutic potential. (Cancer Res 2006; 66(19): 9691-7)

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