The COOH-terminal globular domain of fibrinogen γ chain suppresses angiogenesis and tumor growth

Nobuaki Akakura, Case Hoogland, Yoko K. Takada, Jun Saegusa, Xiaojing Ye, Fu Tong Liu, Anthony Tze Wai Cheung, Yoshikazu Takada

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

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 γ chain has a COOH-terminal globular domain (γC, residues 151-411 of the γ chain, 30 kDa) to which several integrin cell adhesion receptors (e.g., platelet αIIBβ3, endothelial αvβ3, and leukocyte αMβ 2) bind. Integrins play a critical role in signal transduction from fibrin(ogen). We found that γC and its truncation mutant (designated γC399tr), 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 γC or γC399tr grew at similar levels in vitro but grew much slower in vivo than mock-transfected cells. The recombinant purified γC399tr 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 γC and γC399tr. 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.

Original languageEnglish
Pages (from-to)9691-9697
Number of pages7
JournalCancer Research
Volume66
Issue number19
DOIs
Publication statusPublished - Oct 1 2006
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Akakura, N., Hoogland, C., Takada, Y. K., Saegusa, J., Ye, X., Liu, F. T., Cheung, A. T. W., & Takada, Y. (2006). The COOH-terminal globular domain of fibrinogen γ chain suppresses angiogenesis and tumor growth. Cancer Research, 66(19), 9691-9697. https://doi.org/10.1158/0008-5472.CAN-06-1686