The C‐terminal globular domain of fibrinogen γ chain suppresses angiogenesis and tumor growth

Fibrinogen is a major blood protein involved in blood clotting. Fibrinogen induces cell proliferation, but fibrin(ogen) degradation products (e.g., fragment D) are implicated in tissue injury in pathological situations. Fragment D contains the conserved fibrinogen γ chain C‐terminal globular domain (designated γ C). We found that γ C411 and γ C399 (residues 150–411 and 150–399, respectively) effectively induced apoptosis of endothelial cells in vitro, and blocked tube formation of endothelial cells on matrigel in vitro. Native fibrinogen or fragment D did not induce such effects. Consistently, γ C bound, but fragment D or native fibrinogen did not bind to endothelial cells, suggesting that the epitope involved in apoptosis induction is cryptic in fibrinogen or fragment D, but exposed in γ C. We show that integrin αvβ3 is a major γ C receptor in endothelial cells. γ C did not induce apoptosis of cancer cells and keratinocytes. Further, γ C399 suppressed, but γ C411 enhanced, tumor growth in vivo, suggesting that the C‐terminus of γ C411 (residues 400–411) that contains the platelet integrin αIIbβ3‐binding motif may have tumor‐promoting effects in vivo. We show that γ C399 suppressed intratumoral vascularature development in vivo using intravital microscopy. These results suggest that γ C399 is a novel potent proapoptotic protein and has a therapeutic potential.