The COOH-terminal globular domain of fibrinogen gamma chain suppresses angiogenesis and tumor growth.
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 gamma chain has a COOH-terminal globular domain (gamma C, residues 151-411 of the gamma chain, 30 kDa) to which several integrin cell adhesion receptors (e.g., platelet alpha(IIb)beta(3), endothelial alpha(v)beta(3), and leukocyte alpha(M)beta(2)) bind. Integrins play a critical role in signal transduction from fibrin(ogen). We found that gamma C and its truncation mutant (designated gamma 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 gamma C or gamma C399tr grew at similar levels in vitro but grew much slower in vivo than mock-transfected cells. The recombinant purified gamma 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 gamma C and gamma 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.
Akakura
Nobuaki
N
Department of Dermatology, University of California-Davis Medical Center, Sacramento, CA 95817, USA.
Hoogland
Case
C
Takada
Yoko K
YK
Saegusa
Jun
J
Ye
Xiaojing
X
Liu
Fu-Tong
FT
Cheung
Anthony Tze-Wai
AT
Takada
Yoshikazu
Y
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism; D005338:Fibrin Fibrinogen Degradation Products / Q000494:pharmacology; D005340:Fibrinogen / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008175:Lung Neoplasms / Q000098:blood supply / Q000517:prevention & control / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009024:Morphogenesis / Q000187:drug effects; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000502:physiology; D017384:Sequence Deletion; D014162:Transfection
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D005338:Fibrin Fibrinogen Degradation Products; D039302:Integrin alphaVbeta3; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; C015214:fibrinogen D fragment; C524059:fibrinogen gamma (151-411); C524060:fibrinogen gamma 399 truncated; D005340:Fibrinogen