Role of thrombin as a tumor growth factor.
The clinical observation that thrombosis in some patients heralds the onset of malignancy has been recognized for over a century. Thrombin the key terminal enzyme of coagulation also promotes angiogenesis and stimulates tumor-platelet adhesion, adhesion to endothelium, tumor implantation, tumor cell growth and metastasis. The thrombin receptor, a member of the protease-activated receptor family, is expressed on many tumor cell lines and on breast tumor biopsy specimens. In addition to mitogenic effects on fibroblast, smooth muscle cells and endothelial cells, thrombin also exerts direct effects on cancer cells by activation of the cell cycle through downregulation of p27(Kip1) and induction of Skp2, and cyclins D and A. MicroRNA 222, which inhibits p27(Kip1), is upregulated by thrombin. In the transgenic TRAMP mouse model of prostate cancer inhibition of endogenous thrombin by hirudin retards spontaneous tumor growth. Inhibition of thrombin may lead to tumor dormancy and could explain inhibition of tumor growth and metastasis by anticoagulants observed in animal models and a beneficial effect on survival observed in some clinical trials of anticoagulants in cancer patients.
Green
David
D
New York University School of Medicine, Department of Medicine, Division of Hematology, New York, NY, USA. dlg3@nyu.edu
Karpatkin
Simon
S
D000818:Animals; D002460:Cell Line; D019925:Cyclin A / Q000378:metabolism; D056741:Cyclin D / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D024764:Hirudin Therapy; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism; D009842:Oligopeptides / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018179:Receptors, Thrombin / Q000378:metabolism; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D013917:Thrombin / Q000502:physiology*
D019925:Cyclin A; D056741:Cyclin D; D036341:Intercellular Signaling Peptides and Proteins; C546123:MIRN222 microRNA, mouse; D035683:MicroRNAs; D009842:Oligopeptides; D018179:Receptors, Thrombin; D053219:Receptors, Tumor Necrosis Factor, Member 25; D044786:S-Phase Kinase-Associated Proteins; C506034:Tnfrsf25 protein, mouse; C508781:threonyl-phenylalanyl-leucyl-leucyl-arginyl-asparagine; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013917:Thrombin