Tissue factor/factor VIIa inhibitors block angiogenesis and tumor growth through a nonhemostatic mechanism.
An association between cancer and thrombosis has been recognized for more than a century. However, the manner by which tumor growth is regulated by coagulation in vivo remains unclear. To assess the role of coagulation on tumor growth, in vivo, we tested coagulation inhibitors specific for either tissue factor (TF)/factor VIIa (fVIIa) complexes or factor Xa (fXa) for antitumor activity. Here, we show that two inhibitors of TF/fVIIa, TF pathway inhibitor (TFPI) and the nematode anticoagulant protein rNAPc2, inhibit both primary and metastatic tumor growth in mice. In addition, we show that rNAPc2 is also a potent inhibitor of angiogenesis. In contrast, rNAP5, a second nematode anticoagulant protein that specifically inhibits fXa, does not exhibit antitumor activity. Because the hemostatic activity of TF/fVIIa is mediated through activation of fXa, these data suggest that proteolytic activity of TF/fVIIa promotes tumor growth and angiogenesis through a novel proangiogenic mechanism and independently of hemostasis.
Hembrough
Todd A
TA
EntreMed, Inc, Laboratory of Discovery Research, Rockville, Maryland 20850, USA. toddh@entremed.com
Swartz
Glenn M
GM
Papathanassiu
Adonia
A
Vlasuk
George P
GP
Rote
William E
WE
Green
Shawn J
SJ
Pribluda
Victor S
VS
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D015801:Helminth Proteins / Q000494:pharmacology*; D008074:Lipoproteins / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000517:prevention & control; D013925:Thromboplastin / Q000037:antagonists & inhibitors*
D000925:Anticoagulants; D015801:Helminth Proteins; D008074:Lipoproteins; C400226:anti-coagulant protein C2, Ancylostoma caninum; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin; D015942:Factor VIIa