Warfarin inhibition of metastasis: the role of anticoagulation

Warfarin inhibits metastasis in animal models by mechanisms that remain unclear. A better understanding of this phenomenon may clarify processes underlying metastasis in human cancer. We have studied the effects of warfarin on metastasis in a rat model by intravenous injection of Mtln3 mammary carcinoma cells and subsequent counting of pulmonary seedlings. To determine whether warfarin acts principally on the tumour cells or the host, we pretreated either cells or animals with warfarin before intravenous injection of 10(4) Mtln3 cells. Pretreatment of tumour cells had no effect, whilst pretreatment of the host reduced median seedlings from 67 to 4.5 per animal (P less than 0.005). To determine whether warfarin was acting via its anticoagulant action, we reversed warfarin anticoagulation by intravenous injection of coagulation factors II, VII, IX and X. Restoration of coagulation for 12 h immediately after injection of cells completely reversed the warfarin effect (P less than 0.001), but if the injection of factors was delayed for 12 h it had no effect (P = 0.1753). We conclude that warfarin acts principally on the host, not the tumour cell, and that it acts via its effect on coagulation. The restriction of the effect to the first 12 h after tumour cell injection suggests a mechanism involving intravascular processes such as tumour cell survival or endothelial adhesion.