Hemostatic factors support metastasis by impeding NK cell-mediated elimination of embolic tumor cells

Hemostatic factors are critical determinants of tumor cell metastatic potential. Detailed studies of tumor cell metastasis in mice with genetic deficits in key circulating hemostatic factors revealed that deficiencies in prothrombin, fibrinogen, factor XIII and other hemostatic factors greatly reduce the metastatic success of Lewis lung carcinoma (LLC) and other established tumor lines. Metastatic potential was also found to be dramatically reduced in mice with profound deficits in platelet function (e.g., Gaq-/- mice), implying that a platelet/fibrin axis supports the metastasis of embolized tumor cells. Recent studies have focused on two fundamental questions: i) what is the interplay between tumor cell-associated tissue factor (TF) and circulating hemostatic factors in establishing metastatic potential; and ii) what are the mechanisms that link the hemostatic system to tumor cell metastatic potential? To develop the means to explore the relationship between tumor cell-associated TF and downstream hemostatic system components, we established hRas-transformed tumor cells from C57Bl/6-derived TF-null embryonic fibroblasts (TFo/hRas+ cells). A derivative of these cells was subsequently generated that expresses murine TF (TF+/hRas+ cells) through the stable transfection of a wildtype TF transgene. Both tumor lines supported similar and robust primary tumor growth following subcutaneous transplantation into C57Bl/6 mice. However, TF+/hRas+ cells were found to be dramatically more metastatic than TFo/hRas+ cells in experimental metastasis assays. Comparative analyses of experimental metastasis following the introduction of TF+/hRas+ tumor cells into control and Gaq-deficient mice suggest that tumor cell-associated procoagulant and platelet function are cooperative in establishing metastatic lesions. Recent studies in mice with single and combined deficits in hemostatic factors and NK cells imply that one mechanism whereby hemostatic factors support tumor cell survival/metastasis is by protecting embolized tumor cells from active elimination by natural killer (NK) cells. These studies establish another link between the hemostatic and innate immune systems and suggest that tumor cells exploit hemostatic factors to evade NK cell-mediated immune surveillance mechanisms. These findings also suggest the possibility that therapeutic strategies designed to limit tumor cell association with procoagulants and/or platelets could be effective in restricting tumor cell dissemination.