IntroductionTissue factor (TF) is the membrane-associated glycoprotein receptor for coagulation factors VIIa and X that serves as the primary physiologic initiator of blood coagulation. In addition to supporting proteolytic events that ultimately lead to local thrombin generation, TF is also proposed to directly contribute to intracellular signaling events through the TF cytoplasmic domain and TF/fVIIa/fXamediated activation of PAR-1 and PAR-2. 1-4 A significant body of evidence has accumulated linking tumor cell-associated procoagulant function to cancer biology. Multiple clinical studies have shown a correlation between TF expression by tumor cells and advanced disease stage and poor outcome. [5][6][7][8][9] Furthermore, experimental data generated using animal models of tumor metastasis strongly favor the view that TF expression by malignant cells supports metastatic success. [10][11][12][13][14][15] Similarly, thrombin-mediated proteolysis, 16-21 fibrin(ogen), 22,23 and PAR-mediated platelet activation 24 also appear to be significant determinants of metastatic potential. Both platelets and fibrinogen were shown to support metastatic potential by limiting the capacity of natural killer (NK) cells to clear newly established micrometastatic foci. 25,26 However, hemostatic factors are likely to influence tumor dissemination through multiple mechanisms and the precise pathways coupling TF to malignancy remain to be defined.The tandem importance of tumor cell-associated TF and circulating coagulation system components in malignancy is consistent with the hypothesis that TF supports metastasis by providing cancer cells a means of directing proteolytic events leading to local thrombin generation and the formation of tumor cell-associated microthrombi. However, an intriguing alternate possibility is that TF supports tumor cell dissemination by mechanism(s) uncoupled from "traditional" thrombin generation and subsequent thrombus formation. In this regard, significant attention has focused on potential intracellular signaling events coupled to the cytoplasmic portion of TF. This interest was driven in part by early studies indicating that tumor cells expressing a mutant form of TF lacking the cytoplasmic domain were far less metastatic than tumor cells expressing full-length TF. 11,12,14 However, interpretation of these early studies was made more complex by the use of nonmurine tumor lines in xenograft assays in mice, the use of tumor cells expressing human TF or human TF derivatives in a setting where all other factors were of murine origin, and the requisite use of immunocompromised mice. Nevertheless, many studies have provided provocative evidence for an important linkage between TF-mediated signaling events and several key cellular processes capable of influencing metastasis, including cytoskeletal organization, 27 cell adhesion/migration, 28-30 apoptosis, 31,32 and angiogenesis. 33,34 An important role for the TF cytoplasmic domain in cellular signaling is also supported by more recent studies of transgenic mic...

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SummaryLow-dose exposures to common environmental chemicals that are deemed safe individually may be combining to instigate carcinogenesis, thereby contributing to the incidence of cancer. This risk may be overlooked by current regulatory practices and needs to be vigorously investigated.

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