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...

A link between colitis and colon cancer is well established, but the mechanisms regulating inflammation in this context are not fully defined. Given substantial evidence that hemostatic system components are powerful modulators of both inflammation and tumor progression, we employed gene-targeted mice to directly test the hypothesis that the coagulation factor fibrinogen contributes to colitis-associated colon cancer in mice. This fundamental provisional matrix protein was found to be an important determinant of colon cancer. Fibrinogen deficiency resulted in a dramatic diminution in the number of colonic adenomas formed following azoxymethane/dextran sodium sulfate challenge. More detailed analyses in mice expressing a mutant form of fibrinogen that retains clotting function, but lacks the leukocyte integrin receptor αMβ2 binding motif (Fibγ390-396A) revealed αMβ2-mediated engagement of fibrin(ogen) is mechanistically coupled to local inflammatory processes (e.g., IL-6 elaboration) and epithelial alterations which contribute to adenoma formation. Consistent with these findings, the majority of Fibγ390-396A mice developed no discernable adenomas, whereas penetrance was 100% in controls. Furthermore, the adenomas harvested from Fibγ390-396A mice were significantly smaller than those from control mice and less proliferative based on quantitative analyses of mitotic indices, suggesting an additional role for fibrin(ogen) in the growth of established adenomas. These studies demonstrate, for the first time, a unique link between fibrin(ogen) and the development of inflammation-driven malignancy. Given the importance of antecedent inflammation in the progression of numerous cancers, these studies suggest that therapies targeting fibrin(ogen)-αMβ2 interactions may be useful in preventing and/or treating this important subset of malignancies.

Factor XIII transglutaminase supports hematogenous tumor cell metastasis through a mechanism dependent on natural killer cell function. J Thromb Haemost 2008; 6: 812-9.Summary. Background: Multiple studies suggest that the hemostatic and innate immune systems functionally cooperate in establishing the fraction of tumor cells that successfully form metastases. In particular, platelets and fibrinogen have been shown to support metastatic potential through a mechanism coupled to natural killer (NK) cell function. As the transglutaminase that ultimately stabilizes platelet/fibrin thrombi through the covalent crosslinking of fibrin, factor (F) XIII is another thrombin substrate that is likely to support hematogenous metastasis. Objective: Directly define the role of FXIII in tumor growth, tumor stroma formation, and metastasis. Methods: Tumor growth and metastatic potential were quantitatively and qualitatively evaluated in wild-type mice and gene-targeted mice lacking the catalytic FXIII-A subunit. Results: Loss of FXIIIa function significantly diminished hematogenous metastatic potential in both experimental and spontaneous metastasis assays in immunocompetent mice. However, FXIII was not required for the growth of established tumors or tumor stroma formation. Rather, detailed analyses of the early fate of circulating tumor cells revealed that FXIII supports the early survival of micrometastases by a mechanism linked to NK cell function. Conclusions: Factor XIII is a significant determinant of metastatic potential and supports metastasis by impeding NK cell-mediated clearance of tumor cells. Given that these findings parallel previous observations in fibrinogen-deficient mice, an attractive hypothesis is that FXIIImediated stabilization of fibrin/platelet thrombi associated with newly formed micrometastases increases the fraction of tumor cells capable of evading NK cell-mediated lysis.

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