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Blood, 1 July 2007, Vol. 110, No. 1, pp. 133-141.
Prepublished online as a Blood First Edition Paper on March 19, 2007; DOI 10.1182/blood-2007-01-065995.
 Previous Article | Next Article 
Submitted January 3, 2007
Accepted February 24, 2007
Tumor cell-associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-dependent and -independent mechanisms
Joseph S Palumbo, Kathryn E Talmage, Jessica V Massari, Christine M La Jeunesse, Matthew J Flick, Keith W Kombrinck, Zhiwei Hu, Kelley A Barney, and Jay L Degen*
Division of Hematology/Oncology, Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, OH, United States
Division of Developmental Biology, Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, OH, United States
Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, United States
* Corresponding author; email: degenjl{at}cchmc.org.
Tumor cell-associated tissue factor (TF) is a powerful determinant of metastatic potential. TF may increase metastasis by supporting thrombin-mediated proteolysis, through intracellular signaling events mediated by the TF cytoplasmic domain, through TF/fVIIa/fXa-mediated activation of protease-activated receptors, or through a combination of these processes. To better define the relationship between tumor cell-associated TF and circulating hemostatic factors in malignancy, we generated a set of C57Bl/6-derived tumor lines genetically lacking TF, expressing wildtype murine TF, or expressing a mutant TF lacking the cytoplasmic domain. Comparison of the metastatic potential of these cells in immunocompetent mice with genetic deficits in prothrombin, platelet function and fibrinogen revealed that TF supports metastasis through mechanisms independent of the cytoplasmic domain, but dependent on each of these distal hemostatic factors. TF was neither required for primary tumor growth nor necessary for initial localization of embolized tumor cells within the lungs. Rather, tumor cell fate studies indicated TF supports metastasis by increasing the survival of micrometastases. One mechanism linking TF to metastasis is through a fibrin(ogen)- and platelet-dependent restriction in natural killer (NK) cell-mediated clearance of micrometastases. However, TF also supported the early success of micrometastases through an additional mechanism independent of NK cells, but coupled to circulating prothrombin.
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