Mechanisms Linking Hemostatic Factors to Tumor Growth in Mice

Abstract

A persuasive link between hemostatic factors and cancer has been developed through extensive studies of both human and animal malignancies. Coagulation-, platelet- and fibrinolytic-factors all have been tightly associatedwith tumor growth and/or dissemination. Nevertheless, the mechanisms by which these factors influence tumor growth and progression remain to be fully defined. Recent studies of mice with selected deficits in hemostatic factors have generally supported the hypothesis that hemostatic factors contribute significantly to tumor biology. However, the findings with gene-targeted mice have often been unexpected or tumor model-dependent. Particularly enigmatic was the dual finding that neither fibrin(ogen) nor plasmin(ogen) were significant determinants of Lewis lung carcinoma (LLC) or T241 fibrosarcoma tumor growth following transplantation into the dorsal subcutis of immune-compatible mice. However, follow up studies have revealed that tumor growth is critically dependent on plasminogen when LLC and T241 tumors cells are transplanted to another anatomical location, the footpad. Furthermore, the negative impact of plasminogen deficiency on footpad tumor growth was effectively relieved by genetically superimposing a deficit in fibrinogen. The likely mechanistic basis for the suppression of tumor growth in plasminogen-deficient mice was revealed through transmission electron microscopy studies of tumor tissues. Widespread microvascular thrombi were found within footpad tumors of plasminogen-deficient mice, whereas no such lesions were observed within tumors from mice that also lacked fibrinogen. These occlusive events were shown to result in a substantial lengthening of tumor cell doubling time in vivo, but increased tumor cell dropout is also likely to contribute to the diminution of footpad tumor growth in plasminogen-deficient mice. Taken together, these studies show that both plasminogen and fibrinogen can serve as critical determinants of tumor growth, but their importance is dependent on anatomical location/microenvironment. Furthermore, one target of plasmin(ogen) relevant to tumor success in vivo is intravascular fibrin.