Detailed studies of
tumor cell-associated procoagulants and fibrinolytic factors have implied that local
thrombin generation and
fibrin deposition and dissolution may be important in
tumor growth and dissemination. To directly determine whether
fibrin(
ogen) or
plasmin(
ogen) are determinants of the metastatic potential of
circulating tumor cells, this study examined the impact of genetic deficits in each of these key
hemostatic factors on the hematogenous pulmonary
metastasis of 2 established murine
tumors,
Lewis lung carcinoma and the B16-BL6
melanoma. In both
tumor models,
fibrinogen deficiency strongly diminished, but did not prevent, the development of lung
metastasis. The quantitative reduction in
metastasis in
fibrinogen-deficient mice was not due to any appreciable difference in
tumor stroma formation or
tumor growth. Rather,
tumor cell fate studies indicated an important role for
fibrin(
ogen) in sustained adhesion and survival of
tumor cells within the lung. The specific
thrombin inhibitor,
hirudin, further diminished the metastatic potential of
circulating tumor cells in
fibrinogen-deficient mice, although the inhibitor had no apparent effect on
tumor cell proliferation in vitro. The absence of
plasminogen and
plasmin-mediated fibrinolysis had no significant impact on hematogenous
metastasis. The authors concluded that
fibrin(
ogen) is a critical determinant of the metastatic potential of
circulating tumor cells. Furthermore,
thrombin appears to facilitate
tumor dissemination through at least one
fibrin(
ogen)-independent mechanism. These findings suggest that therapeutic strategies focusing on multiple distinct
hemostatic factors might be beneficial in the containment of
tumor metastasis.