Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells

Detailed studies of tumor cell-associated procoagulants and fibrinolytic fa ctors have implied that local thrombin generation and fibrin deposition and dissolution may be important in tumor growth and dissemination. To directl y determine whether fibrin(ogen) or plasmin(ogen) are determinants of the m etastatic potential of circulating tumor cells, this study examined the imp act of genetic deficits in each of these key hemostatic factors on the hema togenous pulmonary metastasis of 2 established murine tumors, Lewis lung ca rcinoma and the B16-BL6 melanoma, In both tumor models, fibrinogen deficien cy strongly diminished, but did not prevent, the development of lung metast asis, The quantitative reduction in metastasis in fibrinogen-deficient mice was not due to any appreciable difference in tumor stroma formation or tum or growth. Rather, tumor cell fate studies indicated an important role for fibrin(ogen) in sustained adhesion and survival of tumor cells within the l ung, The specific thrombin inhibitor, hirudin, further diminished the metas tatic potential of circulating tumor cells in fibrinogen-deficient mice, al though 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 f ibrin(ogen) is a critical determinant of the metastatic potential of circul ating tumor cells. Furthermore, thrombin appears to facilitate tumor dissem ination through at least one fibrin(ogen)-independent mechanism. These find ings suggest that therapeutic strategies focusing on multiple distinct hemo static factors might be beneficial in the containment of tumor metastasis. (C) 2000 by The American Society of Hematology.