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Fibrinogen is a determinant of spontaneous metastasis


, : Fibrinogen is a determinant of spontaneous metastasis. Pediatric Research 49(4 Part 2): 182A, April

Cancer studies in gene-targeted mice with selective deficits in hemostatic factors showed that fibrin(ogen) is an important determinant of hematogenous tumor cell metastasis. Although the mechanistic details remain to be defined, initial studies point to an importance of fibrin(ogen) in the sustained adherence and/or survival of individual embolic tumor cells in the lungs. In this study, we have examined the role of fibrinogen in primary tumor growth, tumor angiogenesis and spontaneous metastasis. Lewis lung carcinoma (LLC) cells were transplanted into the skin of histocompatible C57BL/6 inbred Fib-/- mice and controls. The tumors that formed were monitored for growth and were subsequently eliminated either by surgical resection or focal electron beam radiotherapy (6500 cGy) when they reached approximately 400 mg in size. Thirteen days later the mice were sacrificed and surface pulmonary metastases and regional lymph node metastases were quantitated. Fibrinogen-deficiency resulted in a significant diminution in spontaneous pulmonary metastases regardless of the means used to eliminate the primary tumor. In studies in which the primary tumors were removed surgically, the median number of pulmonary metastatic foci observed in control animals was 29 (n=20) as compared to 3 in Fib-/- animals (n=15) (P<0.01). A similar pattern was observed in mice in which the primary tumors were treated with irradiation. Specifically, a median of 9 metastases was observed in control mice (n=14), whereas a median of 1 (n=11) was observed in Fib-/- mice (P<0.001). Fibrinogen-deficient mice also demonstrated a significant diminution in lymphatic metastases. Lymphatic spread was apparent macroscopically in 12 of 20 (60%) control animals compared to only 3 of 15 (20%) Fib-/- animals (P<0.02). Metastases to other organs were noted on occasion, but these were too rare to make a meaningful comparison between genotypes. In order to examine the impact of fibrinogen on metastatic progression at an earlier phase and without the experimental manipulation of eliminating the primary tumor, green fluorescent protein (GFP)-expressing LLC cells were transplanted and pulmonary micrometastatic foci were counted using a fluorescence-equipped stereo microscope. Consistent with earlier findings, the median number of micrometastatic foci per high-powered field was 32 for control animals (n=15) versus 10 for Fib-/- animals (n=14) (P<0.03). No genotype-dependent differences were noted in the rate of primary tumor growth; suggesting that fibrinogen does not play an essential role in tumor stroma formation or tumor angiogenesis. Consistent with this view, microscopic analysis of tumor tissue sections revealed a typical network of supporting vasculature in tumors generated in animals of both genotypes. Quantitative analyses of tumor sections with immunohistochemically stained vessels showed no difference in vascular density between genotypes. In summary, these data directly demonstrate that fibrinogen is an important determinant of spontaneous metastasis, including both hematogenous and lymphatic. The development of a detailed understanding of the mechanism(s) by which hemostatic factors influence metastatic potential may suggest valuable therapeutic strategies for controlling metastatic disease.

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