Soluble fibrin augments platelet/tumor cell adherence in vitro and in vivo, and enhances experimental metastasis

There is considerable evidence for a relationship between hemostasis and ma lignancy. Since platelet adhesion to tumor cells has been implicated in the metastatic process and plasma levels of fibrinogen (Fg) and soluble fibrin (sFn) monomer are increased in cancer, we hypothesized that these molecule s might enhance tumor-platelet interaction. We therefore studied binding of sFn monomer to tumor cells in a static microplate adhesion assay and deter mined the effect of pre-treating tumor cells with sFn on tumor cell-induced thrombocytopenia and experimental metastasis. Soluble fibrin (produced by adding thrombin to FXIII- and plasminogen-free Fg in the presence of Gly-Pr o-Arg-Pro-amide (GPRP-NH2) significantly increased platelet adherence to tu mor cells. This effect was primarily mediated by the integrins alpha IIb be ta 3 on the platelet and CD 54 (ICAM-1) on the tumor cells. Platelets adher ed to untreated A375 cells (28 +/- 8 platelets/tumor cell) and this was not significantly affected by pre-treatment of the tumor cells with fibrinogen or GPRP-NH2. Although thrombin treatment increased adherence, pre-incubati on of the tumor cells with sFn resulted in a further increase in platelet b inding to tumor cells. In contrast to untreated tumor cells, intravenous in jection of sFn-treated A 375 cells reduced the platelet count in anticoagul ated mice, supporting the in vitro finding that sFn enhanced tumor cell-pla telet adherence. In a more aggressive model of experimental metastasis, tre ating tumor cells with sFn enhanced lung seeding by 65% compared to untreat ed cells. Extrapolation of our data to the clinical situation suggests that coagulation activation, and subsequent increase in circulating Fn monomer, may enhance platelet adhesion to circulating tumor cells and thereby facil itate metastatic spread.