Soluble fibrin inhibits monocyte adherence and cytotoxicity against tumor cells: implications for cancer metastasis

The role of sFn in monocyte adherence and cytotoxicity against tumor cells was initially studied using static microplate adherence and cytotoxicity assays, and under physiologically relevant flow conditions in a microscope perfusion incubator system. Blocking studies were performed using monoclonal antibodies specific for β2 integrins and CD54, and specific peptides which inhibit sFn binding to these receptors.Enhancement of monocyte/tumor cell adherence was observed when only one cell type was bound to sFn, but profound inhibition was observed when sFn was bound to both monocytes and tumor cells. This effect was also reflected in the pattern of monocyte cytotoxicity. Studies using monoclonal blocking antibodies and specific blocking peptides (which did not affect normal coagulation) showed that the predominant mechanism of fibrin inhibition is via its binding to αMβ2 on monocytes, and to CD54 on both leukocytes and tumor cells.sFn inhibits monocyte adherence and cytotoxicity of tumor cells by blocking αLβ2 and αMβ2 binding to tumor cell CD54. These results demonstrate that sFn is immunosuppressive and may be directly involved in the etiology of metastasis. Use of specific peptides also inhibited this effect without affecting coagulation, suggesting their possible use as novel therapeutic agents in cancer metastasis.A relationship between cancer and abnormalities of the coagulation system has been recognized for over 100 years [1]. Thromboembolic disease (usually of unknown etiology), refractory to anticoagulant therapy, may be an early detectable sign of an underlying cancer, which could precede the onset of observable cancer by months or years. Although many cancer patients exhibit clinically significant hemostatic abnormalities, about 50% of all patients (>90% with metastases) have abnormal laboratory coagulation parameters [1], including soluble fibrin (sFn) [2-4], which may also be an early marker undiagnosed malignancy [5]. The presence of sFn in blood has, un