Low molecular weight heparin suppresses tissue factor-mediated cancer cell invasion and migration in vitro

Abstract

Elevated expression of tissue factor (TF) has been associated with an increased risk of thrombosis in the majority of cancers. Moreover, treatment of cancer patients with low molecular weight heparin (LMWH) appears to have beneficial effects that reach beyond controlling the immediate hypercoagulable state. In this study, we investigated the influence of the treatment of cancer cells with LMWH (0-2,000 μg/ml) on cell invasiveness and migration in cancer cell lines from five separate tissues; pancreatic, breast, colocarcinoma, ovarian and melanoma. The rate of cell invasion across collagen IV-coated membranes was suppressed in all cell lines tested on incubation with 2,000 μg/ml LMWH, but BxPC-3 and MDA-MB-231 cells also responded to the lowest concentration of 20 μg/ml LMWH. Furthermore, the rate of cell migration was reduced to varying extents in all of the cell lines tested on incubation with 20 μg/ml or higher concentrations of LMWH. The decrease in the rates of invasion and migration also strongly correlated with the reduction in TF protein expression and TF activity in these cells following incubation with LMWH. Moreover, the LMWH-mediated decreases in cellular invasion in the most affected cell lines (BxPC-3 and MDA-MB-231) were restored by transfection of the cells with the mammalian pCMV-XL5-TF expression vector allowing independent overexpression of TF. In conclusion, LMWH appears to suppress the rate of cancer cell invasion and migration in vitro, through a mechanism that is at least in part dependent on the TF protein expression and activity in cancer cells.