Rationale: Extracellular matrix (ECM) remodeling plays an important role in cancer development. Heparanase is an endo-Β-glycosidase that degrades the ECM heparan sulfate (HS), thereby enhancing tumor invasion and metastasis. Low molecular weight heparin (LMWH) is a highly sulfated analogue of HS, known to improve survival in patients with locally advanced or metastatic cancer, independently of its anti-coagulatory function. LMWH was shown to reduce metastasis in many murine models by multiple mechanisms, however, its effects on heparanase promoting tumor progression is not well described. As the treatment options in primary and metastatic cancer are still limited, low molecular weight heparin might be an interesting addition to the existing systemic anti-tumoral therapies.

Aim: To investigate the anti-metastatic role of LMWH and its impact on the heparanase expression and function. To accomplish this role, we investigate the capacity of enoxaparin, a LMWH frequently used in a clinical setting, to inhibit heparanase expression and function in a metastatic murine model of colon carcinomas cells.

Methods:

To determine the ability of enoxaparin to attenuate metastasis via targeting heparanase, we developed a reproducible murine model of hepatic metastatic cancer by transplanting colon carcinoma cells in mice portal vein. Mice were subjected or not (PBS treated group) to i.v injection of enoxaparin (200 ug/ml), 4 hours before tumor cell injection, followed by daily doses for 8 days. The effects of enoxaparin on tumor cells producing heparanase and other cytokines were assessed in vivo and in vitro.

Results and conclusion:

A marked reduction of hepatic tumor volume was noted in mice receiving enoxaparin compared to PBS treated mice. Enoxaparin effectively attenuated metastasis of MCA38. Our study supports the ability of enoxaparin to inhibit heparanase activity and contributes to impede metastasis progression. By studding cell cycle we demonstrate that enoxaparin interfere with the G1/S checkpoint of the cell cycle. Finally, there is an inhibitory effect of enoxaparin on CXCL9 and CXCL10 expression in mice livers. These data strongly suggest that enoxaparin primarily reduces metastatic disease by inhibiting heparanase function and activity and might be an interesting immune-modulatory molecule in metastatic cancer model.

« Back to 2013 American Transplant Congress