Effect of Fibrin Inhibitory Peptides on Tumor Growth, Metastasis and Angiogenesis

Abstract

Fibrin polymer and soluble fibrin inhibit cellular immunity against melanoma cells in vitro via blockade of tumor CD54/Mac-1 binding, which is reversed by specific fibrin inhibitory peptides (FIP). It was hypothesized that FIP treatment in vivo would enhance the anti-tumor immune response in cancer. To test this, we examined the effect of FIP on tumor growth and metastasis in a syngeneic murine primary tumor and metastasis model. C57BL/6 mice were subcutaneously (primary) or intravenously (metastasis) inoculated with GFP expressing B16 melanoma cells followed by subcutaneous FIP or vehicle every 48 h for 15 days. Mice were euthanized and primary tumor size was measured in both groups. Primary tumors and lungs (metastasis) were excised, cryosectioned and microscopically examined for primary tumor microvessel density (von Willebrand's factor), lung metastases (GFP) and leukocyte infiltration (H&E staining). FIP treatment decreased primary tumor size by 69.2% (0.77 + 0.7 cm3) compared to controls (2.51 + 1.46 cm3, P<0.01), microvessel density was inhibited by 75.9 + 15.1% (P<0.05), and lung metastasis by 47.9 + 26.6% (p<0.01). Conversely, leukocyte infiltration was increased by 11.02 + 1.05% (P<0.05). These results show that FIP reduce tumor growth, metastasis and angiogenesis in vivo, and increase leukocyte infiltration suggesting their potential use as adjuvant therapeutic agents in cancer immunotherapy.