a selective matriptase inhibitor blocks tumor growth and metastasis while displaying potent antiangiogenic activity in an orthotopic murine renal cell cancer model

A Selective Matriptase Inhibitor Blocks Tumor Growth and Metastasis While Displaying Potent Antiangiogenic Activity in an Orthotopic Murine Renal Cell Abstract Matriptase, a type II transmembrane serine protease, is expressed by cells of surface epithelial origin and involved in the progression of various cancers. Previously, significant immune histochemical expression of matriptase in subtypes of RCC with no expression in areas of RCC with sarcomatous differentiation and normal collecting tubules was reported. In this study, we tested if matriptase inhibition can impact primary tumor growth and invasive potential in a model of renal cancer. Initially, the impact of selective matriptase inhibitor compound-15 was evaluated on a murine renal carcinoma cell line in vitro . Results indicated a dose-dependent inhibition of Renca cell proliferation only when cells were cultured in a matrix-independent manner as well as in migration and invasion. In the orthotopic Renca kidney cancer model, compound-15 treatment resulted in dose-dependent inhibition of primary tumor growth and metastasis, which correlated well with inhibition of angiogenesis. An additive effect on tumor growth and metastasis was observed when compound-15 at 0.5 mg/kg was combined with sorafenib, a kinase inhibitor, at 10 mg/kg. Preclinical evidence presented here provides a rationale for inhibition of matriptase with or without sorafenib as a therapeutic modality in renal cancer.