Membrane type I-matrix metalloproteinase promotes human prostate cancer invasion and metastasis

Development of metastases requires cancer cells to breach underlying basement membrane, migrate through interstitial stroma and gain access to blood or lymphatic vessels. Membrane type I-matrix metalloproteinase (MTI-MMP) has been linked with these processes. Expression of MTI-MMP in human prostate cancer correlates with the stage of this disseminated disease. The mechanism underlying this observation, however, still remains to be understood. To study the role of MTI-MMP in prostate cancer dissemination, endogenous and recombinant MTI-MMP expressed in human prostate cancer cell lines (DU-145 and LNCaP) were examined. Using FITC-labeled Matrigel, a soluble basement membrane extract coated coverslips, LNCaP cells stably expressing a chimera of MTI-MMP and Green Fluorescent Protein (MTI-GFP) degraded Matrigel and readily migrated over degraded substrates. The degradation of Matrigel by LNCaP cells expressing MTI-GFP was sensitive to MMP inhibitors, CT-1746 and TIMP-2, but notTIMP-1. Cell migration was dramatically enhanced by expression of MTI-MMR By employing surgical orthotopic implantation of LNCaP cells stably expressing MTI-GFP into the prostate gland of immunodeficient mice, we demonstrated that MTl-MMP promotes lymph node and lung metastasis of prostate cancer cells. Together, these results emphasize the pivotal role of MTI-MMP in prostate cancer dissemination and confirm that MTI-MMP is a suitable target to prevent cancer metastasis.