title: Membrane type 1-matrix metalloproteinase promotes human prostate cancer invasion and metastasis.
abstract: 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 1-matrix metalloproteinase (MT1-MMP) has been linked with these processes. Expression of MT1-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 MT1-MMP in prostate cancer dissemination, endogenous and recombinant MT1-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 MT1-MMP and Green Fluorescent Protein (MT1-GFP) degraded Matrigel and readily migrated over degraded substrates. The degradation of Matrigel by LNCaP cells expressing MT1-GFP was sensitive to MMP inhibitors, CT-1746 and TIMP-2, but not TIMP-1. Cell migration was dramatically enhanced by expression of MT1-MMP. By employing surgical orthotopic implantation of LNCaP cells stably expressing MT1-GFP into the prostate gland of immunodeficient mice, we demonstrated that MT1-MMP promotes lymph node and lung metastasis of prostate cancer cells. Together, these results emphasize the pivotal role of MT1-MMP in prostate cancer dissemination and confirm that MT1-MMP is a suitable target to prevent cancer metastasis.
authors.affiliation: Department of Medicine, State University of New York, Stony Brook, NY 11794-5200, USA. jian.cao@sunysb.edu
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
authors.forename: Christian
authors.initials: C
authors.lastname: Chiarelli
authors.forename: Pallavi
authors.initials: P
authors.lastname: Kozarekar
authors.forename: Howard L
authors.initials: HL
authors.lastname: Adler
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D053511:Matrix Metalloproteinase 14; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000473:pathology*; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000209:etiology / Q000473:pathology*; D014162:Transfection
chemical_list: C507096:Mmp14 protein, mouse; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D053511:Matrix Metalloproteinase 14