Effects of Modification in the Laminin-10 Basal Lamina on Prostate Cancer Invasion

摘要

In order for prostate cancer to metastasize it must invade through a laminin-511 rich barrier. We have previously shown that the matrix metalloprotease MTI-MMP which is expressed in prostate cancer but not in normal prostate tissue cleaves the laminin alpha-5 chain into four distinct fragments. This cleavage allows for increased prostate cancer cell migration in vitro. Laminin-511 cleavage also occurs in vivo in human prostate tissue. Cleavage of laminin-511 and release of laminin-511 fragments leads to altered cell function leading to increased cell migration and invasion in in vitro assays. We have demonstrated that prostate cancer cells treated with laminin-511 that has been cleaved by MTI-MMP have increased EGFR phosphorylation compared with cells grown on tissue culture plastic or intact laminin-511 in a Western blot. We have purified a recombinant 45kDa laminin-511 N-terminal cleavage fragment which contains laminin EGF like domains. Treatment of prostate cancer cells with soluble recombinant fragment demonstrates that the cleaved laminin fragment acts as a trikine activating the EGFR on prostate cancer cells in a Western blot. This work demonstrates that increased MTI-MMP expression in prostate cancer not only cleaves the major laminin surrounding prostate cancer to clear a path for migration, but also releases active fragments from the laminin-511 that signal for increased migration.