Bone marrow stromal cells enhance prostate cancer cell invasion through type I collagen in an MMP-12 dependent manner

At the cellular level, the process of bone metastasis involves many steps. Circulating cancer cells enter the marrow, proliferate, induce neovascularization, and ultimately expand into a clinically detectable, often symptomatic, metastatic deposit. Although the initial establishment and later expansion of the metastatic deposit in bone require tumor cells to possess invasive capability, the exact proteases responsible for this phenotype are not well known. The objective of our study was to take an unbiased approach to determine which proteases were expressed and functional during the initial interactions between prostate cancer cells and bone marrow stromal (BMS) cells. We found that the combination of human prostate cancer PC3 and BMS cells stimulates the invasive ability of cancer cells through type I collagen. The use of inhibitors for each of the major protease families indicated that 1 or more MMPs was responsible for the BMS-induced invasion. Gene profiling and semiquantitative RT-PCR analysis revealed an increased expression of several MMP genes because of PC3/BMS cell interaction. However, only MMP-12 showed an increase in protein expression. Down-regulation of MMP-12 expression in PC3 cells by siRNA inhibited the enhanced invasion induced by PC3/BMS cell interaction. In vivo, MMP-12 was found to be primarily expressed by prostate cancer cells growing in bone. Our data suggest that BMS cells induce MMP-12 expression in prostate cancer cells, which results in invasive cells capable of degradation of type I collagen.