Differential regulation of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 expression in co-cultures of prostate cancer and stromal cells

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Abstract
Tumor–stromal interactions have been suggested to be a critical factor in both tumor invasion and tumor metastasis. Here, we examined the role of tumor–stromal interactions using co‐cultures of prostate cancer (PC) cells derived from primary and metastatic tumors with primary or immortalized stromal (fibroblast and smooth muscle) cells and their effect on matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) expression. Co‐cultures of PC and stromal cells showed enhanced levels of pro‐MMP‐9 and reduced levels of TIMP‐1 and TIMP‐2. Whereas enhanced expression of pro‐MMP‐9 occurred in PC cells, the TIMPs were down‐regulated in stromal cells. Induction of pro‐MMP‐9 and reduction of TIMP expression did not require cell–cell contact and were mediated by a soluble factor(s) present in the conditioned medium of the effector cell. Collagen I is a potent inducer of pro‐MMP‐9 in PC cells. Consistently, preliminary characterization of the soluble factor in the fibroblast conditioned medium revealed m.w. of approximately 100 to 250 kDa, and its effect on pro‐MMP‐9 expression was partly inhibited by an anti‐α2 integrin antibody, a major collagen I receptor. Expression of pro‐MMP‐9 protein and mRNA was also induced in metastatic PC‐3 cells grown in human fetal bone implants in SCID mice. Together, these findings demonstrate the importance of tumor–stromal interactions in the regulation of MMP and TIMP expression and their potential role in PC progression.