Spectrum of matrix metalloproteinase expression in primary and metastatic colon cancer: relationship to the tissue inhibitors of metalloproteinases and membrane type-1-matrix metalloproteinase

The matrix metalloproteinases, MMP-2 and MMP-9, are capable of degrading co mponents of the basement membrane, a vital barrier breached during the prog ression of colorectal cancer. The regulation of MMP-2 activation and subseq uent targets is vital to understanding the metastatic process. MMP-2 was no t expressed by colorectal cancer cells (C170 and C170HM(2)) in vitro but by stromal fibroblasts (46BR.1GI). There was induction of this MMP upon trans well co-cultivation of the colon cancer cells with the fibroblasts but in v ivo growth did not lead to a similar increase in the metastatic tumour cell s (C170HM(2)), MMP-2 again being attributed to the stromal cells. MMP-2 mRN A was overexpressed in human colorectal tumours compared to normal colorect al tissue, which correlated with Dukes' stage and immunolocalized to the st romal compartment of the tumour tissue. The active form of the MMP-2 enzyme was also present in the colorectal tumour tissue (7/8) but essentially abs ent in all normal colon samples examined (1/8). MMP-2 activation was not re lated to an increase in MT-1-MMP mRNA or a decrease in the specific inhibit or TIMP-2 in human tissue. There was however an increase in MMP-2/TIMP-2 ra tio in tumour compared to normal. MMP-9, a target of active MMP-2, was pres ent in the metastatic cell line but expression was down-regulated in the tu mour cells in vivo, gelatin analysis revealed that MMP-9 was almost entirel y attributable to the murine host, confirmed by PGR. There was no increase in mRNA for MMP-9 or its specific inhibitor TIMP-1 in colorectal tumour tis sue compared to normal, MMP-9 protein localized to the inflammatory infiltr ate Fibroblast cells may provide malignant epithelial cells with a ready so urce of enzyme which is crucial to the metastatic process. (C) 2001 Cancer Research Campaign.