Matrix metalloproteinases-2 (MMP-2) and -9 (MMP-9) facilitate tumor invasion and metastasis via basement membrane degradation. In colorectal cancer (CRC) specimens, MMP production is largely stromai in origin, implicating monocytes (M~bs) and fibroblasts. We hypothesize that CRC cells induce stromai cell MMP production. This study examines the differential effect of metastatic and non-metastatic CRC cells on M~ MMP production. The human M~b line THP-I was co-cultured with either a non-metastatic human CRC cell line (SW620-P) or a metastatic clone (SW620-$5) established by serial cecal transplantation of SW620-P in nude mice. Conditioned medium MMP activity and cellular MMP mRNA expression were assessed by gelatinase zymography and Northern blot analysis, respectively. Neither CRC line released MMP-2 or MMP-9. Isolated THP-I M~s produced basal levels of both MMP-2 and MMP-9. The level of MMP-9 activity was increased moderately by co-culture of M~bs with the metastatic SW620-$5 clone, but decreased by the non-metastatic SW620-P cells. MMP-2 activity was greatly augmented by co-culturing M~bs with SW620-$5 cells, but was not affected by SW620-P cells. The stimulatory effect of SW620-$5 cells on MMP-2 secretion was confirmed by Western blot analysis. Both isolated and co-cultured M~bs expressed MMP-2 mRNA while SW620-$5 cells under similar conditions did not, implicating M~bs as the source of increased MMP-2 activity. Since the induction of MMP-2 activity was not associated with a parallel increase in M~b MMP-2 mRNA, the modulation of M~b MMP-2 release appears to be post-transcriptionally regulated. Metastatic CRC cells are distinct from non-metastatic cells in their ability to induce M~b MMP release. This observation emphasizes the role of M~-derived MMPs in facilitating CRC invasion and metastasis and suggests modulation of stromal cell MMP production by CRC cells in a paracrine fashion.