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 stromal in origin, implicating monocytes (M phi s) and fibroblasts. We hypothesize that CRC cells induce stromal cell MMP production. This study examines the differential effect of metastatic and non-metastatic CRC cells on M phi MMP production. The human M phi line THP-1 was co-cultured with either a non-metastatic human CRC cell line (SW620-P) or a metastatic clone (SW620-S5) 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-1 M phi 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 phi s with the metastatic SW620-S5 clone, but decreased by the non-metastatic SW620-P cells. MMP-2 activity was greatly augmented by co-culturing M phi s with SW620-S5 cells, but was not affected by SW620-P cells. The stimulatory effect of SW620-S5 cells on MMP-2 secretion was confirmed by Western blot analysis. Both isolated and co-cultured M phi s expressed MMP-2 mRNA while SW620-S5 cells under similar conditions did not, implicating M phi s as the source of increased MMP-2 activity. Since the induction of MMP-2 activity was not associated with a parallel increase in M phi MMP-2 mRNA, the modulation of M phi MMP-2 release appears to be post-transcriptionally regulated. Metastatic CRC cells are distinct from non-metastatic cells in their ability to induce M phi MMP release. This observation emphasizes the role of M phi-derived MMPs in facilitating CRC invasion and metastasis and suggests modulation of stromal cell MMP production by CRC cells in a paracrine fashion.