Tumor cells can stimulate matrix metalloproteinase (MMP) production by stromal cells through cell-cell interactions mediated by cell adhesion molecules such as extracellular matrix metalloproteinase inducer (human CD147/EMMPRIN, mouse CD147/Basigin). This study sought to characterize whether specific tumor-stromal cell interactions mediated by CD147 promote colon cancer growth by utilizing small interfering (si)RNAs directed against human CD147/EMMPRIN or mouse CD147/Basigin in co-cultures of cancer cells with macrophages and fibroblasts and established human SW620 colon cancer xenograft models in immune deficient mice. We show that blockade of host (mouse) CD147/Basigin expression, but not cancer cell-derived CD147/EMMPRIN, suppresses tumor growth in human colon cancer xenografts. Experiments in vitro indicated that colon cancer cell-stromal cell interactions mediated by CD147 lead to increased MMP-2 expression in fibroblasts but not macrophages. Furthermore, expression of host VEGF-A in both fibroblasts and macrophages is independent of CD147 in vitro and in vivo. Interestingly, inhibition of cancer cell-derived EMMPRIN leads to increased MMP-9 levels in vivo. Our findings provide new insights into CD147-mediated tumor-host interactions mediating colon cancer growth.