Matrix metalloproteinases (MMPs) foster cellular invasion by disrupting extracellular matrix barriers and thereby facilitate tumor development. MMPs are synthesized by both cancer cells and adjacent stromal cells, primarily macrophages. The production of macrophages is regulated by colony-stimulating factor-1 (CSF-1). Tissue CSF-1 expression increased significantly in embryonic and colon cancer xenografts. We, therefore, hypothesized that blocking CSF-1 may suppress tumor growth by decelerating macrophage-mediated extracellular matrix breakdown. Cells expressing CSF-1 and mice xenografted with CSF-1 receptor (c-fms)- and CSF-1-negative malignant human embryonic or colon cancer cells were treated with mouse CSF-1 antisense oligonucleotides. Two weeks of CSF-1 antisense treatment selectively down-regulated CSF-1 mRNA and protein tissue expression in tumor lysates. CSF-1 blockade suppressed the growth of embryonic tumors to dormant levels and the growth of the colon carcinoma by 50%. In addition, tumor vascularity and the expression of MMP-2 and angiogenic factors were reduced. Six-month survival was observed in colon carcinoma mice only after CSF-1 blockade, whereas controls were all dead at day 65. These results suggest that human embryonic and colon cancer cells up-regulate host CSF-1 and MMP-2 expression. Because the cancer cells used were CSF-1 negative, CSF-1 antisense targeted tumor stromal cell CSF-1 production. CSF-1 blockade could be a novel strategy in treatment of solid tumors.