Patients with inflammatory bowel diseases often develop colon carcinoma. Combined
treatment of azoxymethane (AOM) and dextran sulfate sodium (DSS) recapitulates
colitis-associated cancer in mice. AOM/DSS-induced tumor formation was reduced in
CCL3- or its specific receptor, CCR5-deficient mice despite the presence of a massive
infiltration of inflammatory cells. However, AOM/DSS-induced type I collagen-positive
fibroblast accumulation in the colon was reduced in CCL3- or CCR5-deficient mice. This
was associated with depressed expression of heparin-binding epidermal growth factor-like
growth factor (HB-EGF), which is expressed mainly by fibroblasts. Moreover in vitro,
CCL3 induced fibroblasts to proliferate and to enhance HB-EGF expression. Furthermore,
CCR5 blockade reduced tumor formation together with reduced fibroblast accumulation
and HB-EGF expression, even when administered after the development of multiple colon
tumors. Thus, CCL3-CCR5-mediated fibroblast accumulation may be required, in addition
to leukocyte infiltration, to induce full-blown colitis-associated carcinogenesis. Our studies
shed light on a therapeutic potential of CCR5 antagonist for patients with colitis-associated
cancer.