Infliximab Inhibits Colitis Associated Cancer in Model Mice by Downregulating Genes Associated with Mast Cells and Decreasing Their Accumulation

Inflammatory bowel diseases (IBDs), such as Crohn's disease or ulcerative colitis, can be treated with anti TNF-alpha (TNF-a) antibodies (Abs), but they also put patients with IBDs at risk of cancer. We aimed to determine whether the anti TNF-a Ab induces colon cancer development in vitro and in vivo, and to identify the genes involved in colitis-associated cancer. We found that TNF-a (50 ng/mL) inhibited the proliferation, migration, and invasion of HCT8 and COLO205 colon cancer cell lines and that anti TNF-a Ab neutralized TNF-a inhibition in vitro. The effects of anti TNF-a Ab, infliximab (10 mg/kg) were investigated in mouse models of colitis-associated cancer induced by intraperitoneally injected azoxymethane (AOM: 10 mg/kg)/orally administered dextran sodium sulfate (DSS: 2.5%) (AOM/DSS) in vivo. Infliximab significantly attenuated the development of colon cancer in these mice. Microarray analyses and RT-qPCR revealed that mast cell protease 1, mast cell protease 2, and chymase 1 were up-regulated in cancer tissue of AOM/DSS mice; however, those mast cell related genes were downregulated in cancer tissue of AOM/DSS mice with infliximab. These results suggested that mast cells play a pivotal role in the development of cancer associated with colitis in AOM/DSS mice.

Automated summary

This study aimed to investigate the potential of anti TNF-alpha antibodies (Abs) in inducing colon cancer development and identify the genes involved in colitis-associated cancer. The results showed that TNF-a inhibited the proliferation, migration, and invasion of colon cancer cell lines, and the neutralization of TNF-a by anti TNF-a Abs was observed in vitro. In a mouse model of colitis-associated cancer, treatment with infliximab, an anti TNF-a Ab, significantly reduced the development of colon cancer. Furthermore, gene analysis revealed the role of mast cells in the development of cancer associated with colitis.