Editors' ChoiceImmunology

Quenching the Fire Fueling Cancer in the Gut

See allHide authors and affiliations

Science Translational Medicine  07 Jan 2015:
Vol. 7, Issue 269, pp. 269ec5
DOI: 10.1126/scitranslmed.aaa3473

Chronic inflammation has now been linked with a number of diseases including colorectal cancer. Interleukin 17 (IL-17) is a potent inflammatory cytokine that is made by a variety of cell types. Retrospective clinical studies have demonstrated that high IL-17 expression in colorectal tumors is associated with progression to lethal metastatic cancer and is thus a strong indicator of poor clinical outcome. More recent studies have used a spontaneous colorectal tumor mouse model with a mutation in the APC gene (called APCmin)—a gene commonly mutated in human colorectal cancers—to show that gene ablation of IL-17 attenuates tumor growth. A recent study by Wang et al. sheds light on how IL-17 promotes cancer.

The IL-17 receptor is expressed by a large number of cells and is known to have multiple functions in promoting inflammatory responses; thus, it is important to clarify which cell(s) that respond to IL-17 promote cancer. Using a similar mouse model to APCmin, Wang et al. used a series of cell transfer experiments to demonstrate that transformed intestinal epithelial cells themselves respond to IL-17. Then they stimulated “organoids”—intestinal stem cells cultured in a dish to form 3D structures that resemble an intact intestine—with IL-17 and found that the IL-17 did not influence classical Wnt signaling but instead up-regulated NF-κB to promote proliferation, providing some insight into how IL-17 signaling can exacerbate tumor growth.

The authors then asked the more therapeutically relevant question of whether blocking IL-17 will prevent aberrant tumor growth. In the cancer mouse model, long-term treatment with secukinumab and ixekizumab—monoclonal antibodies that block IL-17 signaling currently in clinical trials for treating rheumatoid arthritis and psoriasis—could effectively reduce cellular proliferation and reduce tumor load. Chemotherapy actually induces IL-17 in the intestine, suggesting that chemotherapy might be more useful if IL-17 activity could be blocked. To test this, the authors employed a combination treatment consisting of chemotherapy and anti-IL-17 and found a significant reduction in both tumor size and load and a reduction in overall inflammation. Although this treatment has yet to reach the clinic, these results offer the exciting possibility that monoclonal antibodies that are already being tested in patients for other diseases could also be used to treat colorectal cancer and block the fire fueling gut cancer.

K. Wang et al., Interleukin-17 receptor A signaling in transformed enterocytes promotes early colorectal tumorigenesis. Immunity 41, 1052–1063 (2014). [Abstract]

Navigate This Article