Interleukin-11 is a Marker for Both Cancer- and Inflammation-Associated Fibroblasts that Contribute to Colorectal Cancer Progression

SUMMARY

Interleukin (IL)-11 is a member of the IL-6 family of cytokines and involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11⁺) cells are not fully understood. To characterize IL-11⁺ cells in vivo, we generated Il11 reporter mice. IL-11⁺ cells appeared in the colon of three murine tumor models, and a murine acute colitis model. Il11ra1 or Il11 deletion attenuated the development of colitis-associated colorectal cancer. IL-11⁺ cells expressed fibroblast markers, and genes associated with cell proliferation and tissue repair. IL-11 induced STAT3 phosphorylation in colonic fibroblasts, suggesting the activation of IL-11⁺ fibroblasts. Analysis using the human cancer database revealed that genes enriched in IL-11⁺ fibroblasts were elevated in human colorectal cancer, and correlated with reduced disease-free survival. Together, our results suggested that tumor cells induced IL-11⁺ fibroblasts, and that a feed-forward loop between IL-11 and IL-11⁺ fibroblasts might contribute to tumor development.