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

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.

• Publication year

  2020

• Venue

  bioRxiv

• Publication date

  2020-01-26

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1101/2020.01.25.919795
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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  1998cited by this paper
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  1997cited by this paper
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  1992cited by this paper
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