Interleukin-11 Is the Dominant IL-6 Family Cytokine during Gastrointestinal Tumorigenesis and Can Be Targeted Therapeutically

Among the cytokines linked to inflammation-associated cancer, interleukin (IL)-6 drives many of the cancer “hallmarks” through downstream activation of the gp130/STAT3 signaling pathway. However, we show that the related cytokine IL-11 has a stronger correlation with elevated STAT3 activation in human gastrointestinal cancers. Using genetic mouse models, we reveal that IL-11 has a more prominent role compared to IL-6 during the progression of sporadic and inflammation-associated colon and gastric cancers. Accordingly, in these models and in human tumor cell line xenograft models, pharmacologic inhibition of IL-11 signaling alleviated STAT3 activation, suppressed tumor cell proliferation, and reduced the invasive capacity and growth of tumors. Our results identify IL-11 signaling as a potential therapeutic target for the treatment of gastrointestinal cancers. [Display omitted] •Elevated IL-11 levels in GI tumors correlate with oncogenic STAT3 activation•IL-11 is the dominant IL-6 family cytokine required for GI cancer progression•IL-11/STAT3 signaling promotes tumor cell proliferation and survival•Therapeutic inhibition of IL-11 signaling impedes GI tumorigenesis in vivo