A, schematic representation of some of the major cell types in the stroma and the TME that respond to cytokines via STAT3 (green, stimulation; red, inhibition) and/or produce (black arrow) IL6, IL11, IL22, and other cell type–specific products. A, schematic representation of some of the major cell types in the stroma and the TME that respond to cytokines via STAT3 (green, stimulation; red, inhibition) and/or produce (black arrow) IL6, IL11, IL22, and other cell type–specific products. B, IL6-, IL11-, and IL22-dependent STAT3 signaling ensures effective wound healing (left side of diagram) and enables neoplastic growth of the gastrointestinal epithelium (right side of diagram). Meanwhile, these cytokines are individually dispensable for homeostatic renewal of the mucosa (middle part of diagram). A subset of the proliferating cells, including the stem cells (light pink) toward the bottom of the crypt and within the tumors, preferentially respond (green arrows) to IL11 and a preformed complex comprising IL6 and the soluble IL6Rα (“trans-signaling”), rather than to IL6 through the membrane-bound IL6Rα (“conventional signaling”). Terminally differentiated cells (dark pink) express membrane-associated receptor for IL6 and IL11. Normal intestinal epithelium and its transformed counterpart, which can also produce TGFβ, are a source of IL11. The epithelial target cells for IL22, which is produced primarily by ILC3 cells (see A), have not been characterized. IL6, IL11, and IL22 also act on cells of the stroma and TME (see A). CAF, cancer-associated fibroblasts; DC, dendritic cells; ILC3, innate lymphoid cells; Mac, macrophages; Mgk, megakaryocytes; PMN, polymorphonuclear cells; Treg, regulatory T cells. Matthias Ernst, and Tracy L. Putoczki Clin Cancer Res 2014;20:5579-5588 ©2014 by American Association for Cancer Research