Published OnlineFirst July 29, 2014; DOI: 10.1158/1078-0432.CCR-13-2492 Clinical Cancer Molecular Pathways Research Molecular Pathways: IL11 as a Tumor-Promoting Cytokine—Translational Implications for Cancers Matthias Ernst1,2 and Tracy L. Putoczki1,2 Abstract Emerging evidence suggests that cytokines produced by inflammatory cells act as rheostats to link the degree of wounding and local inflammation to epithelial cell survival, proliferation, and metabolism that collectively underpin the repair response. Among these cytokines, the GP130 family, which encompasses, among others, IL6 and IL11, plays a major role in orchestrating these complex processes through the activation of the latent signal transducer and activator of transcription 3 (STAT3) in the epithelium. However, many of the molecular mechanisms that govern and ensure effective epithelial wound healing and regeneration renewal also promote tumorigenesis and the progression of established cancers. Accordingly, GP130 cytokines endow the inflammatory tumor microenvironment with a capacity to promote "cancer hallmark capabilities" of the malignant epithelium, while simultaneously suppressing the antitumor response of innate and adaptive immune cells. Here, we review some recent insights derived from genetic and therapeutic inhibition of the IL6/IL11–GP130–STAT3 signaling cascade in the context of preclinical mouse models of cancer, which are likely to have implications to other solid malignancies. Clin Cancer Res; 20(22); 1–9. Ó2014 AACR. Background rather than prevent tumorigenesis. Cancers of the gastro- Tumor development and progression are multistep pro- intestinal tract illustrate this paradigm most powerfully, cesses driven by the accumulation of genetic alterations in with compelling clinical correlations between inflammato- cancer-initiating (stem) cells. This is most powerfully illus- ry bowel disease (IBD) and colorectal cancers, or persistent trated for colorectal cancers, where more than 80% of Helicobacter pylori infection and GC (5), respectively. How- sporadic human colorectal cancers are initiated by aberrant ever, even sporadic cancers (e.g., those not associated with activation of the WNT pathway. During the progression chronic inflammation) are embedded in a TME exhibiting from benign adenomatous polyps to frank metastatic can- the "smouldering inflammation" associated with wound- cer, neoplastic cells acquire additional mutations in the healing processes, including the recruitment and matura- TGFb/SMAD4 signaling cascade, KRAS, and TP53 (1). A tion of myeloid cells (4). similar stepwise accumulation is also thought to underpin Among the panoply of cytokines involved with cancer- the development of intestinal-type gastric cancer (GC) with associated inflammation, traditionally emphasis has been driver mutations including those in PI3K and ERBB2 (2). given to IL1b, IL6, IL23, and TNFa as the major cytokines. However, equally important to all stages of tumor initiation Their activities converge on NF-kB and signal transducer and progression are the contributions of the inflammatory and activator of transcription 3 (STAT3). These signaling tumor microenvironment (TME), where cancer cells con- hubs collectively mediate tissue repair, immune homeosta- script and corrupt normal, nonmutated stromal cells for sis, and balance the host’s response to intestinal microbiota their support (3, 4). Indeed, inflammation is a prevailing (6, 7). As a key coordinator of innate immunity and inflam- condition for initiation and progression of the majority of mation, uncontrolled activation of NF-kB activity is solid tumors. Although the adaptive immune response is involved in tumor initiation and progression in tissues in important for immune surveillance and tumor suppression, which cancer-related inflammation typically occurs, includ- chronic and overt inflammation more commonly stimulate ing the gastrointestinal tract and the liver (8). Like NF-kB, which primarily promotes epithelial cell survival, persistent STAT3 activity in cancer and associated immune cells is a 1The Walter and Eliza Hall Institute for Medical Research, Melbourne, recurrent feature of many types of solid tumors and pro- Victoria, Australia. 2Department of Medical Biology, University of Mel- bourne, Melbourne, Victoria, Australia. motes both the survival and proliferation of neoplastic epithelium. Surprisingly, however, aberrant activation of Corresponding Author: Matthias Ernst, The Walter and Eliza Hall Institute for Medical Research, 1G Royal Parade, Parkville, Melbourne, VIC 3052, these transcription factors in cancer cells more often reflects Australia. Phone: 61-393452555; Fax: 61-393470852; E-mail: a cytokine-rich TME, rather than accumulation of oncogen- [email protected] ic mutations in these pathways, or indeed the genes encod- doi: 10.1158/1078-0432.CCR-13-2492 ing these transcription factors (6). Collectively, these obser- Ó2014 American Association for Cancer Research. vations place the STAT3 signaling cascade at the center of an www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst July 29, 2014; DOI: 10.1158/1078-0432.CCR-13-2492 Ernst and Putoczki effective epithelial wound-healing reaction, and many of with thrombopoietic activity (11). However, other biologic the upstream cytokines required for STAT3 activation are activities of IL11 include its capacity to stimulate erythro- derived from myeloid cells. In this context, much attention poiesis, activation of megakaryocytes, and to improve the has been given to the IL6/11 family of cytokines, which are outcomes of adaptive bone marrow transfers in mice (10). defined by their shared use of the GP130 receptor. IL11 also regulates polarization of T cells and macrophages, promotes maturation of bone-resorbing osteoclasts and IL11, a Member of GP130 Cytokine Family associated net bone loss, retains tissue "stem cell" pheno- IL11 forms part of a family of the phylogenetically related types (10), and, through an obligatory requirement of the cytokines IL6, leukemia inhibitory factor (LIF), oncostatin IL11 receptor a-chain, enables the formation of a decidua M (OSM), ciliary neurotrophic factor (CNTF), neuropoietin during pregnancies (12). Like most of the other cytokines in (NPN), cardiotrophin-1 (CT-1), cardiotrophin-like cyto- this family, IL11 is produced by a variety of cells in response kine (CLC), IL27, and IL31 (6, 9). Originally discovered to inflammatory stimuli. as a soluble activity in the supernatant of cultured fibro- All ligands of the GP130 cytokine family form receptor blasts that could stimulate the growth of IL6-dependent complexes with the ubiquitously expressed signal-trans- plasmacytoma cells and associated IgG production (10), ducing GP130 (also called IL6st or CD130) subunit (Fig. 1). IL11 has most extensively been characterized as a cytokine Most of these ligand-occupied receptor complexes consist of Figure 1. Simplified intracellular signaling events that occur α sR in response to GP130 homodimerization as part of a hexameric complex comprising also two identical ligand-specific receptor a-subunits and two molecules of IL6 or IL11, α respectively. A soluble version of GP130 IL6R GP130 IL11Rα the IL6Ra (sRa) can confer trans- signaling in cells that do not P JAK JAK P express the transmembrane IL6Ra SOCS3 receptor, and also activate the 757 P Y Y P STAT1/3, Ras/Erk, and PI3K/ SHP2 mTorc1 signaling cascades. P 765 P STAT1 Y Y PI3K Tyrosine (Y) phosphorylation, 812 P P Y Y P mediated by GP130-associated STAT3 904 SHP2 P Y Y P JAK kinases, are indicated with P P Y 915 Y P green arrows; negative regulators of GP130 signaling are depicted in P STAT1 red, including the STAT3 target Ras mTorc1 Socs3 STAT3 PIAS3 gene . In order for SOCS3 P to exert its maximal negative P STAT3 regulatory activity on gp130 signaling, SOCS needs to P STAT1 Erk STAT1 simultaneously interact with the phosphorylated Y757 residue in P STAT3P P eIF4E STAT3 gp130 and with the JAK kinases in a phospho-independent manner AP1 (78). Meanwhile, the tyrosine P STAT3 CCND1 phosphatase SHP2 is required for BCL2 STAT3 P activation of the Ras/Erk cascade, SOCS3 but SHP2 can also inhibit gp130 signaling through P STAT1 dephosphorylation of the receptor STAT1 P and the STAT proteins. STAT1 and STAT3 homodimers, formed in the cytoplasm in response to tyrosine STAT1/3 Ras–Erk PI3K–mTor phosphorylation (P) of STAT pathway pathway pathway monomers, are actively transported into the nucleus (broken line) where they bind to DNA in a sequence- specific context to elicit transcription of target genes. IL6 sRα IL6/sIL6Rα IL11 The amino acid position of the Y residues required for binding and activation of STAT, SHP2, and © 2014 American Association for Cancer Research SOCS3 are given for murine GP130 (please also refer to text). OF2 Clin Cancer Res; 20(22) November 15, 2014 Clinical Cancer Research Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst July 29, 2014; DOI: 10.1158/1078-0432.CCR-13-2492 Targeting IL6/IL11 Signaling in Solid Cancers a a-receptors (IL6Ra, IL11Ra, CNTFRa, and CT-1Ra) and behavior of both, the neoplastic tumor cells and the non- signal-transducing b-receptors (GP130, LIFR, OSMR, transformed cells of the TME. IL27R/WSX-1, and IL31R/GPL), although LIF, OsM, and IL31 appear to from complexes comprising b-chains only STAT3 Signaling during Epithelial Homeostasis