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.
Highlights • The IL-11/GP130/JAK/STAT3 signaling axis is rate-limiting for the progression of gastrointestinal tumors. • Elevated IL-11 expression is associated with poor breast cancer patient ...prognosis. • Through STAT3, IL-11 endows “Hallmarks of Cancer” activities, including survival, proliferation, invasion, angiogenesis and metastasis. • IL-11 and IL-6 influence breast cancer stem cell dynamics and tumor heterogeneity. • Various strategies to interfere with binding of IL-11 to its cognate IL-11Rα receptor are being developed.
Pancreatic cancer has one of the poorest prognoses of all malignancies, with little improvement in clinical outcome over the past 40 years. Pancreatic ductal adenocarcinoma is responsible for the ...vast majority of pancreatic cancer cases, and is characterised by the presence of a dense stroma that impacts therapeutic efficacy and drives pro-tumorigenic programs. More specifically, the inflammatory nature of the tumour microenvironment is thought to underlie the loss of anti-tumour immunity and development of resistance to current treatments. Inflammatory pathways are largely mediated by the expression of, and signalling through, cytokines, chemokines, and other cellular messengers. In recent years, there has been much attention focused on dual targeting of cancer cells and the tumour microenvironment. Here we review our current understanding of the role of IL-6, and the broader IL-6 cytokine family, in pancreatic cancer, including their contribution to pancreatic inflammation and various roles in pancreatic cancer pathogenesis. We also summarise potential opportunities for therapeutic targeting of these pathways as an avenue towards combating poor patient outcomes.
Review discusses newly emerging role for IL‐11 in inflammation‐associated cancers of the gastrointestinal tract.
IL‐11, a member of the IL‐6 family of cytokines, exerts pleiotropic activities by ...stimulating hemopoiesis and thrombopoiesis, regulating macrophage differentiation, and conferring mucosal protection in the intestine. These effects are mediated by a multimeric complex comprising the ligand‐binding IL‐11Rα and the ubiquitously expressed gp130R β‐subunit, which together, trigger intracellular signaling and engagement of Stat3. In turn, activated Stat3 promotes cell survival and proliferation as well as immune responses associated with inflammatory diseases and tumor progression. IL‐6 and IL‐11 compete for interaction with gp130, resulting in tissue‐specific functions depending on the expression patterns of their respective α‐subunit receptors. Although traditionally, IL‐6 has been associated with aberrant Stat3 activation and associated pathologies, here, we discuss newly emerging roles for IL‐11 in linking inflammation to cancer progression. We propose that in light of the recurrence of persistent STAT3 activation and elevated IL‐11 expression in inflammation‐associated gastrointestinal cancers in humans, inhibition of Stat3 or pharmacologically, more amenable upstream molecules such as IL‐11 may represent novel, therapeutic targets.
Signal transducer and activator of transcription 3 (STAT3) is activated in many cancer types and can regulate pathways involving tumorigenesis, cell proliferation, cell survival and angiogenesis. ...Upstream cytokine signaling through multiple trans-membrane receptors can enhance the activation of STAT3 and promote tumor progression. Importantly, STAT3 activation can also be induced via the Janus-activated kinase 1/2 (JAK1/2) and Src family kinases. Target-specific drug therapies have been developed to inhibit many of the upstream receptor and non-receptor activators of STAT3 and are now approved for clinical use. Recently, resistance to standard-of-care therapies has been linked to constitutive or unabated STAT3 activation, suggesting that combination therapy with STAT3 inhibitors may be of clinical benefit. Furthermore, STAT3 activity has also been shown to regulate self-renewal of cancer stem cells that are often refractory to chemotherapy treatment. This review will focus on STAT3 mediated resistance to cancer therapy and discuss strategies to overcome this resistance.
Cytokines are small signaling proteins that have central roles in inflammation and cell survival. In the half-century since the discovery of the first cytokines, the interferons, over fifty cytokines ...have been identified. Amongst these is interleukin (IL)-6, the first and prototypical member of the IL-6 family of cytokines, nearly all of which utilize the common signaling receptor, gp130. In the last decade, there have been numerous advances in our understanding of the structural mechanisms of IL-6 family signaling, particularly for IL-6 itself. However, our understanding of the detailed structural mechanisms underlying signaling by most IL-6 family members remains limited. With the emergence of new roles for IL-6 family cytokines in disease and, in particular, roles of IL-11 in cardiovascular disease, lung disease, and cancer, there is an emerging need to develop therapeutics that can progress to clinical use. Here we outline our current knowledge of the structural mechanism of signaling by the IL-6 family of cytokines. We discuss how this knowledge allows us to understand the mechanism of action of currently available inhibitors targeting IL-6 family cytokine signaling, and most importantly how it allows for improved opportunities to pharmacologically disrupt cytokine signaling. We focus specifically on the need to develop and understand inhibitors that disrupt IL-11 signaling.
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.
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•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
There are a limited number of clinically useful serum biomarkers to predict tumor onset or treatment response in gastric cancer (GC). For this reason, we explored the serum proteome of the
murine ...model of intestinal-type gastric cancer (IGC). We identified 30 proteins with significantly elevated expression in early
IGC and 12 proteins that were significantly elevated in late
IGC compared to age- and gender-matched wild-type mice. Within these signatures, there was an overlap of 10 proteins commonly elevated in both early- and late-stage disease. These results highlight the potential to identify serum biomarkers of disease stage. Since IGC in the
model can be reversed following therapeutic inhibition of Interleukin (IL)-11, we explored whether the protein signatures we identified could be used to monitor tumor regression. We compared two different therapeutic modalities and found 5 proteins to be uniquely differentially expressed between control animals and animals halfway through treatment, with 10 differentially expressed at the end of treatment. Our findings highlight the potential to identify reliable biomarkers to track IGC tumor regression in response to treatment.
IL-11 is a member of the IL-6 family of cytokines. While it was discovered over 20 years ago, we have very little understanding of the role of IL-11 during normal homeostasis and disease. Recently, ...IL-11 has gained interest for its newly recognized role in the pathogenesis of diseases that are attributed to deregulated mucosal homeostasis, including gastrointestinal cancers. IL-11 can increase the tumorigenic capacity of cells, including survival of the cell or origin, proliferation of cancerous cells and survival of metastatic cells at distant organs. Here we outline our current understanding of IL-11 biology and recent advances in our understanding of its role in cancer. We advocate that inhibition of IL-11 signaling may represent an emerging therapeutic opportunity for numerous cancers.
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