Stat3: Linking inflammation to (gastrointestinal) tumourigenesis

Abstract

Tumourigenesis is a multistage process comprising initiation, promotion and progression that is governed by cumulative (epi-)genetic changes. However, tumour initiation, triggered by mutations in proto-oncogenes and/or tumour suppressor genes, is insufficient for the development of cancers. Tumour promotion often depends on the interaction between initiated cells and the microenvironment where an excessive abundance of inflammatory mediators, including those of the interleukin (IL-)6/glycoprotein 130 (gp130) family, promote their expansion. The activity of most soluble mediators ultimately converges on tumour cells through activation of the latent transcription factors nuclear factor (NF)-κB and signal transducer and activator of transcription (Stat) 3 to enhance survival of neoplastic cells. In addition, Stat3 promotes tumour cell proliferation, invasion and induction of an angiogenic switch. Persistent activation of STAT3 is a unifying hallmark of a majority of solid malignancies. However, persistent STAT3 activation usually occurs in the absence of activating mutations in, or amplification of, the STAT3 gene. Instead, it is associated with an oversupply of autocrine and/or paracrine activating cytokines secreted by tumour and stromal cells and comprising (among others) cytokines that use the gp130 receptor. Interleukin-6, IL-11 and other members of the gp130 cytokine family have been identified in preclinical mouse models as promising therapeutic targets for gastrointestinal, hepatic and breast cancers. Thus, pharmacological interference with specific cytokines and tyrosine kinases that trigger Stat3 activation affords opportunities to therapeutically target the non-redundant tumour-promoting signalling function of Stat3.

The JAK/STAT signaling cascade in gastric carcinoma (Review)

“…Furthermore, it was shown that low-grade intraepithelial lesions in Stat3-deficient mice progress to advanced tubular tumors, thus, affirming the critical role of STAT3 in IEC proliferation and survival in CAC carcinogenesis (92). Additionally, more aggressive tumors have been observed in relation to STAT3 activation, either by epithelial-specific SOCS3 ablation or introduction of SOCS3 binding-deficient gp130 Y757F mutation (93,94). These reports have provided valuable insights into STAT3-driven inflammation and gastric cancer (94).…”

“…In particular, aberrant STAT3 expression has been implicated in gastric adenocarcinoma patients, making STAT3 a promising candidate as a prognostic marker in gastric cancers (79,85,125,126). In gastric cancer, the abnormal STAT3 expression not only contributes to cancer cell proliferation and survival, but also functions in promoting inflammation, EMT transition and metastasis (94,97,127,128). Various in vitro and in vivo studies have confirmed the role of STAT3 in the precancerous pathology of the stomach, indicating that STAT3 may serve as a useful prognostic/diagnostic biomarker for the early detection of gastric cancer and that limiting STAT3 activity could help prevent malignancy (125).…”

“…Additionally, more aggressive tumors have been observed in relation to STAT3 activation, either by epithelial-specific SOCS3 ablation or introduction of SOCS3 binding-deficient gp130 Y757F mutation (93,94). These reports have provided valuable insights into STAT3-driven inflammation and gastric cancer (94).…”

Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway

“…Of these, the induction of JAK/STAT3 activation appears most critical in GI tumorigenesis (32). To investigate whether IL-11 is sufficient to induce STAT3 activation in isolated wild-type epithelium, we incubated primary epithelial crypts isolated from mouse small intestine with recombinant IL-11.…”

The Role of Cytokines in Breast Cancer Development and Progression

“…The initial activation of NF-kB by inflammatory signals activates a self-reinforcing regulatory circuit that comprises IL-6 and Stat3 and converts a stable normal cellular phenotype into a stable neoplastic phenotype without any change in DNA sequence (Iliopoulos and others 2009), linking tumorigenesis to NF-kB activation and inflammation (Ernst and Putoczki 2012).…”