Stat3: linking inflammation to (gastrointestinal) tumourigenesis.
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.
Ludwig Institute for Cancer Research, Melbourne Parkville Branch, Melbourne, Victoria, Australia. matthias.ernst@ludwig.edu.au
Matthias
M
Ernst
Tracy L
TL
Putoczki
D000818:Animals; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000502:physiology; D005770:Gastrointestinal Neoplasms / Q000209:etiology / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology*; D017370:Interleukin-11 / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009857:Oncogenes / Q000235:genetics / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D017370:Interleukin-11; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D050822:Cytokine Receptor gp130