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Stat3: linking inflammation to epithelial cancer - more than a

机译：Stat3：将炎症与上皮癌联系起来-不仅如此

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Inflammation is an important environmental factor that promotes tumourigenesis and the progression of established cancerous lesions, and recent studies have started to dissect the mechanisms linking the two pathologies. These inflammatory and infectious conditions trigger immune and stromal cell release of soluble mediators which facilitate survival and proliferation of tumour cells in a paracrine manner. In addition, (epi-)genetic mutations affecting oncogenes, tumour-suppressor genes, chromosomal rearrangements and amplifications trigger the release of inflammatory mediators within the tumour microenvironment to promote neoplastic growth in an autocrine manner. These two pathways converge in tumour cells and result in activation of the latent signal transducer and activator of transcription 3 (Stat3) which mediates a transcriptional response favouring survival, proliferation and angiogenesis. The abundance of cytokines that activate Stat3 within the tumour microenvironment, which comprises of members of the interleukin (IL) IL6, IL10 and IL17/23 families, underpins a signaling network that simultaneously promotes the growth of neoplastic epithelium, fuels inflammation and suppresses the host's anti-tumour immune response. Accordingly, aberrant and persistent Stat3 activation is a frequent observation in human cancers of epithelial origin and is often associated with poor outcome. Here we summarize insights gained from mice harbouring mutations in components of the Stat3 signaling cascade and in particular of gp130, the shared receptor for the IL6 family of cytokines. We focus on the various feed-back and feed-forward loops in which Stat3 provides the signaling node in cells of the tumour and its microenvironment thereby functionally linking excessive inflammation to neoplastic growth. Although these observations are particularly pertinent to gastrointestinal tumours, we suggest that the tumour's addiction to persistent Stat3 activation is likely to also impact on other epithelial cell-derived cancers. These insights provide clues to the judicious interference of the gp130/Stat3 signaling cascade in therapeutically targeting cancer.
机译：炎症是促进肿瘤发生和已建立的癌性病变进展的重要环境因素，最近的研究已开始剖析将这两种病理联系在一起的机制。这些炎性和感染性疾病触发可溶性介质的免疫和基质细胞释放，其以旁分泌方式促进肿瘤细胞的存活和增殖。此外，影响癌基因，肿瘤抑制基因，染色体重排和扩增的（表）遗传突变触发肿瘤微环境内炎症介质的释放，从而以自分泌方式促进肿瘤的生长。这两个途径在肿瘤细胞中汇合，并导致潜在信号转导子和转录激活子3（Stat3）激活，后者介导有利于生存，增殖和血管生成的转录反应。在白细胞介素（IL）IL6，IL10和IL17 / 23家族的成员中，大量激活肿瘤微环境中Stat3的细胞因子支撑着一个信号网络，该信号网络同时促进肿瘤上皮细胞的生长，促进炎症并抑制宿主的抗肿瘤免疫反应。因此，在上皮起源的人类癌症中经常和持续的Stat3激活是观察到的，并且经常与不良的结果有关。在这里，我们总结了从小鼠体内获得的见解，这些小鼠具有Stat3信号级联，尤其是gp130（细胞因子IL6家族的共享受体）的组件中的突变。我们专注于各种反馈和前馈环，其中Stat3在肿瘤及其微环境的细胞中提供信号传导节点，从而在功能上将过度炎症与肿瘤生长联系在一起。尽管这些观察结果与胃肠道肿瘤特别相关，但我们认为该肿瘤对Stat3持续激活的成瘾性也可能会影响其他上皮细胞衍生的癌症。这些见解为gp130 / Stat3信号级联在治疗性靶向癌症中的明智干预提供了线索。

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