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Inflammation-Induced Cancer: Crosstalk Between Tumours, Immune Cells and Microorganisms

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Inflammation-Induced Cancer: Crosstalk Between Tumours, Immune Cells and Microorganisms REVIEWS Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms Eran Elinav1*, Roni Nowarski2*, Christoph A. Thaiss1*, Bo Hu2,3*, Chengcheng Jin2,4*and Richard A. Flavell2,5 Abstract | Inflammation is a fundamental innate immune response to perturbed tissue homeostasis. Chronic inflammatory processes affect all stages of tumour development as well as therapy. In this Review, we outline the principal cellular and molecular pathways that coordinate the tumour-promoting and tumour-antagonizing effects of inflammation and we discuss the crosstalk between cancer development and inflammatory processes. In addition, we discuss the recently suggested role of commensal microorganisms in inflammation- induced cancer and we propose that understanding this microbial influence will be crucial for targeted therapy in modern cancer treatment. Less than 10% of all cancers are caused by germline muta- infection6. Although the origin and molecular signals tions; the remainder are caused by acquired somatic mutations that drive inflammation during infection may be distinct and environmental factors. In many cases, tumour from inflammation that is caused by other factors, such as development is linked to chronic infection, dietary obesity, noxious inhalants and autoimmunity, many of the factors, obesity, inhaled pollutants, tobacco use or biological concepts that drive and regulate inflammation- autoimmunity1. The unifying principle that underlies associated cancer are similar across the various aetiolo- 1Department of Immunology, these processes is chronic inflammation, which is an gies. Even more intriguing is the emerging possibility Weizmann Institute of aberrantly prolonged form of a protective response to that variation in the commensal microbial ecosystems Science, 100 Herzl Street, a loss of tissue homeostasis2. Similarly, cancer develop- (the microbiota) among individuals may be related to Rehovot 76100, Israel. 2Department of ment can, in many cases, be viewed as a dysregulated the considerable degree of variability noted in the mani- Immunobiology, Yale form of protective tissue repair and growth response. festation of inflammation-associated cancer both among University School of Medicine, Hence, inflammatory and neoplastic processes may co- different inflammatory diseases and among individuals New Haven, Connecticut develop into aberrant “wounds that do not heal” (REF. 3). with the same inflammatory disease. Indeed, commen- 06520, USA. 3Department of Molecular The first observations that linked inflammation to sal microbial elements have recently been associated 7–10 Biophysics and Biochemistry, tumour growth were made by the German physician with inflammation and cancer development . The Yale University School of Rudolf Virchow in the nineteenth century4. Virchow first members of the microbiota to be involved in can- Medicine, New Haven, described leukocyte infiltrates within tumours, which cer development have been identified; they potentially Connecticut 06520, USA. 4 provided the first evidence for what is now commonly represent only the ‘tip of the iceberg’ of a so-far under- Department of Cell Biology, 5 Yale University School of considered a hallmark of cancer . These leukocyte infil- appreciated part of the interplay between inflammation Medicine, New Haven, trates were initially thought to be solely indicative of and cancer. Connecticut 06520, USA. tumour immune surveillance and antitumour immune In this Review, we outline the major molecular 5Howard Hughes Medical responses but it is now clear that they can exert both and cellular pathways that participate in the crosstalk Institute, New Haven, Connecticut 06520, USA. tumour-suppressive and tumour-promoting effects, between cancer cells and inflammatory mediators. *These authors contributed and the underlying mechanisms are starting to be We focus on emerging mechanisms of inflammation- equally to this work. understood. induced carcinogenesis and describe the cellular and Correspondence to Of the multiple inflammatory causes of can- molecular pathways that are involved in inflammation- E.E. and R.A.F. cer susceptibility (TABLE 1), infection has gradually driven incipient neoplasia. We also discuss the new e-mails: [email protected]; been accepted as a major driver of inflammation- perspectives gained from recent studies on the role of [email protected] induced tumorigenesis. Indeed, up to 20% of all cases the commensal microbiota in inflammation-mediated doi:10.1038/nrc3611 of cancer worldwide are associated with microbial tumour development. NATURE REVIEWS | CANCER VOLUME 13 | NOVEMBER 2013 | 759 © 2013 Macmillan Publishers Limited. All rights reserved REVIEWS Key points pre-malignant cell proliferation and inhibited apoptosis in vivo19,20,23. Mechanistically, STAT3 promotes cell pro- • Inflammation is causally related to cancer development, through processes that liferation by upregulating the expression of the cell cycle involve genotoxicity, aberrant tissue repair, proliferative responses, invasion and regulators cyclin D1, cyclin D2 and cyclin B, as well as metastasis. the proto-oncogene MYC, and it increases cell survival • Major inflammatory pathways that are involved in inflammation-induced by upregulating the expression of the anti-apoptotic carcinogenesis converge at the level of the transcription factors signal transducer genes BCL2 and BCL2‑like 1 (BCL2L1; which encodes and activator of transcription 3 (STAT3) and nuclear factor‑κB (NF‑κB). BCL‑X )19,20,24. • Tumours modulate the inflammatory environment by the secretion of soluble growth L factors and chemoattractants, which render inflammatory cells suppressive against Another layer of STAT3 regulation was recently anticancer T cell responses. uncovered. Deletion of sphingosine kinase 2 (Sphk2) • In around 20% of all cases, microbial organisms are the causative agents of in mice identified an important module of CAC cancer-inducing inflammation. develop­ment in which the production of sphingosine- • In addition to bona fide pathogens, pathobionts of the commensal microbiota have 1‑phosphate (S1P) leads to the activation of nuclear recently been recognized as being involved in inflammatory processes that promote factor‑κB (NF‑κB)–IL‑6–STAT3 signalling, which in tumour growth. turn upregulates S1P receptor 1 (S1PR1). This establishes • A better understanding of the role of the microbiota in inflammation-induced cancer a feedforward amplification loop that maintains chronic might prospectively lead to targeted antimicrobial therapies against cancer initiation inflammation and leads to CAC25. Remarkably, in many or progression. cases, excessive STAT3 activation during incipient neo- plasia is the result of immune cell signalling in the tumour microenvironment. Recent evidence from Kras-driven Outside‑in: cancer promotion by inflammation pancreatic cancer models suggests that STAT3 signalling Carcinogenesis is the result of the interplay of multiple has an intrinsic role in pancreatic intra-epithelial neo- cell-intrinsic and cell-extrinsic processes, which include plasia development, even in the absence of inflamma- genomic instability, proliferative abnormality, repro- tory insults17. However, in many cases, epithelial STAT3 gramming of the stromal environment, and aberrant dif- functions in transducing myeloid cell-derived IL‑6 pro- ferentiation between epithelial and mesenchymal states. tumorigenic signals; for example, STAT3 functions in A remarkable characteristic of inflammation is its ability the progression of pancreatic intra-epithelial neoplasia to enable most, if not all, of the core cellular and molec- to pancreatic ductal adenocarcinoma but does not func- ular capabilities that are required for tumorigenesis5. tion in its initiation18. Similarly, in the liver, low-grade Although the mechanisms by which inflammatory cells inflammation induced by obesity in the diethylnitrosa- promote neoplastic transformation are not fully under- mine (DEN)-induced hepatocellular carcinoma (HCC) stood, we discuss below the major mechanistic principles model was also shown to activate tumorigenic STAT3 of inflammation-induced cancer on the basis of recent signalling via production of IL‑6 and tumour necrosis research advances and the current understanding of the factor (TNF)26. A regulatory mechanism that may fur- tumorigenic process, and pay particular attention to ther elucidate the role of the IL‑6–STAT3 axis in tumour the development of incipient neoplasia (FIG. 1). initiation and progression was shown in immortalized mammary cells where transient activation of the onco- Promoting proliferative and survival signalling. Cancer protein SRC triggered an epigenetic switch to a constant growth results in loss of homeostatic tissue architecture. transformed state induced by STAT3 activation27. SRC The control of tissue architecture and function is mostly activation induced an NF‑κB‑dependent inflamma- governed by the regulation of soluble growth factors and tory response that mediated increased IL‑6 expression their receptors that convey proliferative, homeostatic by decreasing the transcription of its negative regulator and survival signals. Cancer cells exploit growth factor microRNA let‑7. Increased IL‑6 levels activated STAT3 signalling by several common strategies: altering endo- transcription, which was necessary for cell transforma- cytosis and receptor cycling; inhibiting negative-feedback tion, and in parallel activated NF‑κB. This established mechanisms that
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