Inflammation predisposes to the development of cancer and promotes all stages of tumorigenesis. Cancer cells, as well as surrounding stromal and inflammatory cells, engage in well-orchestrated ...reciprocal interactions to form an inflammatory tumor microenvironment (TME). Cells within the TME are highly plastic, continuously changing their phenotypic and functional characteristics. Here, we review the origins of inflammation in tumors, and the mechanisms whereby inflammation drives tumor initiation, growth, progression, and metastasis. We discuss how tumor-promoting inflammation closely resembles inflammatory processes typically found during development, immunity, maintenance of tissue homeostasis, or tissue repair and illuminate the distinctions between tissue-protective and pro-tumorigenic inflammation, including spatiotemporal considerations. Defining the cornerstone rules of engagement governing molecular and cellular mechanisms of tumor-promoting inflammation will be essential for further development of anti-cancer therapies.
Inflammation predisposes to the development of cancer and promotes all stages of tumorigenesis. Cancer cells, as well as surrounding stromal and inflammatory cells, engage in well-orchestrated reciprocal interactions to form an inflammatory tumor microenvironment (TME). Cells within the TME are highly plastic, continuously changing their phenotypic and functional characteristics. Here, we review the origins of inflammation in tumors, and the mechanisms whereby inflammation drives tumor initiation, growth, progression, and metastasis. We discuss how tumor-promoting inflammation closely resembles inflammatory processes typically found during development, immunity, maintenance of tissue homeostasis, or tissue repair and illuminate the distinctions between tissue-protective and pro-tumorigenic inflammation, including spatiotemporal considerations. Defining the cornerstone rules of engagement governing molecular and cellular mechanisms of tumor-promoting inflammation will be essential for further development of anti-cancer therapies.
Connection between inflammation and cancer is a rapidly developing field. Epidemiological data suggests that inflammation along with distinct arms of host immune system plays a very important role in ...the development and progression of many different cancers. Inflammatory bowel disease (IBD) is an important risk factor for the development of colon cancer, namely, colitis-associated cancer (CAC). The molecular mechanisms by which inflammation promotes cancer development are still being uncovered and may differ between CAC and other forms of colorectal cancer. Recent work has shed light on the role of distinct immune cells, cytokines, and other immune mediators in virtually all of the steps of colonic tumorigenesis, including tumor initiation and promotion as well as progression and metastasis. The close proximity of colonic tumors to the myriad of intestinal microbes, as well as instrumental role of microbiota in IBD, introduces microbes as new players capable of triggering inflammation and possibly promoting tumorigenesis. Various mechanisms of CAC tumorigenesis as well as new possible hints for the future approaches for prevention and therapy are discussed in this review.
Inhibition of programmed cell death is considered to be a major aspect of tumorigenesis. Indeed, several key oncogenic transcription factors, such as NF-κB and STAT3, exert their tumor-promoting ...activity at least in part through upregulation of survival genes. However, many cancers develop in response to chronic tissue injury, in which the resulting cell death increases the tumorigenic potential of the neighboring cells. In this review, we discuss a resolution to this paradox based on cell death-mediated induction of tumor promoting inflammatory cytokines, which enhance cell survival and trigger compensatory proliferation in response to tissue injury.
Interleukin-17A (IL-17A) is a pro-inflammatory cytokine linked to rapid malignant progression of colorectal cancer (CRC) and therapy resistance. IL-17A exerts its pro-tumorigenic activity through its ...type A receptor (IL-17RA). However, IL-17RA is expressed in many cell types, including hematopoietic, fibroblastoid, and epithelial cells, in the tumor microenvironment, and how IL-17RA engagement promotes colonic tumorigenesis is unknown. Here we show that IL-17RA signals directly within transformed colonic epithelial cells (enterocytes) to promote early tumor development. IL-17RA engagement activates ERK, p38 MAPK, and NF-κB signaling and promotes the proliferation of tumorigenic enterocytes that just lost expression of the APC tumor suppressor. Although IL-17RA signaling also controls the production of IL-6, this mechanism makes only a partial contribution to colonic tumorigenesis. Combined treatment with chemotherapy, which induces IL-17A expression, and an IL-17A neutralizing antibody enhanced the therapeutic responsiveness of established colon tumors. These findings establish IL-17A and IL-17RA as therapeutic targets in colorectal cancer.
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•IL-17RA signals within transformed enterocytes to promote CRC development•IL-17RA activates ERK, p38 MAPK, and NF-κB in transformed enterocytes•IL-17RA signals are required for growth and progression of aberrant crypt foci•IL-17A neutralization enhances therapeutic responsiveness
IL-17 is a pro-inflammatory cytokine that promotes colorectal cancer development, but the underlying mechanism has been unclear. Wang et al. show that IL-17 signals directly to tumor cells to promote early colon tumorigenesis by facilitating tumor cell proliferation.
Tumor-associated inflammation is a consequence and a driver of tumorigenesis. Three papers in this issue of
Cancer Cell demonstrate the importance of tumor-elicited inflammation in the development ...and progression of pancreatic ductal adenocarcinoma and esophageal squamous carcinoma. Disruption of tissue homeostasis culminates in activation of STAT3, generating a pro-tumorigenic inflammatory microenvironment.
A myriad of microbes living together with the host constitutes the microbiota, and the microbiota exerts very diverse functions in the regulation of host physiology. Microbiota regulates cancer ...initiation, progression, metastasis, and responses to therapy. Here we review known pro-tumorigenic and anti-tumorigenic functions of microbiota, and mechanisms of how microbes can shape tumor microenvironment and affect cancer cells as well as activation and functionality of immune and stromal cells within the tumor. While some of these mechanisms are distal, often distinct members of microbiota travel with and establish colonization with the tumors in the distant organs. We further briefly describe recent findings regarding microbiota composition in metastasis and highlight important future directions and considerations for the manipulation of microbiota for cancer treatment.
Chronic inflammation drives the progression of colorectal cancer (CRC). Increased expression of interleukin (IL)-17A is associated with poor prognosis, and IL-17A blockade curbs tumor progression in ...preclinical models of CRC. Here we examined the impact of IL-1 signaling, a key regulator of the IL-17 pathway, in different cell types within the CRC microenvironment. Genetic deletion of the IL-1 receptor (IL-1R1) in epithelial cells alleviated tumorigenesis in the APC model of CRC, demonstrating a cell-autonomous role for IL-1 signaling in early tumor seed outgrowth. T cell specific ablation of IL-1R1 decreased tumor-elicited inflammation dependent on IL-17 and IL-22, thereby reducing CRC progression. The pro-tumorigenic roles of IL-1 were counteracted by its effects on myeloid cells, particularly neutrophils, where IL-1R1 ablation resulted in bacterial invasion into tumors, heightened inflammation and aggressive CRC progression. Thus, IL-1 signaling elicits cell-type-specific responses, which, in aggregate, set the inflammatory tone of the tumor microenvironment and determine the propensity for disease progression.
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•IL-1R regulates inflammation, but its blanket inactivation does not reduce CRC•Deletion of IL-1R in epithelium delays CRC development independent of inflammation•T-cell-specific IL-1R deletion reduces TEI cytokine expression and CRC progression•Myeloid IL-1R deletion promotes tumor-specific dysbiosis, inflammation and CRC growth
Dmitrieva-Posocco et al. use conditional gene deletion approaches in a model of colorectal cancer and find that IL-1 has distinct effects on different cell types in the tumor microenvironment. The tumor-promoting effects of IL-1 are both inflammation dependent and independent, whereas its tumor-suppressive effects rely on neutrophil-mediated control of bacterial invasion.
Cytokines have recently emerged as important players in tumor promotion and progression. In this issue of Cancer Cell, Putoczki and colleagues report the importance of interleukin 11 in a variety of ...gastrointestinal malignances and lay down a framework for its potential inhibition in a variety of human cancers.
The intestinal epithelium harbors large populations of activated and memory lymphocytes, yet these cells do not cause tissue damage in the steady state. We investigated how intestinal T cell effector ...differentiation is regulated upon migration to the intestinal epithelium. Using gene loss- and gain-of-function strategies, as well as reporter approaches, we showed that cooperation between the transcription factors T-bet and Runx3 resulted in suppression of conventional CD4+ T helper functions and induction of an intraepithelial lymphocyte (IEL) program that included expression of IEL markers such as CD8αα homodimers. Interferon-γ sensing and T-bet expression by CD4+ T cells were both required for this program, which was distinct from conventional T helper differentiation but shared by other IEL populations, including TCRαβ+CD8αα+ IELs. We conclude that the gut environment provides cues for IEL maturation through the interplay between T-bet and Runx3, allowing tissue-specific adaptation of mature T lymphocytes.
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•T-bet is upregulated by CD4+ IELs•T-bet deficiency leads to reduced CD8αα IEL populations•Runx3 cooperates with T-bet to suppress helper T cell function and induce IEL program•IFN-γR and IL-27Rα play complementary roles for IEL subpopulations
It is unclear how intestinal T cell effector differentiation is regulated upon migration to the intestinal epithelium. Mucida and colleagues found that the gut environment provides cues for intraepithelial lymphocyte maturation through the interplay between the transcription factors T-bet and Runx3.
Background & Aims Interleukin (IL)-17 signaling has been implicated in lung and skin fibrosis. We examined the role of IL-17 signaling in the pathogenesis of liver fibrosis in mice. Methods Using ...cholestatic and hepatotoxic models of liver injury, we compared the development of liver fibrosis in wild-type mice with that of IL-17RA −/− mice and of bone marrow chimeric mice devoid of IL-17 signaling in immune and Kupffer cells ( IL-17RA −/− to wild-type and IL-17A −/− to wild-type mice) or liver resident cells (wild-type to IL-17RA −/− mice). Results In response to liver injury, levels of Il-17A and its receptor increased. IL-17A increased appeared to promote fibrosis by activating inflammatory and liver resident cells. IL-17 signaling facilitated production of IL-6, IL-1, and tumor necrosis factor-α by inflammatory cells and increased the expression of transforming growth factor-1, a fibrogenic cytokine. IL-17 directly induced production of collagen type I in hepatic stellate cells by activating the signal transducer and activator of transcription 3 (Stat3) signaling pathway. Mice devoid of Stat3 signaling in hepatic stellate cells ( GFAPStat3 −/− mice) were less susceptible to fibrosis. Furthermore, deletion of IL-23 from immune cells attenuated liver fibrosis, whereas deletion of IL-22 exacerbated fibrosis. Administration of IL-22 and IL-17E (IL-25, a negative regulator of IL-23) protected mice from bile duct ligation-induced liver fibrosis. Conclusions IL-17 induces liver fibrosis through multiple mechanisms in mice. Reagents that block these pathways might be developed as therapeutics for patients with cirrhosis.
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