Inflammatory bowel diseases (IBDs) are debilitating conditions that result in intestinal damage due to chronic inflammation. In addition, the perpetual state of inflammation predisposes individuals to the development of colitis associated cancer (CAC). Because of the immense immune cell infiltration into colon, cytokines produced by immune cells are major players in the initiation and progression of IBD and CAC. In this review, we will explore the functions of many key cytokines and their roles in IBD and CAC, as well as their influences on the immune system and stromal cells. Finally, we will briefly discuss current therapies and current clinical trials targeting cytokines in IBD.

Inflammation has long been suspected to play a major role in the pathogenesis of cancer. Only recently however, have some mechanisms of its tumor promoting effects come to light. Microbes, both commensal and pathogenic, are critical regulators of the host immune system, and ultimately, of inflammation. Consequently, microbes have the potential power to influence tumor progression as well, through a wide variety of routes, including chronic activation of inflammation, alteration of tumor microenvironment, induction of genotoxic responses, and metabolism. In this review, we will provide a general overview of commensal microbiota, inflammation and cancer, and how microbes fit into this emerging field.

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 cellautonomous 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.Immunity 50, 166-180, January 15, 2019 167 for the help with graphical abstract, and E. Fearon (U Michigan) for CDX2Cre, CDX2ERT, and Apc f/f mice. We thank Histology laboratory of Department of Pathology at FCCC for tissue processing and slide preparation and LAF, Flow Cytometry, Cell Culture and Microscopy Facilities at FCCC.

The tumor microenvironment offers multiple targets for cancer therapy, including pro-tumorigenic inflammation. Natural compounds represent an enormous source of new anti-inflammatory and anticancer agents. We previously showed that the styryl lactone goniothalamin (GTN) has promising antiproliferative and anti-inflammatory activities. Because inflammation is a major driver of colorectal cancer (CRC), we therefore evaluated the therapeutic and preventive potentials of GTN in colitis, colitis-associated cancer (CAC) and spontaneous CRC. First, in a simplistic model of inflammation in vitro, GTN was able to inhibit cytokine production in bone marrow-derived macrophages induced by lipopolysaccharide. Next, in dextran sulfate sodium (DSS) induced-colitis model, mice treated with GTN displayed restored tissue architecture, increased cell proliferation in the colonic crypts and reduced epithelial damage. Moreover, colon tissue from GTN-treated mice had significantly less expression of the inflammatory genes interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), S100A9, interleukin 23A (IL-23A), IL-22 and IL-17A. In the azoxymethane/DSS model of CAC, GTN reduced tumor multiplicity, load and size. Additionally, GTN suppressed production of IL-6, IL-17 and TNF-α in tumor tissue, as well as abrogated stromal immune cell activation and nuclear translocation of NF-κB. Finally, in a tamoxifen inducible model of sporadic CRC, GTN-treated mice had significantly fewer tumors and decreased levels of IL-17A, IL-6, S100A9 and TNF-α protein within the tumors. These results suggest that GTN possesses anti-inflammatory and antitumor activities and represents a preventive and therapeutic agent modulating the inflammatory environment in the colon during colitis as well as CAC and CRC development.

Colorectal cancer (CRC) is the 2nd most common cause of cancer deaths in the United States and other developed countries, despite important advances in detection, surgery and chemotherapy. It becomes increasingly clear that not only cell autonomous events in cancer cells are required for tumor growth and progression. Growing CRC tumors possess the ability to recruit inflammatory cells and upregulate inflammatory cytokines - a phenomenon recently introduced as “Tumor elicited inflammation”(TEI). The mechanisms of TEI induction and tumor promotion are not yet well defined. IL23/IL17 pathway is one of the established regulators of TEI. While in mice the ablation of IL-23 signaling results in a uniform loss of IL-17 response and in a decrease in tumor growth; in humans IL23/IL-23R gene expression signature is not always consistent with elevated IL-17 signature, implicating that there should be other regulators of IL-17 and TEI induction in tumors. IL-1 pathway is important for the induction of T helper IL-17 producing cells (Th17) and for the production of IL-17 by innate lymphoid cells (ILC), both in mice and in humans. IL-1 pathway is also implicated in host defense, immunity and tumorigenesis, with some of its functional characteristics similar to IL-23 pathway. In addition, IL-1, much alike IL-23, can be also induced by various microbial derived and host derived ‘danger signals’ readily available within the tumor microenvironment. Our own data suggests that components of IL-1 pathway are upregulated in CRC tumors. Therefore, we hypothesized, that IL-1 pathway might be an important regulator of TEI and CRC tumorigenesis. Using genetic tools and animal models, we examined if IL-1 has the potential role in different stage of CRC and whether it serves as an important regulator of TEI and CRC tumor cells proliferation and survival. Citation Format: Oxana Dmitrieva, David Possoco, Ralph A. Francescone, Vivianty Hou, Debora B. Vendramini-Costa, Sergey Grivennikov. Role of Interleukin 1 signaling in tumor elicited inflammation and colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3186. doi:10.1158/1538-7445.AM2015-3186