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1.
Immunity ; 50(1): 166-180.e7, 2019 01 15.
Article in English | MEDLINE | ID: mdl-30650375

ABSTRACT

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.


Subject(s)
Colorectal Neoplasms/immunology , Inflammation/metabolism , Interleukin-17/metabolism , Interleukin-1/metabolism , Neutrophils/immunology , Salmonella Infections, Animal/immunology , Salmonella/immunology , Animals , Carcinogenesis , Cells, Cultured , Humans , Interleukin-1/genetics , Interleukin-1/immunology , Interleukins/metabolism , Mice , Mice, Knockout , Neutrophils/ultrastructure , Organ Specificity , Receptors, Interleukin-1/genetics , Signal Transduction , Tumor Microenvironment , Interleukin-22
2.
Carcinogenesis ; 38(1): 51-63, 2017 01.
Article in English | MEDLINE | ID: mdl-27797827

ABSTRACT

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 1ß (IL-1ß), 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.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Cell Transformation, Neoplastic/drug effects , Colitis/complications , Colorectal Neoplasms/prevention & control , Inflammation Mediators/antagonists & inhibitors , Pyrones/pharmacology , Animals , Azoxymethane/toxicity , Biological Products/pharmacology , Carcinogens/toxicity , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Cells, Cultured , Colitis/chemically induced , Colorectal Neoplasms/etiology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Cytokines/antagonists & inhibitors , Cytokines/genetics , Cytokines/metabolism , Dextran Sulfate/toxicity , Inflammation/chemically induced , Inflammation/complications , Inflammation Mediators/metabolism , Macrophages/drug effects , Macrophages/metabolism , Macrophages/pathology , Mice , Mice, Inbred C57BL
3.
Inflamm Bowel Dis ; 21(2): 409-18, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25563695

ABSTRACT

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. 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 colitis-associated cancer. In this review, we will explore the functions of many key cytokines and their roles in IBD and colitis-associated cancer, 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.


Subject(s)
Colitis/complications , Cytokines/immunology , Immune System/immunology , Inflammatory Bowel Diseases/physiopathology , Neoplasms/etiology , Animals , Humans , Inflammatory Bowel Diseases/immunology , Neoplasms/pathology
4.
Cancer J ; 20(3): 181-9, 2014.
Article in English | MEDLINE | ID: mdl-24855005

ABSTRACT

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 become known. 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, as well as how microbes fit into this emerging field.


Subject(s)
Inflammation/microbiology , Microbiota , Neoplasms/microbiology , Animals , Humans , Inflammation/immunology , Inflammation/pathology , Neoplasms/immunology , Neoplasms/pathology
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