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  • br Oduwole OO Peltoketo H Poliandri A

    2020-08-30

    
    [28] Oduwole OO, Peltoketo H, Poliandri A, Vengadabady L, Chrusciel M, Doroszko M, et al. Constitutively active follicle-stimulating hor-mone receptor enables androgen-independent spermatogenesis. J Clin Invest 2018;128:1787–92.
    [29] Alimirah F, Chen J, Basrawala Z, Xin H, Choubey D. DU-145 and PC-3 human prostate cancer cell lines express androgen receptor: implications for the androgen receptor functions and regulation. FEBS Lett 2006;580:2294–300.
    [30] Chen SY, Wulf G, Zhou XZ, Rubin MA, Lu KP, Balk SP. Activation of beta-catenin signaling in prostate cancer by peptidyl-prolyl isomer-ase Pin1-mediated abrogation of the androgen receptor-beta-catenin interaction. Mol Cell Biol 2006;26:929–39. Article
    Cell-Type-Specific Responses to Interleukin-1 Control Microbial Invasion and Tumor-Elicited Inflammation in Colorectal Cancer
    Graphical Abstract Authors
    Oxana Dmitrieva-Posocco,
    Giorgio Trinchieri, Ari Waisman,
    Sergei I. Grivennikov
    Correspondence
    [email protected]
    In Brief
    Dmitrieva-Posocco et al. use conditional gene ST 2825 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.
    Highlights
    d IL-1R regulates inflammation, but its blanket inactivation does not reduce CRC
    d Deletion of IL-1R in epithelium delays CRC development independent of inflammation
    d T-cell-specific IL-1R deletion reduces TEI cytokine expression and CRC progression
    d Myeloid IL-1R deletion promotes tumor-specific dysbiosis, inflammation and CRC growth
    Immunity Article
    Cell-Type-Specific Responses to Interleukin-1 Control Microbial Invasion and Tumor-Elicited Inflammation in Colorectal Cancer
    Oxana Dmitrieva-Posocco,1,2 Amiran Dzutsev,3 David F. Posocco, 1 Vivianty Hou,1 Wuxing Yuan,3 Vishal Thovarai,4 Ilgiz A. Mufazalov,5 Matthias Gunzer,6 Igor P. Shilovskiy,2 Musa R. Khaitov,2 Giorgio Trinchieri,3 Ari Waisman,5 and Sergei I. Grivennikov1,7,* 1Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA 2Personalized Medicine and Molecular Immunology, National Research Center – Institute of Immunology, FMBA, Moscow, 115478, Russia 3Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
    4Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA 5Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, 55131, Germany 6University Duisburg-Essen, University Hospital, Institute for Experimental Immunology and Imaging, 45122 Essen, Germany 7Lead contact *Correspondence: [email protected]
    SUMMARY
    Chronic inflammation drives the progression of colo-rectal cancer (CRC). Increased expression of inter-leukin (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 micro-environment. 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 progres-sion. The pro-tumorigenic roles of IL-1 were counter-acted by its effects on myeloid cells, particularly neu-trophils, 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 aggre-gate, set the inflammatory tone of the tumor microen-vironment and determine the propensity for disease progression.
    INTRODUCTION
    A particularly important component of the pro-tumorigenic microenvironment is the presence of inflammatory cells and the subsequent chronic inflammatory response. Although chronic inflammation is a well-established driver in many can-cers (Mantovani et al., 2008), inflammation also appears to play a deleterious role in cancers without overt underlying inflam-matory etiologies. This phenomenon, characterized by a tumor’s
    ability to recruit inflammatory immune cells to the local micro-environment to drive both tumor growth and progression, is referred to as tumor-elicited inflammation (TEI) (Grivennikov et al., 2012). The relevance of TEI is illustrated by the efficacy of anti-inflammatory treatments in reducing mortality from can-cers that are classically thought of as ‘‘non-inflammatory’’ (Roth-well et al., 2012).