Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4

Chronic inflammation is a known risk factor for tumorigenesis, yet the precise mechanism of this association is currently unknown. The inflammasome, a multiprotein complex formed by NOD-like receptor (NLR) family members, has recently been shown to orchestrate multiple innate and adaptive immune responses, yet its potential role in inflammation-induced cancer has been little studied. Using the azoxymethane and dextran sodium sulfate colitis-associated colorectal cancer model, we show that caspase-1–deficient (Casp1−/−) mice have enhanced tumor formation. Surprisingly, the role of caspase-1 in tumorigenesis was not through regulation of colonic inflammation, but rather through regulation of colonic epithelial cell proliferation and apoptosis. Consequently, caspase-1–deficient mice demonstrate increased colonic epithelial cell proliferation in early stages of injury-induced tumor formation and reduced apoptosis in advanced tumors. We suggest a model in which the NLRC4 inflammasome is central to colonic inflammation-induced tumor formation through regulation of epithelial cell response to injury.

[1]  F. Marincola,et al.  MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18 , 2010, The Journal of experimental medicine.

[2]  H. Herfarth,et al.  The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer , 2010, The Journal of experimental medicine.

[3]  J. Tschopp,et al.  Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome , 2010, Gut.

[4]  M. Kastan,et al.  The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. , 2010, Immunity.

[5]  N. Beauchemin,et al.  Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. , 2010, Immunity.

[6]  Richard Bonneau,et al.  Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome , 2010, Proceedings of the National Academy of Sciences.

[7]  J. Tschopp,et al.  Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors , 2009, Nature Medicine.

[8]  J. Tschopp,et al.  T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes , 2009, Nature.

[9]  Wendy S. Beane,et al.  Regeneration: The origin of cancer or a possible cure? , 2009, Seminars in cell & developmental biology.

[10]  H. Herfarth,et al.  Modulation of the Intestinal Microbiota Alters Colitis-Associated Colorectal Cancer Susceptibility , 2009, PloS one.

[11]  Richard A Flavell,et al.  A protective function for interleukin 17A in T cell–mediated intestinal inflammation , 2009, Nature Immunology.

[12]  M. Karin,et al.  IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. , 2009, Cancer cell.

[13]  Ozge Canli,et al.  gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. , 2009, Cancer cell.

[14]  F. Sutterwala,et al.  NLRC4/IPAF: a CARD carrying member of the NLR family. , 2009, Clinical immunology.

[15]  P. Allavena,et al.  Cancer-related inflammation , 2008, Nature.

[16]  Richard A. Flavell,et al.  Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants , 2008, Nature.

[17]  N. Mukaida,et al.  Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. , 2008, The Journal of clinical investigation.

[18]  F. Sutterwala,et al.  Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome , 2007, The Journal of experimental medicine.

[19]  C. Sasakawa,et al.  Differential Regulation of Caspase-1 Activation, Pyroptosis, and Autophagy via Ipaf and ASC in Shigella-Infected Macrophages , 2007, PLoS pathogens.

[20]  M. Blasco,et al.  Cellular Senescence in Cancer and Aging , 2007, Cell.

[21]  R. Medzhitov,et al.  Regulation of Spontaneous Intestinal Tumorigenesis Through the Adaptor Protein MyD88 , 2007, Science.

[22]  M. Neurath,et al.  High resolution colonoscopy in live mice , 2006, Nature Protocols.

[23]  V. Radha,et al.  Involvement of caspase 1 and its activator Ipaf upstream of mitochondrial events in apoptosis , 2006, The FEBS journal.

[24]  Alan Aderem,et al.  Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1β via Ipaf , 2006, Nature Immunology.

[25]  M. Swanson,et al.  Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection , 2006, The Journal of experimental medicine.

[26]  V. Dixit,et al.  Cryopyrin activates the inflammasome in response to toxins and ATP , 2006, Nature.

[27]  S. Akira,et al.  Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3 , 2006, Nature.

[28]  T. Kundu,et al.  Caspase-1 activator Ipaf is a p53-inducible gene involved in apoptosis , 2005, Oncogene.

[29]  Stefan Wirtz,et al.  TGF-β Suppresses Tumor Progression in Colon Cancer by Inhibition of IL-6 trans-Signaling , 2004 .

[30]  R. Kiesslich,et al.  TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. , 2004, Immunity.

[31]  V. Dixit,et al.  Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf , 2004, Nature.

[32]  A. Jemal,et al.  Annual report to the nation on the status of cancer, 1975-2000, featuring the uses of surveillance data for cancer prevention and control. , 2003, Journal of the National Cancer Institute.

[33]  F. Martinon,et al.  The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. , 2002, Molecular cell.

[34]  P. Dickman,et al.  Family history as a risk factor for colorectal cancer in inflammatory bowel disease. , 2001, Gastroenterology.

[35]  H. Adami,et al.  Infections as a major preventable cause of human cancer , 2000, Journal of internal medicine.

[36]  A. Jarry,et al.  Interleukin 1 and interleukin 1β converting enzyme (caspase 1) expression in the human colonic epithelial barrier. Caspase 1 downregulation in colon cancer , 1999, Gut.

[37]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.