Intestinal inhibition of Atg7 prevents tumour initiation through a microbiome-influenced immune response and suppresses tumour growth

被引：156

作者：

Levy, Jonathan ^{[1
,2
]}

Cacheux, Walfran ^{[1
,2
,3
,4
]}

Bara, Medhi Ait ^{[1
,2
]}

L'Hermitte, Antoine ^{[1
,2
]}

Lepage, Patricia ^{[5
,6
]}

Fraudeau, Marie ^{[1
,2
]}

Trentesaux, Coralie ^{[1
,2
]}

Lemarchand, Julie ^{[1
,2
]}

Durand, Aurelie ^{[1
,2
]}

Crain, Anne-Marie ^{[1
,2
,7
]}

Marchiol, Carmen ^{[1
,2
]}

Renault, Gilles ^{[1
,2
]}

Dumont, Florent ^{[1
,2
]}

Letourneur, Franck ^{[1
,2
]}

Delacres, Myriam ^{[8
,9
,10
,11
]}

Schmitt, Alain ^{[1
,2
]}

Terris, Benoit ^{[1
,2
,12
]}

Perret, Christine ^{[1
,2
]}

Chamaillard, Mathias ^{[8
,9
,10
,11
]}

Couty, Jean-Pierre ^{[1
,2
,7
]}

Romagnolo, Beatrice ^{[1
,2
]}

机构：

[1] Univ Paris 05, CNRS, Inst Cochin, UMR8104, F-75014 Paris, France

[2] Inst Natl Sante & Rech Med INSFRM, U1016, F-75014 Paris, France

[3] Inst Curie, Dept Med Oncol, F-75248 Paris 05, France

[4] Inst Curie, Dept Genet, Pharmacogen Unit, F-75248 Paris 05, France

[5] INRA, Micalis UMR1319, F-78352 Jouy En Josas, France

[6] AgroParis Tech, Micalis UMR1319, F-78350 Jouy En Josas, France

[7] Univ Paris Diderot, Sorbonne Paris Cite, UFR Sci Vivant, F-75013 Paris, France

[8] Univ Lille Nord France, F-59000 Lille, France

[9] Ctr Infect & Immun Lille, Inst Pasteur Lille, F-59800 Lille, France

[10] CNRS, Unite Mixle Rech, F-59046 Lille, France

[11] Inst Nat Sante & Rech Med, F-59045 Lille, France

[12] Univ Paris 05, Hop Cochin, AP HP, Serv Anat & Cytol Pathol, F-75014 Paris, France

来源：

NATURE CELL BIOLOGY | 2015年 / 17卷 / 08期

关键词：

AUTOPHAGY GENE ATG16L1; REGULATORY T-CELLS; TUMORIGENESIS; CANCER; MICE; INFLAMMATION; MOUSE; PROGRESSION; ACTIVATION; EXPRESSION;

D O I：

10.1038/ncb3206

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Here, we show that autophagy is activated in the intestinal epithelium in murine and human colorectal cancer and that the conditional inactivation of Atg7 in intestinal epithelial cells inhibits the formation of pre-cancerous lesions in Apc(+/-) mice by enhancing anti-tumour responses. The antibody-mediated depletion of CD8(+) T cells showed that these cells are essential for the anti-tumoral responses mediated by the inhibition of autophagy. We show that Atg7 deficiency leads to intestinal dysbiosis and that the microbiota is required for anticancer responses. In addition, Atg7 deficiency resulted in a stress response accompanied by metabolic defects, AMPK activation and p53-mediated cell-cycle arrest in tumour cells but not in normal tissue. This study reveals that the inhibition of autophagy within the epithelium may prevent the development and progression of colorectal cancer in genetically predisposed patients.

引用

页码：1062 / U440

页数：24

共 58 条

[1] Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine [J].

Andreu, P ;

Colnot, S ;

Godard, C ;

Gad, S ;

Chafey, P ;

Niwa-Kawakita, M ;

Laurent-Puig, P ;

Kahn, A ;

Robine, S ;

Perret, C ;

Romagnolo, B .

DEVELOPMENT, 2005, 132 (06) :1443-1451

[2]

[Anonymous], GUT

[3] Intestinal Epithelial Autophagy Is Essential for Host Defense against Invasive Bacteria [J].

Benjamin, Jamaal L. ;

Sumpter, Rhea, Jr. ;

Levine, Beth ;

Hooper, Lora V. .

CELL HOST & MICROBE, 2013, 13 (06) :723-734

[4] Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses [J].

Berg, DJ ;

Davidson, N ;

Kuhn, R ;

Muller, W ;

Menon, S ;

Holland, G ;

ThompsonSnipes, L ;

Leach, MW ;

Rennick, D .

JOURNAL OF CLINICAL INVESTIGATION, 1996, 98 (04) :1010-1020

[5] Metabolic Regulation by p53 Family Members [J].

Berkers, Celia R. ;

Maddocks, Oliver D. K. ;

Cheung, Eric C. ;

Mor, Inbal ;

Vousden, Karen H. .

CELL METABOLISM, 2013, 18 (05) :617-633

[6] A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells [J].

Cadwell, Ken ;

Liu, John Y. ;

Brown, Sarah L. ;

Miyoshi, Hiroyuki ;

Loh, Joy ;

Lennerz, Jochen K. ;

Kishi, Chieko ;

Kc, Wumesh ;

Carrero, Javier A. ;

Hunt, Steven ;

Stone, Christian D. ;

Brunt, Elizabeth M. ;

Xavier, Ramnik J. ;

Sleckman, Barry P. ;

Li, Ellen ;

Mizushima, Noboru ;

Stappenbeck, Thaddeus S. ;

Virgin, Herbert W. .

NATURE, 2008, 456 (7219) :259-U62

[7] Role of Autophagy and Autophagy Genes in Inflammatory Bowel Disease [J].

Cadwell, Ken ;

Stappenbeck, Thaddeus S. ;

Virgin, Herbert W. .

AUTOPHAGY IN INFECTION AND IMMUNITY, 2009, 335 :141-167

[8] QIIME allows analysis of high-throughput community sequencing data [J].

Caporaso, J. Gregory ;

Kuczynski, Justin ;

Stombaugh, Jesse ;

Bittinger, Kyle ;

Bushman, Frederic D. ;

Costello, Elizabeth K. ;

Fierer, Noah ;

Pena, Antonio Gonzalez ;

Goodrich, Julia K. ;

Gordon, Jeffrey I. ;

Huttley, Gavin A. ;

Kelley, Scott T. ;

Knights, Dan ;

Koenig, Jeremy E. ;

Ley, Ruth E. ;

Lozupone, Catherine A. ;

McDonald, Daniel ;

Muegge, Brian D. ;

Pirrung, Meg ;

Reeder, Jens ;

Sevinsky, Joel R. ;

Tumbaugh, Peter J. ;

Walters, William A. ;

Widmann, Jeremy ;

Yatsunenko, Tanya ;

Zaneveld, Jesse ;

Knight, Rob .

NATURE METHODS, 2010, 7 (05) :335-336

[9] Cooperation between CD4+ and CD8+ T cells:: When, where, and how [J].

Castellino, Flora ;

Germain, Ronald N. .

ANNUAL REVIEW OF IMMUNOLOGY, 2006, 24 :519-540

[10] Intestinal macrophages and dendritic cells: what's the difference? [J].

Cerovic, Vuk ;

Bain, Calum C. ;

Mowat, Allan M. ;

Milling, Simon W. F. .

TRENDS IN IMMUNOLOGY, 2014, 35 (06) :270-277

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