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

Nat Cell Biol. 2015 Aug;17(8):1062-73. doi: 10.1038/ncb3206. Epub 2015 Jul 27.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Adenocarcinoma / genetics
  • Adenocarcinoma / immunology
  • Adenocarcinoma / microbiology
  • Adenocarcinoma / pathology
  • Adenocarcinoma / prevention & control*
  • Adenoma / genetics
  • Adenoma / immunology
  • Adenoma / microbiology
  • Adenoma / pathology
  • Adenoma / prevention & control*
  • Animals
  • Autophagy
  • Autophagy-Related Protein 7
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / microbiology
  • Cell Cycle Checkpoints
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / immunology
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Colon / immunology
  • Colon / metabolism*
  • Colon / microbiology
  • Colon / pathology
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / microbiology
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / prevention & control*
  • Disease Models, Animal
  • Dysbiosis
  • Enzyme Activation
  • Female
  • Genes, APC
  • Host-Pathogen Interactions
  • Humans
  • Immunity, Mucosal*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microbiota / immunology*
  • Microtubule-Associated Proteins / deficiency*
  • Microtubule-Associated Proteins / genetics
  • Time Factors
  • Tumor Burden
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin-Activating Enzymes / metabolism*

Substances

  • Atg7 protein, mouse
  • Microtubule-Associated Proteins
  • Tumor Suppressor Protein p53
  • AMP-Activated Protein Kinases
  • Atg7 protein, human
  • Autophagy-Related Protein 7
  • Ubiquitin-Activating Enzymes