The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non-cell-autonomous mechanisms

J Exp Med. 2018 Mar 5;215(3):911-926. doi: 10.1084/jem.20170934. Epub 2018 Feb 8.


Developmental genes contribute to cancer, as reported for the homeobox gene Cdx2 playing a tumor suppressor role in the gut. In this study, we show that human colon cancers exhibiting the highest reduction in CDX2 expression belong to the serrated subtype with the worst evolution. In mice, mosaic knockout of Cdx2 in the adult intestinal epithelium induces the formation of imperfect gastric-type metaplastic lesions. The metaplastic knockout cells do not spontaneously become tumorigenic. However, they induce profound modifications of the microenvironment that facilitate the tumorigenic evolution of adjacent Cdx2-intact tumor-prone cells at the surface of the lesions through NF-κB activation, induction of inducible nitric oxide synthase, and stochastic loss of function of Apc This study presents a novel paradigm in that metaplastic cells, generally considered as precancerous, can induce tumorigenesis from neighboring nonmetaplastic cells without themselves becoming cancerous. It unveils the novel property of non-cell-autonomous tumor suppressor gene for the Cdx2 gene in the gut.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CDX2 Transcription Factor / genetics*
  • Carcinogenesis / genetics*
  • Carcinogenesis / pathology*
  • Cecum / pathology
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • Gene Expression Regulation, Neoplastic
  • Heterozygote
  • Humans
  • Intestinal Neoplasms / genetics*
  • Intestinal Neoplasms / pathology*
  • Intestines / pathology
  • Metaplasia
  • Mice
  • NF-kappa B / metabolism
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Nitric Oxide Synthase Type II / metabolism
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • Tumor Microenvironment


  • CDX2 Transcription Factor
  • NF-kappa B
  • Nitric Oxide Synthase Type II