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