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.

如同源异型框基因Cdx2在肠道中起着抑癌作用的报道，发育基因有助于癌症。在这项研究中，我们显示出CDX2表达下降最高的人类结肠癌属于锯齿亚型，进化最差。在小鼠中，成年肠道上皮细胞中Cdx2的嵌合敲除会诱导不完全的胃型化生病变的形成。化生敲除细胞不会自发地致癌。但是，它们诱导了微环境的深刻修饰，从而促进了相邻Cdx2的致瘤性进化。通过NF-κB活化，诱导型一氧化氮合酶的诱导以及Apc功能的随机丧失，在病灶表面形成完整的易发肿瘤细胞。这项研究提出了一种新的范式，即通常被认为是癌前期的化生细胞可以诱导邻近的非化生细胞发生肿瘤而不会自身癌变。它揭示了肠中Cdx2基因的非细胞自治肿瘤抑制基因的新颖特性。