The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non-cell-autonomous mechanisms
The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non-cell-autonomous mechanisms
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DOI：
10.1084/jem.20170934
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发表时间：
2018-03-01
影响因子：
15.3
通讯作者：
Duluc, Isabelle
中科院分区：
文献类型：
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作者：
Balbinot, Camille;Armant, Olivier;Duluc, Isabelle
发育基因有助于癌症，如报道的同源异型盒基因Cdx 2在肠道中发挥肿瘤抑制作用。在这项研究中，我们表明，表现出CDX 2表达最高降低的人类结肠癌属于进化最差的锯齿亚型。在小鼠中，嵌合体敲除成年肠上皮中的Cdx 2诱导形成不完全胃型化生病变。化生性敲除细胞不会自发地成为致瘤细胞。然而，它们诱导微环境的深刻改变，通过NF-κ B活化、诱导型一氧化氮合酶的诱导和Apc功能的随机丧失，促进病变表面邻近Cdx 2完整的肿瘤易感细胞的致瘤性演变。这项研究提出了一个新的范例，即化生细胞，通常被认为是癌前病变，可以诱导邻近的非化生细胞的肿瘤发生，而不会使自己癌变。它揭示了肠道中Cdx 2基因非细胞自主肿瘤抑制基因的新特性。
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-kappa B 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.