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

Abstract

Balbinot et al. show that intestinal epithelial cells depleted in the homeobox gene Cdx2 acquire an imperfect gastric-type metaplastic phenotype that, through changes in the microenvironment, induces the tumorigenic evolution of adjacent Cdx2-intact cells without themselves becoming cancerous.

Metaplastic Cdx2-depleted cells can be very disruptive neighbors

“…Strong CDX2 down-regulation was shown to be associated with one particular subtype characterized by serrated precursor neoplasia, stromal infiltration, stem-cell–like features, and poor prognosis (Marisa et al, 2013). In the current mouse study, Balbinot et al (2018) found the expected, cecal polypoid lesions with some degree of gastric metaplasia. This was confirmed by transcriptomic analysis where intestinal markers such as Cdx1 or Alpi were down-regulated and several gastric markers (e.g., Tff1/2, Cldn18, Muc1/6) were up-regulated.…”

“…In the search for a mechanism, Balbinot et al (2018) looked again at the transcriptome of gastric metaplasia present in the cecum. They found up-regulation of several cytokines and chemokines previously associated with malignancy.…”

“…One of the pending questions Balbinot et al (2018) did not address relates to why Cdx2-negative cells do not themselves initiate neoplasia. Speculatively, the answer may lie in the way the intestinal epithelium is renewed.…”

Pyloric metaplasia, pseudopyloric metaplasia, ulcer‐associated cell lineage and spasmolytic polypeptide‐expressing metaplasia: reparative lineages in the gastrointestinal mucosa

“…This observation might implicate Paneth cells as an origin for the formation of UACL, but this requires further investigation. Of note, loss of Cdx2 in the intestines of mice leads to the development of a pyloric-type metaplasia expressing antral mucins, TFF1, and TFF2 [64,65]. Thus, loss of the expression of the Cdx2 master-regulator transcription factor in stem cells may also account for colonic lineage reprogramming towards an antral mucous gland phenotype.…”

Chromatin de-condensation by switching substrate elasticity

“…Maf factors are involved in the cell stress response and can interact alternatively with Bach or Nfe to promote transcription repression or activation 36 . It is also interesting that expression of the homeobox gene Cdx2 and the nuclear receptor family gene Hnf4α, two major regulators of intestinal homeostasis with tumour suppressor activity 37 – 39 , was downregulated, as well as stimulation of the Macc1 gene involved in metastasis 40 .

Figure 8 Functional clustering annotation of the differentially expressed genes.

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