Mechanisms of regulation of normal and metaplastic intestinal differentiation

The gastrointestinal tract is an organized structure originating from the three embryonic germ layers: endoderm, mesoderm and ectoderm. Morphological changes that accompany its formation are relatively well known, although the underlying molecular mechanisms are still poorly defined. Intestinal metaplasia, resulting from an epithelial transdifferentiation process, is considered a precursor lesion of gastric adenocarcinoma, a malignancy with serious consequences in terms of morbidity and mortality worldwide. Similarly to gastrointestinal embryonic development, molecular changes involved in the development of this lesion that recapitulate the intestinal development, out of time and space, are also widely unknown. In this review we present, briefly, the process of formation of the digestive tract, from its embryonic age to adulthood, with emphasis on anterior-posterior patterning and on molecular mechanisms that may play an important role. In addition, we try to establish a parallel and understand what mechanisms can, through their deregulation, originate the metaplastic lesion. Cdx genes appear to be the main regulators of normal intestinal differentiation and also to be largely involved in the metaplastic epithelial transdifferentiation process. However, control of gene expression both during intestinal development and in intestinal metaplasia is complex and seems to depend on several transcription factors. More extensive studies about the mechanisms underlying intestinal metaplasia are needed if we aim to prevent neoplasia development and all its negative consequences in persons at risk.