Mini-Symposium
Biology of intestinal metaplasia in 2008: More than a simple phenotypic alteration

https://doi.org/10.1016/j.dld.2008.02.029Get rights and content

Abstract

This review concentrates on one main aspect of cancerization in the oesophagus and stomach: principally, intestinal metaplasia. There are at least two other important pathways that lead to cancer and do not need such a morphological transformation. One is the gastric type of carcinoma on the Lauren classification, which arises directly from the stem cell zone and is the signet ring form of cancer, while the other is spasmolytic polypeptide-expressing metaplasia (SPEM)—spasmolytic polypeptide (TFF2) expressing metaplasia, where the gastric glands become filled with TFF2-expressing cells and may also lead to gastric dysplasia and cancer. The development of intestinal metaplasia is complex. Here, we examine intestinal metaplasia in molecular terms, noting the over-expression of Cdx1, Cdx2, Pdx1, Oct1, TFF3 and the downregulation of Hedgehog signalling; Runx3 is deactivated by epigenetic silencing, and pathways such as Wnt and MARK/ERK are involved. These changes start to explain the principles of the development of intestinal metaplasia and suggest that the regulation of these genes is of importance in the development of gastric cancer.

Section snippets

Intestinal metaplasia (IM)

Metaplasia is defined as a potentially reversible change from a fully differentiated cell type to another, implying adaptation to environmental stimuli and is an important phenomenon for several reasons. Firstly, IM is frequently found in the gastrointestinal tract (particularly in the oesophagus and stomach), being the most commonly recognized metaplasia of the upper gut is intestinal metaplasia. This occurs as a result of Helicobacter pylori infection, chronic bile reflux [1], [2], [3], [4]

Genes and transcription factors in intestinal metaplasia

IM is a critically important change in the gastric mucosa. Most modern concepts of the origin of the intestinal type of gastric carcinoma place IM as the first morphological change [31], [32]. However, the mechanism of development of IM in the human stomach has yet to be clarified in detail but since it involves a change from gastric to intestinal phenotype the study of early gut development might be fruitful. Regional specification of the embryo involves transcription factors that regulate

Sox gene family

Gastric transcription factors, such as the Sox gene family, which play key roles in embryogenesis [116], [117], may also be important in the development of IM. Sox proteins moved centre-stage with the identification of Sry as the gene determining testis development in mouse and man. This gene was a member of a new family, related by an amino-acid motif showing homology to other known or putative DNA-binding domains [118]. The Sox gene family (Sry like HMG box gene) is characterized by a

POU family

POU proteins are expressed in early embryogenesis in many organs and systems, play fundamentally important roles in the organ development and in the growth and differentiation of cells. The POU domain is the conserved DNA-binding domain of a family of developmental regulators and transcription factors and was defined by analysing the products of three mammalian genes, Pit-l, Oct-l and Oct-2 [128]. It consists of a conserved POU-specific domain and a POU homeodomain, connected by a variable

Runt-related transcription factor gene 3 (RUNX3)

The RUNX family of transcription factors plays a pivotal role during normal development and also in tumourigenesis [137]. The RUNX3 protein is expressed in most chief cells and a few gastrin-producing G cells in normal gastric mucosa, but not in IM and human gastric cancer cells [138]. These data support the concept that Runx3 is a tumour suppressor gene in human gastric carcinoma and that the lack of Runx3 is causally related to the genesis and progression of human gastric cancer [137], [139].

MAPK/ERK pathway

The MAPK/ERK pathway is a signal transduction pathway that couples intracellular responses to the binding of growth factors to cell surface receptors. This pathway is complex and includes many components [142]. Mitogen-activated protein kinases (MAPK) are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate many cellular activities, such as gene expression, mitosis, differentiation and cell survival/apoptosis. In this field, particular emphasis has been

Conclusions

One constant in the aetiology of gastric cancer is oxyntic atrophy or loss of parietal cells that leads to emergence of metaplastic lineages that are predisposed to neoplastic transformation. Traditionally, IM, which is characterized by the presence of a goblet-type, mucin-secreting cell lineage, has received the most consideration as a precursor of gastric and oesophagus cancer. Recent investigations have led to re-evaluation of the true origin of IM. For the moment, this pathogenesis has been

Conflict of interest statement

None declared.

Acknowledgements

We extend our sincere thanks to Dr. Richard Poulsom and Dr. Stuart McDonald for support and assistance in preparing this manuscript.

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