Genome‐wide analysis of the oxyntic proliferative isthmus zone reveals ASPM as a possible gastric stem/progenitor cell marker over‐expressed in cancer

Abstract

The oxyntic proliferative isthmus zone contains the main stem/progenitor cells that provide for physiological renewal of the distinct mature cell lineages in the oxyntic epithelium of the stomach. These cells are also proposed to be the potential cells‐of‐origin of gastric cancer, although little is known about their molecular characteristics and specific biological markers are lacking. In this study, we developed a method for serial section‐navigated laser microdissection to isolate cells from the proliferative isthmus zone of rat gastric oxyntic mucosa for genome‐wide microarray gene expression analysis. Enrichment analysis showed a distinct gene expression profile for the isthmus zone, with genes regulating intracellular processes such as the cell cycle and ribosomal activity. The profile was also related to stem cell transcriptional networks and stomach neoplasia. Genes expressed uniquely in the isthmus zone were associated with E2F transcription factor 1 (E2F1), which participates in the self‐renewal of stem cells and in gastric carcinogenesis. One of the unique genes was Aspm [Asp (abnormal spindle) homologue, microcephaly‐associated (Drosophila)]. Here we show ASPM in single scattered epithelial cells located in the proliferative isthmus zone of rat, mouse and human oxyntic mucosa, which do not seem to be actively dividing. The ASPM‐expressing cells are mainly mature cell marker‐deficient, except for a limited overlap with cells with neuroendocrine and tuft cell features. Further, both ASPM and E2F1 were expressed in human gastric cancer cell lines and increased and correlated in human gastric adenocarcinomas compared to non‐tumour mucosa, as shown by expression profile analyses and immunohistochemistry. The association between ASPM and the transcription factor E2F1 in gastric tissue is relevant, due to their common involvement in crucial cell fate‐regulatory mechanisms. Our results thus introduce ASPM as a novel possible oxyntic stem/progenitor cell marker that may be involved in both normal gastric physiology and gastric carcinogenesis. © 2015 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

A candidate gastric stem/progenitor cell marker revealed by genome‐wide analysis

“…Further examination showed a strong correlation of ASPM and E2F1 mRNA levels in human gastric samples. Taken together, the authors propose that the E2F1-ASPM regulation axis may also be involved in gastric carcinogenesis besides normal physiology [14].…”

“…This report [14], together with a series of other elegant publications, has substantially expanded our knowledge of gastric stem cells in the murine system. However, the literature is rather scarce concerning the human stomach, which is radically different from the rodent stomach.…”

“…E2F1 is a transcription factor previously found to be involved in various biological processes including cell cycle control and cell survival, as well as stemness maintenance. Importantly, the authors found that all of the 12 E2F1 target genes uniquely expressed in the isthmus region are predicted to be associated with gastric neoplasia [14].…”

“…In recent work published in The Journal of Pathology, Vange et al investigated the very first question towards a better understanding of the gastric stem cells in the isthmus, namely the biomarkers of those cells [14]. The histology of gastric stem cells was first described by Karam and Leblond back in 1993 [8].…”

“…They found that ASPM is expressed in scattered cells mainly in the isthmus zone of rat, mouse or human oxyntic mucosa by immunohistochemical (IHC) staining or in situ hybridization. ASPM-expressing cells are epithelial cell marker E-cadherin-positive but do not seem to express markers of differentiated parietal cells, mucous neck cells, or tuft cells in rats, although a few of them are A candidate gastric stem cell marker revealed 5 positive for tuft cell or neuroendocrine cell markers in human samples [14]. On the basis of their isthmus zone localization and deficiency of mature cell markers, ASPM-positive cells are proposed by the authors to be putative oxyntic stem progenitor cells (Figure 1).…”