JCSMR Special School Seminar: Cellular origin of gastric cancer and molecular carcinogenesis of colon cancer

Associate Professor Ki Taek Nam, DVM, PhD, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea

The gastric epithelium is geographically heterogeneous, containing functionally distinct pyloric and fundic mucosal lineages. In humans, the loss of parietal cells is a prerequisite step for the development of intestinal-type gastric cancer. Active chronic gastritis, most often caused by Helicobacter pylori infection, progresses to multifocal atrophic gastritis with loss of parietal cells and chief cells and the appearance of metaplastic lineages that are predisposed to neoplastic transformation. Thus, oxyntic atrophy, the loss of parietal cells, represents the critical alteration of the gastric mucosal most associated with gastric preneoplasia. The loss of parietal cells leads to the development of 2 identifiable metaplasias associated with gastric cancer: intestinal metaplasia (IM) and spasmolytic polypeptide-expressing metaplasia (SPEM). Recently, our studies showed that SPEM is an early metaplastic change in the fundus of the stomach in the setting of Amphiregulin (AR) deficiency. IM evolved in the setting of precedent SPEM, suggesting that IM arises from SPEM. These findings in AR-null mice represent the first mouse model of both SPEM and IM induction associated with eventual neoplasia.
We have hypothesized that SPEM arises from proliferating cells in gland bases, either from a cryptic progenitor cell or by transdifferentiation of mature chief cells. Taking advantage of the chief cell-restricted expression of Mist1-Cre-ER(T2), we used lineage mapping to examine whether SPEM lineages were derived from chief cells in 3 independent models of induction by DMP-777 treatment, L-635 treatment, or H felis infection. Treatment of mice with L-635 for 3 days led to rapid parietal cell loss, induction of a prominent inflammatory infiltrate, and emergence of SPEM. In all 3 models, SPEM developed, at least in part, from transdifferentiation of chief cells. We further found that acute parietal cell loss in the setting of inflammation (L-635 treatment) led to more rapid induction and expansion of SPEM derived from transdifferentiation of chief cells. These studies provide direct evidence by lineage tracing that SPEM evolves from differentiated chief cells. Thus, mature gastric chief cells have the ability to act as cryptic progenitors and reacquire proliferative capacity within the context of mucosal injury and inflammation.
Transformation of epithelial cells is associated with loss of cell polarity, which includes alterations in cell morphology as well as changes in the complement of plasma membrane proteins. Rab proteins regulate polarized trafficking to the cell membrane and therefore represent potential regulators of this neoplastic transition. Here we have demonstrated a tumor suppressor function for Rab25 in intestinal neoplasia in both mice and humans. Human colorectal adenocarcinomas exhibited reductions in Rab25 expression independent of stage, with lower Rab25 expression levels correlating with substantially shorter patient survival. In wild-type mice, Rab25 was strongly expressed in cells luminal to the proliferating cells of intestinal crypts. While Rab25-deficient mice did not exhibit gross pathology, ApcMin/+ mice crossed onto a Rab25-deficient background showed a 4-fold increase in intestinal polyps and a 2-fold increase in colonic tumors compared with parental ApcMin/+ mice. Rab25-deficient mice had decreased beta1 integrin staining in the lateral membranes of villus cells, and this pattern was accentuated in Rab25-deficient mice crossed onto the ApcMin/+ background. Additionally, Smad3+/- mice crossed onto a Rab25-deficient background demonstrated a marked increase in colonic tumor formation. Taken together, these results suggest that Rab25 may function as a tumor suppressor in intestinal epithelial cells through regulation of protein trafficking to the cell surface.

Date & time

12–1pm 19 February 2014


Seminar Room 2 (3.378) The John Curtin School of Medical Research, Building 131, Garran Road, ANU


 Laura Vitler
 +61 2 6125 2589

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