Gastric adenocarcinoma remains the second most common cause of cancer-related death worldwide. The vast majority of gastric cancer evolves in the stomach in the setting of chronic atrophic gastritis usually in association with Helicobacter pylori infection. While the role of H. pylori as the proximate cause of gastric carcinogenesis is well established, the cellular basis of lineage changes that lead to development of preneoplastic metaplasia and progression to cancer remain unclear. The normal gastric fundic mucosa is assembled from a heterogeneous group of epithelial lineages responsible for the normal secretion of mucins, pepsinogen and HCl. Chronic injury associated with H. pylori infection leads to prominent changes in the composition of the gastric epithelia, with loss of parietal cells (oxyntic atrophy), expansion of surface cells (foveolar hyperplasia) and mucous cell metaplasia. Two metaplastic lineages are now acknowledged in the setting of oxyntic atrophy in humans: intestinal metaplasia (characterized by the presence of intestinal goblet cells in the gastric mucosa) and Spasmolytic Polypeptide Expressing Metaplasia (SPEM; characterized by presence of antral type mucous cells in the body of the stomach). However, Helicobacter infection in mice leads only to SPEM. Over the past 15 years, we have investigated the factors that lead to the development of SPEM in the face of oxyntic atrophy. Using lineage-mapping studies in mice, we have demonstrated that SPEM arises, not from professional progenitor cells, but from transdifferentiation of mature Mist1-expressing chief cells into mucous cell metaplasia. All of these results support the hypotheses that loss of parietal cells from the gastric fundic mucosa induces the development of SPEM from transdifferentiation of chief cells. Since SPEM appears to be the initial pre-cancerous metaplastic response to oxyntic atrophy, it is critical to understand how transdifferentiation of chief cells leads to the emergence of SPEM as the central initial event required for the development of dysplasia and neoplasia in the stomach. We will therefore continue our studies of the origin of metaplasia through the prosecution of three specific aims: First, we will examine the plasticity of chief cell transdifferentiation into metaplasia. Sice our present studies suggest that the ability to transdifferentiate may be a general property of chief cells, we will evaluate whether transdifferentiation induced by oxyntic atrophy is a polyclonal process. Because induction of SPEM is reversible in acute oxyntic atrophy, we will use lineage-mapping studies to evaluate whether SPEM transdifferentiation is directly reversible back into chief cells. Second, we will evaluate the role of CD44variant in the initiation of SPEM. Since we have found that up-regulation of CD44variant marks the earliest point yet identified in the process of transdifferentiation, we will seek to identify critical gene transcription changes attendant with CD44variant up- regulation in chief cells. Further, we will examine whether inhibition of the xCT cystine-glutamate antiporter, a target for activation by CD44variant, can alter the induction or progression of SPEM. Third, we will examine the role of miRNAs in the induction of metaplastic phenotypes by determining whether targeted loss of Dicer expression in chief cells alters the induction of SPEM. All of these studies will help identify fundamental mechanisms involved in chief cell transdifferentiation and may lead to insights in how pre-neoplastic metaplastic lineage changes can be prevented or reversed.

Public Health Relevance

Gastric cancer is the second most common cause of cancer-related death worldwide. American military actions often expose soldiers to areas with higher prevalence for gastric cancer and increasingly immigrants from high gastric cancer regions in South America are playing a greater role in the US military. Thus, gastric cancer represents a probable increased risk for future Veterans. Given the dismal overall survival for patients with gastric cancer, identification of pre cancerous lesions and the development of strategies to arrest the progression or even reverse these changes is a high priority. The present proposed investigations seek to establish a greater knowledge of the reversibility of pre-cancerous metaplastic changes in the stomach and evaluate novel approaches to arresting pre-cancerous changes.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000930-08
Application #
9551504
Study Section
Gastroenterology (GAST)
Project Start
2010-09-01
Project End
2019-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
156385783
City
Nashville
State
TN
Country
United States
Zip Code
37212
Choi, Eunyoung; Lantz, Tyler L; Vlacich, Gregory et al. (2018) Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach. Gut 67:1595-1605
Meyer, Anne R; Goldenring, James R (2018) Injury, repair, inflammation and metaplasia in the stomach. J Physiol 596:3861-3867
Goldenring, James R (2018) Pyloric metaplasia, pseudopyloric metaplasia, ulcer-associated cell lineage and spasmolytic polypeptide-expressing metaplasia: reparative lineages in the gastrointestinal mucosa. J Pathol 245:132-137
Petersen, Christine P; Meyer, Anne R; De Salvo, Carlo et al. (2018) A signalling cascade of IL-33 to IL-13 regulates metaplasia in the mouse stomach. Gut 67:805-817
Means, Anna L; Freeman, Tanner J; Zhu, Jing et al. (2018) Epithelial Smad4 Deletion Up-Regulates Inflammation and Promotes Inflammation-Associated Cancer. Cell Mol Gastroenterol Hepatol 6:257-276
Bockerstett, Kevin A; Osaki, Luciana H; Petersen, Christine P et al. (2018) Interleukin-17A Promotes Parietal Cell Atrophy by Inducing Apoptosis. Cell Mol Gastroenterol Hepatol 5:678-690.e1
Jeong, Sangho; Choi, Eunyoung; Petersen, Christine P et al. (2017) Distinct metaplastic and inflammatory phenotypes in autoimmune and adenocarcinoma-associated chronic atrophic gastritis. United European Gastroenterol J 5:37-44
Mills, Jason C; Goldenring, James R (2017) Metaplasia in the Stomach Arises From Gastric Chief Cells. Cell Mol Gastroenterol Hepatol 4:85-88
Goldenring, James R; Mills, Jason C (2017) Isthmus Time Is Here: Runx1 Identifies Mucosal Stem Cells in theĀ Gastric Corpus. Gastroenterology 152:16-19
Bertaux-Skeirik, Nina; Wunderlich, Mark; Teal, Emma et al. (2017) CD44 variant isoform 9 emerges in response to injury and contributes to the regeneration of the gastric epithelium. J Pathol 242:463-475

Showing the most recent 10 out of 25 publications