Adenocarcinoma in the human stomach evolves in the setting of Helicobacter pylori- induced oxyntic atrophy and chronic mucous cell metaplasia. Our recent lineage mapping studies have demonstrated that metaplasia in the gastric fundus in mice does not arise from the professional progenitor cells located in the upper neck region of the glands, but rather develops from transdifferentiation of mature chief cells into Spasmolytic Polypeptide Expressing Metaplasia, or SPEM. These studies have led to a significant paradigm shift in the concepts for the origin of gastric neoplasia, suggesting that pre-neoplastic lineages do not arise from professional resident mucosal progenitor cell populations, but rather develop from transdifferentiation of mature zymogenic cell lineages. Furthermore, multiple studies now indicate that SPEM, under the influence of inflammation, can develop both increased proliferation and increasing levels of intestinalizing gene expression, and in humans gives rise to goblet cell intestinal metaplasia. Our recent investigations have demonstrated that macrophages are responsible for the promotion of proliferative SPEM progression, but the precise mediators that are responsible for the progression of SPEM towards intestinalization and dysplasia remain unknown. We therefore hypothesize that discrete intrinsic mucosal and macrophage-derived factors regulate not only the evolution, but also the progression of SPEM to more proliferative, preneoplastic metaplasia. To address this hypothesis, we will pursue two specific aims: First, we will examine the role of macrophages in the evolution and progression of metaplasia. Second, we will evaluate the role of Ras activation in evolution of SPEM from transdifferentiating chief cells and the further intestinalization of SPEM lineages in a novel model of metaplasia driven by inducible expression of activated K-Ras in chief cells. While our previous investigations have focused on the establishment of a novel pathway for generation of metaplasia through transdifferentiation of chief cells, the present investigations now focus on the mechanisms that might drive metaplasias to preneoplasia.

Public Health Relevance

Metaplasias are the major precursor lesions for gastric cancer. This proposal seeks to understand the induction and progression of metaplasia towards cancer and how an understanding of pre-cancerous lesions can lead to improved approaches for early detection and treatment.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01DK101332-01A1
Application #
8722082
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Carrington, Jill L
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Nashville
State
TN
Country
United States
Zip Code
37212