Gastric Carcinogenesis in a Novel Genetically Engineered Mouse Model
Abstract
Background: Gastric cancer is the second highest cause of cancer-related death worldwide, and the highest incidence of stomach cancer is in Asia and Latin America with factors, such as highly salted foods or Helicobacter pylori infection, which may increase chances of stomach cancer development. Also, investigations have documented a prominent increased risk of gastric cancer in the United States in recent immigrant populations, especially those from Latin America. Importantly, Latino immigrants represent an increasingly important group of recruits for military service, and so it is likely that gastric cancer will become an increasing concern in the United States military personnel. Gastric cancer develops in the setting of extensive pre-cancerous changes in the stomach lining called metaplasia. In the human stomach, two types of metaplasia are associated with development of intestinal-type cancers: intestinal metaplasia (IM) and Spasmolytic Polypeptide Expressing Metaplasia (SPEM). The initial trigger for these changes is loss of the cells that make stomach acid. After these cells are lost, we know from previous studies that the stomach cells that secrete gastric digestive enzymes in the normal stomach, known as chief cells, turn into metaplastic mucous cells. Another finding that is important for understanding where gastric cancer comes from is that Ras activity, an important cancer driver, is increased in at least 40% of gastric cancers. However, there is very limited understanding of how all these factors work together to cause gastric cancer to develop. This is largely because there are no mouse models that develop the full spectrum of gastric pre-cancerous and cancerous lesions seen in human patients. Overall Objective: My goal in this study is to understand the biology of active KRas in gastric chief cells as an origin of metaplasia and invasive gastric cancer. Since it is presently unclear which particular cell types in the stomach can act as a cell-of-origin in gastric carcinogenesis, there are few effective targeted therapeutic approaches in gastric cancer patients. Specific Objectives: (1) Generate a mouse model (GIF-rtTA mouse) that specifically allows genetic manipulation of the chief cells in the stomach. (2) Investigate how activation of KRas only in the chief cells can result in gastric adenocarcinoma and/or could make the cancer invasive or metastatic. (3) Develop novel metaplasia cell lines by "organoid" in vitro culture technology to examine whether the metaplasia organoids can develop into a solid tumor, which would support the idea of chief cells as cells-of-origin for gastric cancer. Benefits: Previous studies have not yet led to a full understanding the processes of gastric adenocarcinoma development. If we know the cell of origin, then this will allow us to develop therapies that specifically target that cell type. Thus, my idea of testing whether chief cells are the origin of metaplasia and gastric cancer is of fundamental importance. If my novel mouse model develops gastric adenocarcinoma, I expect this study will lead us to a greater understanding of the mechanisms of gastric cancer development. Also, positive findings would enable novel therapeutic approaches targeting Ras signaling with the intention of halting metaplasia to prevent development of advanced gastric cancer in the future. Risks: We seek to understand the mechanisms of gastric cancer development by developing novel preclinical mouse models. Therefore, no clinical risks are involved and risks to animals will be minimized. It is hoped that these preclinical studies could lead to targeted therapeutic interventions with minimal clinical side effects.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710257
Entities
People
- Eunyoung Choi
Organizations
- United States Army
- Vanderbilt University