Targeting Unique Precancerous Stem Cell Populations in the Stomach
Abstract
Gastric cancer is the third highest cause of cancer-related death worldwide. As large numbers of immigrants from high gastric cancer incidence regions, such as South America and Asia, have entered the United States over the past decades, the incidence of gastric cancer is beginning to rise. The effect of this increase on the military and Veteran populations is likely to become more prominent in the coming years due to increased numbers of Latino and Asian immigrants serving in the armed forces. Unfortunately, in the United States most gastric cancers are identified late in their evolution at a time when they have become very aggressive and complex. This makes treating these cancers very difficult and so gastric cancer has an extremely poor cure rate. Thus, identifying and treating pre-cancerous lesions in the stomach represents a much more promising approach, because it allows treatment intervention at a time when changes in the lining of the stomach might be reversible and the target lesions are relatively simple and uniform. The normal stomach is lined by cells that are responsible for the initiation of food digestion through the secretion of acid, which accomplishes initial breakdown of food. Infection of the stomach with the bacterium Helicobacter pylori induces a loss of acid secreting cells within the lining of the stomach. The absence of acid secreting cells leads to the development of a new set of cells lining the stomach, which release protective mucin proteins that can coat the stomach lining and act to promote healing, a process known as “metaplasia.” While these new mucus secreting cells can be part of a healing response in the short term, if they are maintained in the lining of the stomach in the presence of on-going inflammation due to continued infection with H. pylori, then they can undergo changes that lead to the development of pre-cancerous cells known as “dysplasia” in the stomach. We believe that if we can identify the processes that lead to the formation and progression of the precancerous metaplastic cells, then we can target and eliminate these cells before actual cancers ever arise. We have recently developed a mouse model that develops metaplastic cells that progress to more aggressive precancerous lesions. We have been able to isolate these cells and grow them in the laboratory, and we have found that they contain cells that may be acting as precursors of cancer. We therefore are now proposing to isolate populations of metaplastic and dysplastic cells from humans to identify similar pre-cancerous precursors. We will isolate directly groups of cells within human metaplasia and dysplasia in the stomach that may act as the true precursors of cancer (so-called cancer stem cells). Isolation of these cells will allow us to obtain greater knowledge into the behavior of particular cells that have the direct ability to progress into cancer. These approaches will allow us to identify fundamental properties of pre-cancerous cells within metaplastic lineages in the stomach. We will also be able to test therapeutic strategies for limiting the growth of pre-cancerous stem cells. This knowledge will aid in the identification of new therapeutic targets for arresting or even reversing the evolution of cancer from pre-cancerous cells in the stomach. This strategy would allow prevention of cancer in high-risk populations and could prevent the high mortality seen in patients who develop frank gastric cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010542
Entities
People
- James R. Goldenring
Organizations
- United States Army
- Vanderbilt University