CSI Researchers Unveil Novel Insights into the Induction of Gastric Carcinogenesis

Within the stomach corpus (main body), tubular invaginations are divided into regions known as the pit, isthmus, neck and base. In particular, the isthmus comprises rapidly proliferating cells, known as isthmus stem cells. Since the inner lining of the stomach is constantly damaged by food, pathogens and foreign substances, the isthmus plays an important role in replacing damaged tissue with new cells quickly apart from generating various mature cells in the corpus, such as acid-producing parietal cells, chief cells and mucin-producing mucous cells. Chief cells, which secrete digestive enzyme, pepsinogen C, are considered to be terminally differentiated, post-mitotic cells.  Around the year 2010, researchers found that chief cells regain their proliferation capacity for tissue repair when the stomach is damaged, suggesting that these chief cells would develop into cancer cells: the cell of origin of cancer. While different groups of researchers have reported that isthmus stem cells are the only cells of origin of cancer, these groups also were unable to show the entire process of gastric cancer development. As a result, this has sparked tremendous controversy in the field.

Here, a research team helmed by Professor Yoshiaki Ito, Senior Principal Investigator at the Cancer Science Institute of Singapore (CSI Singapore), zeroed in on the genetic cause of gastric cancer and observed frequent activation of Kras, inactivation of APC (Adenomatous Polyposis Coli) and inactivation of p53 tumor suppressor. Motivated by the aim to uncover an association between the activation of oncogenic Kras in chief cells and gastric cancer initiation,  the research team targeted the expression of oncogenic Kras specifically in chief cells by using the promoter of pepsinogen C (PGC). Although the PGC protein is expressed exclusively in chief cells, PGC transcript has been found to be expressed in virtually all cell types in the stomach corpus. With this newly established finding, Professor Ito and his team elucidated that  oncogenic Kras-induced metaplasia, the first precancerous stage, started from the isthmus stem cells, which are perpetually active. Furthermore, the research team also found that chief cells must be damaged first before regaining proliferation capacity.

Following  the introduction of oncogenic Kras, Professor Ito and his team inactivated APC, which induced intramucosal gastric cancer.  Taking a step further, they then deleted the p53 gene, which brought on a very aggressive metastatic cancer. Owing to the stomach-specific expression of PGC promoter, these step-wise carcinogenic changes occurred only in the stomach corpus, and not in other tissues. To date, this is the only mouse model for gastric cancer with such specificity.

With respect to the cell of origin, findings from Prof. Ito’s previous study (Gut, 2020) revealed that chief cells are likely to be the cells of origin, therefore lending support to the team’s findings, which suggest that both isthmus stem cells and chief cells could be the cells of origin.

Finally, high expression of RUNX3 has been observed upon p53 deletion and when tumors became metastatic, uncovering a possible association between RUNX3 and gastric cancer metastasis.  Interestingly, a previous study by others has also yielded similar results, where a very high level of RUNX3 expression was observed in a metastatic pancreatic cancer mouse model after inactivation of tumor suppressor activity of p53 (Cell, 2015).  Since metastasis is responsible for most cancer deaths, the team hopes to further their research by delving into the role of RUNX3 in metastasis.

Read more about the study HERE.