E-cadherin in gastric cancer
Abstract of thesis entitled
E-cadherin and Gastric Cancer
Submitted by Chan On On, Annie
for the degree of Doctor of Philosophy
at The Univeristy of Hong Kong in March 2003
Gastric cancer remains the second most common malignancy globally. It progresses through histological changes, the Correa? cascade, during which a number of molecular changes occurs. Helicobacter pylori is an important etiological factor in gastric carcinogenesis. E-cadherin is an adhesion molecule expressed on all epithelial cells, and is responsible for homotypic cell adhesion. It acts as both a tumor suppressor and invasion suppressor in gastric carcinogenesis, as evidenced by the observation that germline mutation is detected in familial gastric cancer, sporadic mutation is detected in more than 50% of the diffuse type of gastric cancer, and methylation the CpG island leading to gene inactivation is shown to be the second genetic hit in familial gastric cancer. The aims of this thesis are: 1) to study the role of E-cadherin in the early stage of gastric carcinogenesis, especially its relation with H. pylori and 2) to study the clinical application of E-cadherin in gastric cancer patients.
The study on the expression E-cadherin gastric carcinogenesis showed that a significant decrease in expression was observed in chronic atrophic gastritis and intestinal metaplasia and progressed along the Correa? cascade. The decrease in expression was mostly accounted for by methylation at the CpG island of E-cadherin. More importantly, H. pylori infection was found to be the only independent factor associated with E-cadherin methylation by multivariate analysis. I postulated that H. pylori induced E-cadherin methylation through the mechanism of increasing interleukin 1? and then through the production of nitric oxide and the subsequent activation of DNA methyltransferase, thus resulting in gene methylation. Hence, I tested the hypothesis that methylation at E-cadherin could be reversed by eradicating H. pylori. Patients who presented with dyspepsia and received H. pylori eradication therapy showed a significant decrease in E-cadherin methylation as compared with those receiving no eradication therapy. In addition, the change in methylation was independent of the reversal of gastric mucosa pathology. On the other hand E-cadherin methylation frequency showed no difference in patients with intestinal metaplasia with or without H. pylori infection. These findings suggested that H. pylori eradication therapy might reverse methylation in patients with chronic gastritis without gastric cancer, thus halting the process of gastric carcinogenesis.
The clinical application of soluble E-cadherin was further investiged. High level of soluble E-cadherin predicted inoperability and advanced disease. Furthermore, soluble E-cadherin > 10,000 ng/ml predicted a survival of less than 3 years in 90% of patients by multivariate analysis. The role of soluble E-cadherin as a therapeutic monitoring marker in predicting tumor recurrence after curative resection
was studied prospectively. Patients with tumor recurrence were more likely to have significant increases in soluble E-cadherin change as compared with the pre-operative levels. The increase was observed immediately post-operation, from one to six months
Observations in this thesis provide insights into the initiation steps of gastric carcinogenesis, with important implications in the future development of chemoprevention. Finally, the potential clinical applications of soluble E-cadherin were identified.
School:The University of Hong Kong
School Location:China - Hong Kong SAR
Source Type:Master's Thesis
Keywords:cell adhesion molecules helicobacter pylori stomach cancer genetic aspects
Date of Publication:01/01/2004