Epstein-Barr virus and gastric carcinoma: virus-host interactions leading to carcinoma

Abstract

Epstein-Barr virus (EBV)-associated gastric carcinoma (GC) is a distinct subgroup of GC, comprising 10% of all cases of GC. EBV-associated carcinoma is the monoclonal growth of EBV-infected epithelial cells, and it represents a model of virus-host interactions leading to carcinoma. EBV-infected cells express several latent proteins (latency I program of viral latent gene expression) in EBV-associated GC. However, latent membrane protein 2A (LMP2A) up-regulates the cellular survivin gene through the NFkB pathway, conferring resistance to apoptotic stimuli on the neoplastic cells. EBV-associated GC also shows characteristic abnormality, that is, global and non-random CpG island methylation of the promoter region of many cancer-related genes. Since the viral genes are also regulated by promoter methylation in the infected cells, the DNA methylation mechanism specific to EBV-associated GC may be an exaggeration of the cellular mechanism, which is primarily for defense against foreign DNA. Production of several immunomodulator molecules, inducing tumor-infiltrating lymphocyte and macrophages, serves to form the characteristic histologic pattern in EBV-associated GC. The proposed sequence of events within the mucosa is as follows: EBV infection of certain gastric stem cells; expression of viral latent genes; abnormality of signal pathways caused by viral gene products; DNA methylation-mediated repression of tumor suppressor genes; and monoclonal growth of EBV-infected cells through interaction with other etiologic factors. Potentially useful therapeutic approaches to EBV-associated GC are those that utilize the virus-host interactions, such as bortezomib-induced and viral enzyme-targeted radiotherapy.

Figure 1

Pathology of Epstein–Barr virus (EBV)‐associated gastric carcinoma. EBV‐encoded small RNA (EBER) in situ hybridization demonstrates that positive signals are present in the nuclei of all the neoplastic cells in intramucosal and advanced carcinomas. The remaining pyloric glands (*) in the intramucosal carcinoma and the infiltrating lymphocytes in the advanced carcinoma are negative for signals.

Figure 2

Viral latent membrane protein 2A (LMP2A) in cancer: its structure and downstream signal pathways. The figure summarizes the signal pathways, the activation of which has been reported in epithelial cells and cancer.

Figure 3

Factors associated with epigenetic abnormality in virus‐associated neoplasms. The possible mechanisms of epigenetic abnormalities that have been reported include direct interaction of viral proteins with DNA methyl transferases (DNMT), up‐regulation of dnmt genes by viral proteins, and increased expression of polycomb group proteins.

Figure 4

Epstein–Barr virus (EBV)‐associated gastric carcinoma, from EBV infection to the development of carcinoma. A possible sequence of events within the mucosa is illustrated.