Antibodies Against Epstein-Barr Virus as Disease Markers of Gastric Cancer: A Systematic Review.

Introduction: Gastric cancer is the fourth deadliest cancer worldwide. Due to the lack of specific early symptoms and noninvasive methods for early detection, the prognosis of gastric cancer patients is poor. Gastric cancer has a well-recognized infectious etiology, with Helicobacter pylori and Epstein-Barr Virus being the main associated infectious agents. Although other Epstein-Barr Virus-associated malignancies often manifest with abnormal levels of anti-Epstein-Barr Virus antibodies, it is not clear whether this is also true for gastric cancer. Potentially, these antibodies could serve as a noninvasive tool for gastric cancer screening or as markers for gastric cancer risk and provide a better understanding of the participation of Epstein-Barr Virus in the development of this neoplasm. Methods: We conducted a systematic review of articles analyzing anti-Epstein-Barr Virus serology in gastric cancer and precursor lesions following PRISMA guidelines. Patients were classified according to the Correa cascade of gastric lesions and whether they were positive or negative by EBER-in situ hybridization (Epstein-Barr Virus-associated gastric cancer and Epstein-Barr Virus-nonassociated gastric cancer, respectively). Results: We retrieved 16 articles involving 9735 subjects from 12 different countries and 4 databases, PubMed, SciELO, Scopus, and Google Scholar. Higher antibody titers were observed not only in Epstein-Barr Virus-associated gastric cancer than in Epstein-Barr Virus-nonassociated gastric cancer but also in Epstein-Barr Virus-nonassociated gastric cancer and gastric cancer-precursor lesions when compared with patients with mild dyspepsia or healthy controls. In all cases, the associations were predominantly with antibodies directed against lytic cycle antigens. Conclusion: Data support the role of Epstein-Barr Virus lytic reactivation in the development of advanced gastric lesions. However, more studies are needed to confirm these associations, particularly the association with lesions considered negative by EBER-in situ hybridization, and to establish a set of antibodies and thresholds indicative of enhanced risk to develop these lesions.

IL-8 Secreted by Gastric Epithelial Cells Infected with Helicobacter pylori CagA Positive Strains Is a Chemoattractant for Epstein-Barr Virus Infected B Lymphocytes.

Helicobacter pylori and EBV are considered the main risk factors in developing gastric cancer. Both pathogens establish life-lasting infections and both are considered carcinogenic in humans. Different lines of evidence support that both pathogens cooperate to damage the gastric mucosa. Helicobacter pylori CagA positive virulent strains induce the gastric epithelial cells to secrete IL-8, which is a potent chemoattractant for neutrophils and one of the most important chemokines for the bacterium-induced chronic gastric inflammation. EBV is a lymphotropic virus that persists in memory B cells. The mechanism by which EBV reaches, infects and persists in the gastric epithelium is not presently understood. In this study, we assessed whether Helicobacter pylori infection would facilitate the chemoattraction of EBV-infected B lymphocytes. We identified IL-8 as a powerful chemoattractant for EBV-infected B lymphocytes, and CXCR2 as the main IL-8 receptor whose expression is induced by the EBV in infected B lymphocytes. The inhibition of expression and/or function of IL-8 and CXCR2 reduced the ERK1/2 and p38 MAPK signaling and the chemoattraction of EBV-infected B lymphocytes. We propose that IL-8 at least partially explains the arrival of EBV-infected B lymphocytes to the gastric mucosa, and that this illustrates a mechanism of interaction between Helicobacter pylori and EBV.

Epstein-Barr Virus Infection Is Associated with Elevated Hepcidin Levels.

EBV and Helicobacter pylori (H. pylori) cause highly prevalent persistent infections as early as in childhood. Both pathogens are associated with gastric carcinogenesis. H. pylori interferes with iron metabolism, enhancing the synthesis of acute-phase proteins hepcidin, C-reactive protein (CRP), and α-1 glycoprotein (AGP), but we do not know whether EBV does the same. In this study, we correlated the EBV antibody levels and the serum levels of hepcidin, CRP, and AGP in 145 children from boarding schools in Mexico City. We found that children IgG positive to EBV antigens (VCA, EBNA1, and EA) presented hepcidin, AGP, and CRP levels higher than uninfected children. Hepcidin and AGP remained high in children solely infected with EBV, while CRP was only significantly high in coinfected children. We observed positive correlations between hepcidin and EBV IgG antibodies (p < 0.5). Using the TCGA gastric cancer database, we also observed an association between EBV and hepcidin upregulation. The TCGA database also allowed us to analyze the two important pathways controlling hepcidin expression, BMP−SMAD and IL-1ß/IL-6. We observed only the IL-1ß/IL-6-dependent inflammatory pathway being significantly associated with EBV infection. We showed here for the first time an association between EBV and enhanced levels of hepcidin. Further studies should consider EBV when evaluating iron metabolism and anemia, and whether in the long run this is an important mechanism of undernourishment and EBV gastric carcinogenesis.