Abstract
Epstein-Barr virus (EBV) is best known for infection of B cells, in which it usually establishes an asymptomatic lifelong infection, but is also associated with the development of multiple B cell lymphomas. EBV also infects epithelial cells and is associated with all cases of undifferentiated nasopharyngeal carcinoma (NPC). EBV is etiologically linked with at least 8% of gastric cancer (EBVaGC) that comprises a genetically and epigenetically distinct subset of GC. Although we have a very good understanding of B cell entry and lymphomagenesis, the sequence of events leading to EBVaGC remains poorly understood. Recently, ephrin receptor A2 (EPHA2) was proposed as the epithelial cell receptor on human cancer cell lines. Although we confirm some of these results, we demonstrate that EBV does not infect healthy adult stem cell-derived gastric organoids. In matched pairs of normal and cancer-derived organoids from the same patient, EBV only reproducibly infected the cancer organoids. While there was no clear pattern of differential expression between normal and cancer organoids for EPHA2 at the RNA and protein level, the subcellular location of the protein differed markedly. Confocal microscopy showed EPHA2 localization at the cell-cell junctions in primary cells, but not in cancer cell lines. Furthermore, histologic analysis of patient tissue revealed the absence of EBV in healthy epithelium and presence of EBV in epithelial cells from inflamed tissue. These data suggest that the EPHA2 receptor is not accessible to EBV on healthy gastric epithelial cells with intact cell-cell contacts, but either this or another, yet to be identified receptor may become accessible following cellular changes induced by inflammation or transformation, rendering changes in the cellular architecture an essential prerequisite to EBV infection.
Highlights
Epstein-Barr virus (EBV) is a gammaherpesvirus that infects more than 90% of the world’s population
The sequence of events leading to EBV-associated gastric cancer (GC) (EBVaGC) remains unclear
Using human adult healthy stem cell-derived gastric organoids, microscopy showed the ephrin receptor A2 (EPHA2) receptor was strictly localized to cell-cell junctions and inaccessible to EBV, resulting in poor infection
Summary
Epstein-Barr virus (EBV) is a gammaherpesvirus that infects more than 90% of the world’s population. While the virus is well-known to infect B cells, causing infectious mononucleosis, Burkitt and Hodgkin lymphoma [1], it infects epithelial cells and is associated with nasopharyngeal carcinoma and gastric cancer (GC) [2]. EBV-associated gastric cancer (EBVaGC) represents 8–10% of all GC cases worldwide, accounting for up to 80,000 cases per year [3,4]. The exact sequence of events leading to EBVaGC is still a conundrum. It is unclear whether viral entry into healthy cells initiates the pathogenic changes, or whether host cell modifications must precede the infection
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