Epstein-Barr Virus and the Pathogenesis of Nasopharyngeal Carcinomas

The conceptthatEpstein-Barr Virus (EBV) is one etiological factor ofNPC is supported by multiple clinical and experimental observations including the consistency of the association and the demonstration of the oncogenic potential of viral products contained in most tumors. There is growing evidence supporting a scenario of mutual virus-cell interactions in malignant NPC cells: viral products cooperate with cellular factors to sustain the malignant phenotype whereas specific intra-cellular metabolic and signalling conditions contribute to the inhibition of the viral lytic cycle. Untranslated small viral RNAs are suspected to exert substantial oncogenic effects. The EBERs which interact with cellular receptors of double-strand RNAs have the capacity to block interferon pathways and to stimulate IGF-1 production by epithelial cells. A number of microRNAs are transcribed from the viral genome for which cellular targets are under investigation. Some of them have the capacity to block the expression of cellular pro-apoptotic proteins like PUMA and Bim1. Viral membrane proteins—LMP1 and LMP2—activate multiple signalling pathways, especially the PI-3-kinase pathways and a unique NF-κB pathway which depends on nuclear translocation of a Bcl3/p50/p50 complex. EBNA1 which is required for the maintenance of the viral genome in proliferating malignant cells probably also has direct oncogenic effects especially through the disruption of PML nuclear bodies. BARF1 is another viral protein which is abundantly secreted by NPC cells; it is suspected to contribute to their abnormal proliferation and local immune suppression. Investigations on the premalignant nasopharyngeal mucosa suggest that alterations of the cellular genome—especially DNA losses in the 3p and 9p chromosomes—occur early, sometimes several decades prior to tumor development. Establishment of latent EBV infection in some of these premalignant cells probably results in a high risk of rapid progression from one infected cell towards a monoclonal invasive tumor. Multiple genetic variations are found in EBV isolates. Whether some genetic variants of EBV carry a higher risk of NPC is still under investigation. The continued expression of viral products in NPC cells provides multiple opportunities for immuno-therapy, use of inhibitors targeting critical activated pathways and/or specific molecular therapy directed toward the viral functions.