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Review
. 2015 Jan;235(2):323-33.
doi: 10.1002/path.4448.

The role of Epstein-Barr virus in epithelial malignancies

Sai-Wah Tsao  1 , Chi Man Tsang, Ka-Fai To, Kwok-Wai Lo
Affiliations
Free PMC article
Review

The role of Epstein-Barr virus in epithelial malignancies

Sai-Wah Tsao et al. J Pathol. 2015 Jan.
Free PMC article

Abstract

The close association of Epstein-Barr virus (EBV) infection with non-keratinizing nasopharyngeal carcinomas and a subset of gastric carcinomas suggests that EBV infection is a crucial event in these cancers. The difficulties encountered in infecting and transforming primary epithelial cells in experimental systems suggest that the role of EBV in epithelial malignancies is complex and multifactorial in nature. Genetic alterations in the premalignant epithelium may support the establishment of latent EBV infection, which is believed to be an initiation event. Oncogenic properties have been reported in multiple EBV latent genes. The BamH1 A rightwards transcripts (BARTs) and the BART-encoded microRNAs (miR-BARTs) are highly expressed in EBV-associated epithelial malignancies and may induce malignant transformation. However, enhanced proliferation may not be the crucial function of EBV infection in epithelial malignancies, at least in the early stages of cancer development. EBV-encoded gene products may confer anti-apoptotic properties and promote the survival of infected premalignant epithelial cells harbouring genetic alterations. Multiple EBV-encoded microRNAs have been reported to have immune evasion functions. Genetic alterations in host cells, as well as inflammatory stroma, could modulate the expression of EBV genes and alter the growth properties of infected premalignant epithelial cells, encouraging their selection during carcinogenesis.

Keywords: BARTs; Epstein-Barr virus; LMP1; gastric carcinoma; lymphoeptithelioma-like carcinomas; nasopharyngeal carcinoma.

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Figures

Figure 1
Figure 1
Epstein–Barr virus (EBV) latent infection in various epithelial malignancies. (A) Histopathology of Epstein–Barr virus (EBV)-positive carcinomas (upper panel) and their corresponding EBER in situ hybridization (lower panel). Nasopharyngeal carcinomas (NPC) most commonly form syncytial sheets or scattered undifferentiated carcinoma cells among dense lymphoplasmacytic infiltrate, and hence display features of lympho-epithelioma-like carcinoma (LELC). A subset of gastric carcinomas which harbour EBV show morphological features of LELC or, more commonly, resemble the usual gastric adenocarcinoma but with variable amounts of lymphoplasmacytic infiltrate. EBV-positive carcinomas in lung and other head and neck regions (e.g. tonsil) have the morphological features of LELC. Rarely, cholangiocarcinoma can harbour EBV. EBV-positive cholangiocarcinoma usually displays morphology of adenocarcinoma with small tubular glands among dense lymphoplasmacytic infiltrate. A representative case of EBV-associated gastric adenocarcinoma, LELC of lung and tonsil and EBV-positive cholangiocarcinoma, are illustrated. (Upper panel) Haematoxylin and eosin (H&E) stain, original magnification = ×400; (lower panel) EBER in situ hybridization, original magnification = ×400. (B) Detection of LMP1 expression in NPC and LELC of lung by immunohistochemical (IHC) staining: (upper panel) LMP1 staining pattern in representative samples of NPC and LELC of lung; LMP is typically expressed in only a small population of scattered carcinoma cells: (lower panel) LMP1 expression patterns in three NPC xenografts; in Xeno-2117 and C17, LMP1 is also expresssed in a small population of scattered carcinoma cells; however, in C15, the IHC staining signal of LMP1 exhibits diffuse positivity; original magnification = ×400.
Figure 2
Figure 2
Epstein–Barr virus (EBV) latent genes target cancer hallmarks of epithelial malignancies. EBV contributes multiple cancer hallmarks of epithelial malignancies by expressing type II latent genes. These EBV latent genes induce oncogenic properties by disrupting various cellular and signalling machineries, as described in this review. The constitutively expressed latent genes (EBNA1, EBER1/2 and miR-BARTs) are shown in the green boxes. They mainly contribute to the resistance of cell death, the counteraction of the host immune responses and the induction of genomic instability. The heterogeneously expressed LMPs (orange boxes) are viral oncogenes and play roles in almost all described cancer hallmarks. The expression of high levels of LMPs in a subset of tumour cells may help them to acquire stemness properties and drive tumour progression in invasive epithelial cancers.
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