Induction of chemokine (C‐C motif) ligand 5 by Epstein–Barr virus infection enhances tumor angiogenesis in nasopharyngeal carcinoma

Abstract

Nasopharyngeal carcinoma (NPC) is etiologically associated with Epstein–Barr virus (EBV) infection and is known to be highly vascularized. Previous studies have suggested that EBV oncoproteins contribute to NPC angiogenesis. However, the regulatory network of EBV in angiogenesis still remains elusive. Herein, we reveal a novel mechanism of EBV‐induced angiogenesis in NPC. First, we showed that EBV‐infected NPC cell lines generated larger tumors with more microvessels in mouse xenograft models. Subsequent proteomic analysis revealed that EBV infection increased the expression of a series of angiogenic factors, including chemokine (C‐C motif) ligand 5 (CCL5). We then proved that CCL5 was a target of EBV in inducing tumor angiogenesis and growth. Further investigation through transcriptome analysis indicated that the pro‐angiogenic function of CCL5 might be mediated by the PI3K/AKT pathway. Furthermore, we confirmed that activation of the PI3K/AKT and hypoxia‐inducible factor‐1α pathways was essential for CCL5‐promoted angiogenesis. Finally, the immunohistochemical analysis of human NPC specimens also showed that CCL5 was correlated with angiogenesis. Taken together, our study identifies CCL5 as a key EBV‐regulated molecular driver that promotes NPC angiogenesis, suggesting it as a potential therapeutic target.

Relationship between pretreatment concentration of plasma Epstein‐Barr virus DNA and tumor burden in nasopharyngeal carcinoma: An updated interpretation

“…We hypothesize that a higher rate of tumor cell loss associated with larger tumor volume and poorer oxygen supply may account for this phenomenon. Furthermore, higher proliferation rates and favorable tumor angiogenesis associated with advanced N category and larger tumor volume may be another explanation …”

“…Tumor angiogenesis is associated with metastasis and may account for release of EBV DNA into circulation. A preclinical research revealed that EBV infection could promote the production of chemokine (C‐C motif) ligand 5, which increases vascular endothelial growth factor expression and NPC angiogenesis by interacting with the PI3K/AKT and hypoxia‐inducible factor‐1α pathways . It also has been found that level of plasma EBV DNA is also associated with tumor cell metabolic activity measured by PET/CT and circulating cytokines which may reflect the immune and inflammatory status of the body .…”

Genome-wide profiling of Epstein-Barr virus integration by targeted sequencing in Epstein-Barr virus associated malignancies

“…Western blot analysis was performed as previously described 44. Cells were lysed in RIPA lysis buffer containing protease inhibitors (Roche).…”

CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands

“…CCL5 may cause differentiation of cancer stem cells into endothelial cells as observed in the ovarian cancer model [ 103 ]. This chemokine is also induced by the Epstein–Barr virus (EBV) (human herpesvirus 4) in nasopharyngeal carcinoma cells, which leads to angiogenesis [ 104 ]. It may also indirectly cause lymphangiogenesis by increasing VEGF-C expression, as observed in chondrosarcoma cells [ 105 ].…”