Epstein-Barr Virus Induces Lymphangiogenesis and Lympth Node Metastasis via Upregulation of VEGF-C in Nasopharyngeal Carcinoma

Abstract

Lymphatic metastasis is a common clinical symptom in nasopharyngeal carcinoma (NPC), the most common Epstein-Barr virus (EBV)-associated head and neck malignancy. However, the effect of EBV on NPC lymph node (LN) metastasis is still unclear. In this study, we demonstrated that EBV infection is strongly associated with advanced clinical N stage and lymphangiogenesis of NPC. We found that NPC cells infected with EBV promote LN metastasis by inducing cancer-associated lymphangiogenesis, whereas these changes were abolished upon clearance of EBV genomes. Mechanistically, EBV-induced VEGF-C contributed to lymphangiogenesis and LN metastasis, and PHLPP1, a target of miR-BART15, partially contributed to AKT/HIF1a hyperactivity and subsequent VEGF-C transcriptional activation. In addition, administration of anti-VEGF-C antibody or HIF1α inhibitors attenuated the lymphangiogenesis and LN metastasis induced by EBV. Finally, we verified the clinical significance of this prometastatic EBV/VEGF-C axis by determining the expression of PHLPP1, AKT, HIF1a, and VEGF-C in NPC specimens with and without EBV. These results uncover a reasonable mechanism for the EBV-modulated LN metastasis microenvironment in NPC, indicating that EBV is a potential therapeutic target for NPC with lymphatic metastasis. Implications: This research demonstrates that EBV induces lymphangiogenesis in NPC by regulating PHLPP1/p-AKT/HIF1a/VEGF-C, providing a new therapeutic target for NPC with lymphatic metastasis.

Nasopharyngeal carcinoma ecology theory: cancer as multidimensional spatiotemporal “unity of ecology and evolution” pathological ecosystem

“…Consistent with the “seed and soil” theory of metastasis proposed by Paget in 1889 78 , the best predictors of the success of ecological dispersal are those variables that whether cancer cells have enough ecological adaptive and reproductive ability 79 - 81 . In the primary sites, for example, NPC cells can secrete matrix metalloproteinases that physically alter their environments 82 - 84 , contribute to angiogenesis via vascular endothelial growth factor (VEGF) production 85 - 87 , manipulate the content and functions of extracellular vesicles (EVs) 88 - 92 or change tight vascular capillary endothelial walls by inducing endothelial-mesenchymal transition (EnMT) 93 of the organ ecosystem. This is well reflected in the detection of magnetic resonance imaging (MRI) with extensive local infiltration of adjacent soft tissues, erosion of skull base, etc.…”

Super Enhancer Driven Hyaluronan Synthase 3 Promotes Malignant Progression of Nasopharyngeal Carcinoma

“…NPC is characterized by high invasion and early metastasis, 70-80% of NPC patients have developed cervical lymph node metastases at the first diagnosis [2][3][4][5]. Cancer research has been elucidating mechanisms of metastasis for decades [57,58].…”

“…Owing to this unique anatomical structure of nasopharyngeal cavity, NPC can be difficult to make an early diagnosis [1]. In addition, NPC is characterized by high invasion and early metastasis, 70-80% of NPC patients have developed cervical lymph node metastases at the first diagnosis [2][3][4][5]. However, the underlying mechanism of NPC metastasis is still not NPC is characterized as having comparatively low mutation rate, widespread hypermethylation, high copy number alterations and chromosome abnormalities by Genome-wide studies [6][7][8][9][10][11][12][13][14].…”

Role of the VEGF in virus‐associated cancers

“…To confirm the relation between EBV and VEGF, Early antigen antibody (EA‐IgA) and viral capsid antigen IgA were analysed by ELISA, and significant correlation between them was found 46 . In contrast to the articles mention above, 10–49 the data of one article did not find VEGF in EBER positive cells (peripheral T‐cell lymphomas and Hodgkin's disease) 47,48 . (Figure 1).…”