2. Academic Validation
  3. Epstein-Barr virus causes vascular abnormalities in epithelial malignancies through upregulating ANXA3-HIF-1α-VEGF pathway

Epstein-Barr virus causes vascular abnormalities in epithelial malignancies through upregulating ANXA3-HIF-1α-VEGF pathway

  • Oncogene. 2024 May 22. doi: 10.1038/s41388-024-03061-w.
Yuanyuan Chen # 1 2,  Muping Di # 3,  Yan Tang # 1 2,  Jingjing Zhao 1 2,  Qijing Wang 1 2,  Zhixing Guo 1 4,  Yongqiang Li 1 2,  Dijun Ouyang 1 2,  Jieying Yang 1 2,  Hao Chen 1 2,  Yan Wang 1 2,  Desheng Weng 1 2,  Qiuzhong Pan 5 6,  Tong Xiang 7 8,  Jianchuan Xia 9 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.
  • 2 Department of Biotherapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.
  • 3 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
  • 4 Department of UItrasonic Diagnosis, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.
  • 5 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China. panqzh@sysucc.org.cn.
  • 6 Department of Biotherapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China. panqzh@sysucc.org.cn.
  • 7 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China. xiangtong@sysucc.org.cn.
  • 8 Department of Experimental Research, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China. xiangtong@sysucc.org.cn.
  • 9 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China. xiajch@mail.sysu.edu.cn.
  • 10 Department of Biotherapy, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China. xiajch@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 38778160 DOI: 10.1038/s41388-024-03061-w
Abstract

Angiogenesis is one of the characteristics of malignant tumors, and persistent generation of abnormal tumor blood vessels is an important factor contributing to tumor treatment resistance. Epstein-Barr virus (EBV) is a highly prevalent DNA oncogenic virus that is associated with the development of various epithelial malignancies. However, the relationship between EBV Infection and tumor vascular abnormalities as well as its underlying mechanisms is still unclear. In this study, we found that compared to EBV-uninfected tumors, EBV-infected tumors were more angiogenic, but the neovascularization was mostly immature vessels without pericyte attachment in both clinical patient tumor samples and mouse xenograft models; These immature vessels exhibited aberrant functionality, characterized by poor blood perfusion and increased vascular permeability. The vascular abnormalities caused by EBV Infection exacerbated tumor hypoxia and was responsible for accelerated tumor growth. Mechanistically, EBV Infection upregulated ANXA3-HIF-1α-VEGF pathway. Silencing the ANXA3 gene or neutralizing ANXA3 with an antibody can diminish vascular abnormalities, thereby increasing immune cell infiltration and alleviating treatment resistance. Finally, a new therapy combining ANXA3 blockade and NK cell + PD1 antibody significantly inhibited the growth of EBV-infected xenografts in mice. In conclusion, our study identified a previously unrecognized role for EBV Infection in tumor vascular abnormalities and revealed its underlying mechanism that upregulated the ANXA3-HIF-1α-VEGF pathway. ANXA3 is a potential therapeutic target for EBV-infected tumors and ANXA3 blockade to improve vascular conditions, in combination with NK cell + PD1 antibody therapy, holds promise as an effective treatment strategy for EBV-associated epithelial malignancies.

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