外泌体在EB病毒(EBV)相关癌症中的致病作用
21 September 2017
Sin-Yeang Teow, Kitson Liew, Alan Soo-Beng Khoo and Suat-Cheng Peh
摘要
Exosomes are 40- to 100-nm membrane-bound small vesicles that carry a great variety of cellular cargoes including proteins, DNA, messenger RNAs (mRNAs), and microRNAs (miRNAs). These nanovesicles are detected in various biological fluids such as serum, urine, saliva, and seminal fluids. Exosomes serve as key mediators in intercellular communication by facilitating the transfer and exchange of cellular components from cells to cells. They contain various pathogenic factors whereby their adverse effects have been implicated in multiple viral infections and cancers. Interestingly, accumulating evidences showed that exosomes derived from tumour viruses or oncoviruses, exacerbate virus-associated cancers by remodelling the tumour microenvironment. In this review, we summarize the contributing factors of Epstein-Barr virus (EBV) products-containing exosomes in viral pathogenesis and their potential implications in EBV-driven malignancies. Understanding the biological role of these exosomes in the disease would undoubtedly boost the development of a more comprehensive strategy to combat EBV-associated cancers and to better predict the therapeutic outcomes. Furthermore, we also highlight the potentials and challenges of EBV products-containing exosomes being employed as diagnostic markers and therapeutic targets for EBV-related cancers. Since these aspects are rather underexplored, we attempt to underline interesting areas that warrant further investigations in the future.
参考资料
- HogenEsch, H., & Nikitin, A. Y. (2012). Challenges in pre-clinical testing of anti-cancer drugs in cell culture and in animal models. Journal of Controlled Release, 164, 183–186.
- Hait, W. N. (2010). Anticancer drug development: The grand challenges. Nature Reviews Drug Discovery, 9, 253–254.
- Thanki, K., Gangwal, R. P., Sangamwar, A. T., et al. (2013). Oral delivery of anticancer drugs: Challenges and opportunities. Journal of Controlled Release, 170, 15–40.
- Stuurman, F. E., Nuijen, B., Beijnen, J. H., et al. (2013). Oral anticancer drugs: Mechanisms of low bioavailability and strategies for improvement. Clinical Pharmacokinetics, 52, 399–414.
- Chen, F., Zhuang, X., Lin, L., et al. (2015). New horizons in tumour microenvironment biology: Challenges and opportunities. BMC Medicine, 13, 45.
- Sun, Y. (2016). Tumour microenvironment and cancer therapy resistance. Cancer Letters, 380, 205–215.
- Woller, N., & Kühnel, F. (2014). Virus infection, inflammation and prevention of cancer. Recent Results in Cancer Research, 193, 33–58.
- Chiantore, M. V., Mangino, G., Zangrillo, M. S., et al. (2015). Role of the microenvironment in tumorigenesis: Focus on virus-induced tumours. Current Medicinal Chemistry, 22, 958–974.
- Kahlert, C., & Kalluri, R. (2013). Exosomes in tumour microenvironment influence cancer progression and metastasis. Journal of Molecular Medicine, 91, 431–437.
- Roma-Rodrigues, C., Fernandes, A. R., & Baptista, P. V. (2014). Exosome in tumour microenvironment: Overview of the crosstalk between normal and cancer cells. BioMed Research International, 2014, 179486.
- Milane, L., Singh, A., Mattheolabakis, G., et al. (2015). Exosome mediated communication within the tumour microenvironment. Journal of Controlled Release, 219, 278–294.
- Teow, S. Y., Nordin, A. C., Ali, S. A., et al. (2016). Exosomes in human immunodeficiency virus type I pathogenesis: Threat or opportunity? Advances in Virology, 2016, 9852494.
- Madison, M. N., & Okeoma, C. M. (2015). Exosomes: Implications in HIV-1 pathogenesis. Viruses, 7, 4093–4118.
- Schwab, A., Meyering, S. S., Lepene, B., et al. (2015). Extracellular vesicles from infected cells: Potential for direct pathogenesis. Frontiers in Microbiology, 6, 1132.
- Alenquer, M., & Amorim, M. J. (2015). Exosome biogenesis, regulation, and function in viral infection. Viruses, 7, 5066–5083.
- Kowal, J., Arras, G., Colombo, M., et al. (2016). Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proceedings of the National Academy of Sciences of the United States of America, 113, E968–E977.
- Iwakiri, D. (2014). Epstein-Barr virus-encoded RNAs: Key molecules in viral pathogenesis. Cancers, 6, 1615–1630.
- Canitano, A., Venturi, G., Borghi, M., et al. (2013). Exosomes released in vitro from Epstein-Barr virus (EBV)-infected cells contain EBV-encoded latent phase mRNAs. Cancer Letters, 337, 193–199.
- Longatti, A. (2015). The dual role of exosomes in hepatitis A and C virus transmission and viral immune activation. Viruses, 7, 6707–6715.
- Chahar, H. S., Bao, X., & Casola, A. (2015). Exosomes and their role in the life cycle and pathogenesis of RNA viruses. Viruses, 7, 3204–3225.
- Jaworski, E., Narayanan, A., Van Duyne, R., et al. (2014). Human T-lymphotropic virus type 1-infected cells secrete exosomes that contain Tax protein. Journal of Biological Chemistry, 289, 22284–22305.
- Meckes, D. G., Jr. (2015). Exosomal communication goes viral. Journal of Virology, 89, 5200–5203.
- Aga, M., Bentz, G. L., Raffa, S., et al. (2014). Exosomal HIF1α supports invasive potential of nasopharyngeal carcinoma-associated LMP-positive exosomes. Oncogene, 33, 4613–4622.
- Keryer-Bibens, C., Pioche-Durieu, C., Villemant, C., et al. (2006). Exosomes released by EBV-infected nasopharyngeal carcinoma cells convey the viral latent membrane protein 1 and the immunomodulatory protein galectin 9. BMC Cancer, 6, 283.
- Mrizak, D., Martin, N., Barjon, C., et al. (2014). Effect of nasopharyngeal carcinoma-derived exosomes on human regulatory T cells. Journal of the National Cancer Institute, 107, 363.
- Liu, J., Sun, H., Wang, X., et al. (2014). Increased exosomal microRNA-21 and microRNA-146a levels in the cervicovaginal lavage specimens of patients with cervical cancer. International Journal of Molecular Sciences, 15, 758–773.
- Ko, Y. H. (2015). EBV and human cancer. Experimental & Molecular Medicine, 47, e130.
- Pattle, S. B., & Farrell, P. J. (2006). The role of Epstein-Barr virus in cancer. Expert Opinion on Biological Therapy, 6, 1193–1205.
- Yang, C., & Robbins, P. D. (2011). The roles of tumour-derived exosomes in cancer pathogenesis. Clinical and Developmental Immunology, 2011, 842849.
- Zhang, X., Yuan, X., Shi, H., et al. (2015). Exosomes in cancer: Small particle, big player. Journal of Hematology & Oncology, 8, 83.
- Meckes, D. G., Shair, K. H. Y., Marquitz, A. R., et al. (2010). Human tumour virus utilizes exosomes for intercellular communication. Proceedings of the National Academy of Sciences of the United States of America, 107, 20370–20375.
- Thompson, M. P., & Kurzrock, R. (2004). Epstein-Barr virus and cancer. Clinical Cancer Research, 10, 803–821.
- Young, L. S., Yap, L. F., & Murray, P. G. (2016). Epstein-Barr virus: More than 50 years old and still providing surprises. Nature Reviews Cancer, 16, 789–802.
- Ahmed, W., Philip, P. S., Tariq, S., et al. (2014). Epstein-Barr virus-encoded small RNAs (EBERs) are present in fractions related to exosomes released by EBV-transformed cells. PLoS One, 9, e99163.
- Ahsan, N., Kanda, T., Nagashima, K., et al. (2005). Epstein-Barr virus transforming protein LMP plays a critical role in virus production. Journal of Virology, 79, 4415–4424.
- Hurwitz, S. N., Nkosi, D., Conlon, M. M., et al. (2016). CD63 regulates Epstein-Barr virus LMP exosomal packaging, enhancement of vesicle production, and non-canonical NF-κB signaling. Journal of Virology, 02251–16.
- Nanbo, A., Kawanishi, E., Yoshida, R., et al. (2013). Exosomes derived from Epstein-Barr virus-infected cells are internalized via caveola-dependent endocytosis and promote phenotypic modulation in target cells. Journal of Virology, 87, 10334–10347.
- Flanagan, J., Middeldorp, J., & Sculley, T. (2003). Localization of the Epstein-Barr virus protein LMP1 to exosomes. Journal of General Virology, 84, 1871–1879.
- Meckes, D. G., Jr., Gunawardena, H. P., Dekroon, R. M., et al. (2013). Modulation of B-cell exosome proteins by gamma herpesvirus infection. Proceedings of the National Academy of Sciences of the United States of America, 110, E2925–E2933.
- Ikeda, M., & Longnecker, R. (2007). Cholesterol is critical for Epstein-Barr virus latent membrane protein 2A trafficking and protein stability. Virology, 360, 461–468.
- Allen, M. D., Young, L. S., & Dawson, C. W. (2005). The Epstein-Barr virus-encoded LMP-2A and LMP2B proteins promote epithelial cell spreading and motility. Journal of Virology, 79, 1789–1802.
- Rechsteiner, M. P., Berger, C., Zauner, L., et al. (2008). Latent membrane protein 2B regulates susceptibility to induction of lytic Epstein-Barr virus infection. Journal of Virology, 82, 1739–1747.
- Ahmed, W., & Khan, G. (2014). The labyrinth of interactions of Epstein-Barr virus-encoded small RNAs. Reviews in Medical Virology, 24, 3–14.
- Iwakiri, D., & Takada, K. (2010). Role of EBERs in the pathogenesis of EBV infection. Advances in Cancer Research, 107, 119–136.
- Pegtel, D. M., Cosmopoulos, K., Thorley-Lawson, D. A., et al. (2010). Functional delivery of viral miRNAs via exosomes. Proceedings of the National Academy of Sciences of the United States of America, 107, 6328–6333.
- Verweij, F. J., van Eijndhoven, M. A. J., Middeldorp, J., et al. (2013). Analysis of viral microRNA exchange via exosomes in vitro and in vivo. Methods in Molecular Biology, 1024, 53–68.
- Vallhov, H., Gutzeit, C., Johansson, S. M., et al. (2011). Exosomes containing glycoprotein 350 released by EBV-transformed B cells selectively target B cells through CD21 and block EBV infection in vitro. Journal of Immunology, 186, 73–82.
- Dukers, D. F., Meij, P., Vervoort, M. B., et al. (2000). Direct immunosuppressive effects of EBV-encoded latent membrane protein 1. Journal of Immunology, 165, 663–670.
- Ceccarelli, S., Visco, V., Raffa, S., et al. (2007). Epstein-Barr virus latent membrane protein 1 promotes concentration in multivesicular bodies of fibroblast growth factor 2 and its release through exosomes. International Journal of Cancer, 121, 1494–1506.
- Busson, P., Zhang, Q., Guillon, J. M., et al. (1992). Elevated expression of ICAM1 (CD54) and minimal expression of LFA3 (CD58) in Epstein-Barr-virus-positive nasopharyngeal carcinoma cells. International Journal of Cancer, 50, 863–867.
- Jung, W. C., Jang, Y. J., Kim, J. H., et al. (2012). Expression of intercellular adhesion molecule-1 and e-selectin in gastric cancer and their clinical significance. Journal of Gastric Cancer, 12, 140–148.
- Terol, M. J., López-Guillermo, A., Bosch, F., et al. (1998). Expression of the adhesion molecule ICAM-1 in non-Hodgkin’s lymphoma: Relationship with tumour dissemination and prognostic importance. Journal of Clinical Oncology, 16, 35–40.
- Verweij, F. J., van Eijndhoven, M. A., Hopmans, E. S., et al. (2011). LMP association with CD63 in endosomes and secretion via exosomes limits constitutive NF-κB activation. EMBO Journal, 30, 2115–2129.
- Thorley-Lawson, D. A., & Gross, A. (2004). Persistence of the Epstein-Barr virus and the origins of associated lymphomas. The New England Journal of Medicine, 350, 1328–1337.
- Eliopoulos, A. G., & Young, L. S. (1998). Activation of the cJun N-terminal kinase (JNK) pathway by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP). Oncogene, 16, 1731–1742.
- Thornburg, N. J., Kulwichit, W., Edwards, R. H., et al. (2006). LMP signaling and activation of NF-kappaB in LMP transgenic mice. Oncogene, 25, 288–297.
- Johansson, P., Jansson, A., Rüetschi, U., et al. (2010). The p38 signaling pathway upregulates expression of the Epstein-Barr virus LMP oncogene. Journal of Virology, 84, 2787–2797.
- Lambert, S. L., & Martinez, O. M. (2007). Latent membrane protein 1 of EBV activates phosphatidylinositol 3-kinase to induce production of IL-10. Journal of Immunology, 179, 8225–8234.
- Dawson, C. W., Laverick, L., Morris, M. A., et al. (2008). Epstein-Barr virus-encoded LMP regulates epithelial cell motility and invasion via the ERK-MAPK pathway. Journal of Virology, 82, 3654–3664.
- Chen, H., Hutt-Fletcher, L., Cao, L., et al. (2003). A positive autoregulatory loop of LMP expression and STAT activation in epithelial cells latently infected with Epstein-Barr virus. Journal of Virology, 77, 4139–4148.
- Husaini, R., Ahmad, M., & Khoo, A. S. (2011). Epstein-Barr virus latent membrane protein LMP1 reduces p53 protein levels independent of the PI3K-Akt pathway. BMC Research Notes, 4, 551.
- Hoe, S., Lee, E., Khoo, A. S., & Peh, S. (2009). p53 and nasopharyngeal carcinoma: A Malaysian study. Pathology, 41, 561–565.
- Kung, C. P., Meckes, D. G., Jr., & Raab-Traub, N. (2011). Epstein-Barr virus LMP activates EGFR, STAT3, and ERK through effects on PKCdelta. Journal of Virology, 85, 4399–4408.
- Stewart, S., Dawson, C. W., Takada, K., et al. (2004). Epstein-Barr virus-encoded LMP-2A regulates viral and cellular gene expression by modulation of the NF-kappaB transcription factor pathway. Proceedings of the National Academy of Sciences of the United States of America, 101, 15730–15735.
- Pang, M. F., Lin, K. W., & Peh, S. C. (2009). The signaling pathways of Epstein-Barr virus-encoded latent membrane protein 2A (LMP-2A) in latency and cancer. Cellular & Molecular Biology Letters, 14, 222–247.
- Shair, K. H., Bendt, K. M., Edwards, R. H., et al. (2012). Epstein-Barr virus-encoded latent membrane protein 1 (LMP) and LMP-2A function cooperatively to promote carcinoma development in a mouse carcinogenesis model. Journal of Virology, 86, 5352–5365.
- Dawson, C. W., Port, R. J., & Young, L. S. (2012). The role of the EBV-encoded latent membrane proteins LMP and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC). Seminars in Cancer Biology, 22, 144–153.
- Shinozaki-Ushiku, A., Kunita, A., & Fukayama, M. (2015). Update on Epstein-Barr virus and gastric cancer. International Journal of Oncology, 46, 1421–1434.
- Brooks, L., Yao, Q. Y., Rickinson, A. B., et al. (1992). Epstein-Barr virus latent gene transcription in nasopharyngeal carcinoma cells: Coexpression of EBNA1, LMP, and LMP2 transcripts. Journal of Virology, 66, 2689–2697.
- He, L., & Hannon, G. J. (2004). MicroRNAs: Small RNAs with a big role in gene regulation. Nature Reviews Genetics, 5, 522–531.
- Bartel, D. P. (2009). MicroRNA target recognition and regulatory functions. Cell, 136, 215–233.
- Lo, A. K., To, K. F., Lo, K. W., et al. (2007). Modulation of LMP protein expression by EBV-encoded microRNAs. Proceedings of the National Academy of Sciences of the United States of America, 104, 16164–16169.
- Zhu, J. Y., Pfuhl, T., Motsch, N., et al. (2009). Identification of novel Epstein-Barr virus microRNA genes from nasopharyngeal carcinomas. Journal of Virology, 83, 3333–3341.
- Cai, L., Ye, Y., Jiang, Q., et al. (2015). Epstein-Barr virus-encoded microRNA BART1 induces tumour metastasis by regulating PTEN-dependent pathways in nasopharyngeal carcinoma. Nature Communications, 6, 7353.
- Marquitz, A. R., Mathur, A., Chugh, P. E., et al. (2014). Expression profile of microRNAs in Epstein-Barr virus-infected AGS gastric carcinoma cells. Journal of Virology, 88, 1389–1393.
- Shinozaki-Ushiku, A., Kunita, A., Isogai, M., et al. (2015). Profiling of virus-encoded microRNAs in Epstein-Barr virus-associated gastric carcinoma and their roles in gastric carcinogenesis. Journal of Virology, 89, 5581–5591.
- Piccaluga, P. P., Navari, M., De Falco, G., et al. (2016). Virus-encoded microRNA contributes to the molecular profile of EBV-positive Burkitt lymphomas. Oncotarget, 7, 224–240.
- Vereide, D. T., Seto, E., Chiu, Y. F., et al. (2014). Epstein-Barr virus maintains lymphomas via its miRNAs. Oncogene, 33, 1258–1264.
- Pandya, D., Mariani, M., He, S., et al. (2015). Epstein-Barr virus microRNA expression increases aggressiveness of solid malignancies. PLoS One, 10, e0136058.
- Melo, S. A., Sugimoto, H., O’Connell, J. T., et al. (2014). Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell, 26, 707–721.
- Thind, A., & Wilson, C. (2016). Exosomal miRNAs as cancer biomarkers and therapeutic targets. Journal of Extracellular Vesicles, 5, 31292.
- Ye, S. B., Li, Z. L., Luo, D. H., et al. (2014). Tumour-derived exosomes promote tumour progression and T-cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma. Oncotarget, 5, 5439–5452.
- Yang, Q., Diamond, M. P., & Al-Hendy, A. (2016). The emerging role of extracellular vesicle-derived miRNAs: Implication in cancer progression and stem cell related diseases. Journal of Clinical Epigenetics, 2, Article 13.
- Matsumura, T., Sugimachi, K., Iinuma, H., et al. (2015). Exosomal microRNA in serum is a novel biomarker of recurrence in human colorectal cancer. British Journal of Cancer, 113, 275–281.
- Choi, H., Lee, H., Kim, S. R., et al. (2013). Epstein-Barr virus-encoded microRNA BART15-3p promotes cell apoptosis partially by targeting BRUCE. Journal of Virology, 87, 8135–8144.
- Klibi, J., Niki, T., Riedel, A., et al. (2009). Blood diffusion and Th1-suppressive effects of galectin-9-containing exosomes released by Epstein-Barr virus-infected nasopharyngeal carcinoma cells. Blood, 113, 1957–1966.
- Daker, M., Bhuvanendran, S., Ahmad, M., Takada, K., & Khoo, A. S. (2013). Deregulation of lipid metabolism pathway genes in nasopharyngeal carcinoma cells. Molecular Medicine Reports, 7, 731–741.
- Ariza, M. E., Rivailler, P., Glaser, R., et al. (2013). Epstein-Barr virus encoded dUTPase containing exosomes modulate innate and adaptive immune responses in human dendritic cells and peripheral blood mononuclear cells. PLoS One, 8, e69827.
- Huang, S. H., Li, Y., Zhang, J., et al. (2013). Epidermal growth factor receptor-containing exosomes induce tumour-specific regulatory T cells. Cancer Investigation, 31, 330–335.
- Ansari, M. A., Singh, V. V., Dutta, S., et al. (2013). Constitutive interferon-inducible protein 16-inflammasome activation during Epstein-Barr virus latency I, II, and III in B and epithelial cells. Journal of Virology, 87, 8606–8623.
- Shao, H., Chung, J., & Issadore, D. (2016). Diagnostic technologies for circulating tumour cells and exosomes. Bioscience Reports, 36, e00292.
- Lin, J., Li, J., Huang, B., et al. (2015). Exosomes: Novel biomarkers for clinical diagnosis. The Scientific World Journal, 2015, 657086.
- Munson, P., & Shukla, A. (2015). Exosomes: Potential in cancer diagnosis and therapy. Medicines, 2, 310–327.
- An, T., Qin, S., Xu, Y., et al. (2015). Exosomes serve as tumour markers for personalized diagnostics owing to their important role in cancer metastasis. Journal of Extracellular Vesicles, 4, 27522.
- Cappello, F., Logozzi, M., Campanella, C., et al. (2016). Exosome levels in human body fluids: A tumour marker by themselves? European Journal of Pharmaceutical Sciences, 96, 93–98.
- Houali, K., Wang, X., Shimizu, Y., et al. (2007). A new diagnostic marker for secreted Epstein-Barr virus encoded LMP and BARF1 oncoproteins in the serum and saliva of patients with nasopharyngeal carcinoma. Clinical Cancer Research, 13, 4993–5000.
- Mao, Y., Zhang, D. W., Zhu, H., et al. (2012). LMP and LMP-2A are potential prognostic markers of extranodal NK/T-cell lymphoma, nasal type (ENKTL). Diagnostic Pathology, 7, 178.
- Yip, T. T., Ngan, R. K., Fong, A. H., et al. (2014). Application of circulating plasma/serum EBV DNA in the clinical management of nasopharyngeal carcinoma. Oral Oncology, 50, 527–538.
- De Paoli, P., Pratesi, C., & Bortolin, M. T. (2007). The Epstein Barr virus DNA levels as a tumour marker in EBV-associated cancers. Journal of Cancer Research and Clinical Oncology, 133, 809–815.
- Stevens, S. J., Verkuijlen, S. A., Hariwiyanto, B., et al. (2006). Noninvasive diagnosis of nasopharyngeal carcinoma: Nasopharyngeal brushings reveal high Epstein-Barr virus DNA load and carcinoma-specific viral BARF1 mRNA. International Journal of Cancer, 119, 608–614.
- Stevens, S. J. C., Verkuijlen, S. A. W. M., Hariwiyanto, B., et al. (2005). Diagnostic value of measuring Epstein-Barr Virus (EBV) DNA load and carcinoma-specific viral mRNA in relation to anti-EBV immunoglobulin A (IgA) and IgG antibody levels in blood of nasopharyngeal carcinoma patients from Indonesia. Journal of Clinical Microbiology, 43, 3066–3073.
- Zhang, G., Zong, J., Lin, S., et al. (2015). Circulating Epstein-Barr virus microRNAs miR-BART7 and miR-BART13 as biomarkers for nasopharyngeal carcinoma diagnosis and treatment. International Journal of Cancer, 136, E301–E312.
- Zheng, X. H., Lu, L. X., Cui, C., et al. (2016). Epstein-Barr virus miR-BART1-5p detection via nasopharyngeal brush sampling is effective for diagnosing nasopharyngeal carcinoma. Oncotarget, 7, 4972–4980.
- Gourzones, C., Ferrand, F. R., Vérillaud, B., et al. (2012). Biological tools for NPC population screening and disease monitoring. In P. Busson (Ed.), Nasopharyngeal carcinoma: Keys for translational medicine and biology (pp. 101–117). Landes and Springer.
- Dales, J. P., Beaufils, N., Silvy, M., et al. (2010). Hypoxia inducible factor 1α gene (HIF-1α) splice variants: Potential prognostic biomarkers in breast cancer. BMC Medicine, 8, 44.
- Weber, D. C., Tille, J. C., Combescure, C., et al. (2012). The prognostic value of expression of HIF1α, EGFR and VEGF-A, in localized prostate cancer for intermediate- and high-risk patients treated with radiation therapy with or without androgen deprivation therapy. Radiation Oncology, 7, 66.
- Valadi, H., Ekström, K., Bossios, A., et al. (2007). Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biology, 9, 654–659.
- Iero, M., Valenti, R., Huber, V., et al. (2008). Tumour-released exosomes and their implications in cancer immunity. Cell Death & Differentiation, 15, 80–88.
- Yu, S., Cao, H., Shen, B., et al. (2015). Tumour-derived exosomes in cancer progression and treatment failure. Oncotarget, 6, 37151–37168.
- Cao, Y., Yang, L., Jiang, W., et al. (2014). Therapeutic evaluation of Epstein-Barr virus-encoded latent membrane protein-1 targeted DNAzyme for treating of nasopharyngeal carcinomas. Molecular Therapy, 22, 371–377.
- Hutajulu, S. H., Kurnianda, J., Tan, I. B., et al. (2014). Therapeutic implications of Epstein-Barr virus infection for the treatment of nasopharyngeal carcinoma. Therapeutics and Clinical Risk Management, 10, 721–736.
- Lee, H. G., Kim, H., Kim, E. J., et al. (2015). Targeted therapy for Epstein-Barr virus-associated gastric carcinoma using low-dose gemcitabine-induced lytic activation. Oncotarget, 6, 31018–31029.
- Stoker, S. D., Novalić, Z., Wildeman, M. A., et al. (2015). Epstein-Barr virus-targeted therapy in nasopharyngeal carcinoma. Journal of Cancer Research and Clinical Oncology, 141, 1845–1857.
- Chua, D. T., Wei, W. I., Wong, M. P., et al. (2008). Phase II study of gefitinib for the treatment of recurrent and metastatic nasopharyngeal carcinoma. Head & Neck, 30, 863–867.
- Ma, B., Hui, E. P., King, A., et al. (2008). A phase II study of patients with metastatic or locoregionally recurrent nasopharyngeal carcinoma and evaluation of plasma Epstein-Barr virus DNA as a biomarker of efficacy. Cancer Chemotherapy and Pharmacology, 62, 59–64.
- Lee, N. Y., Zhang, Q., Pfister, D. G., et al. (2012). Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): A phase 2 multi-institutional trial. The Lancet Oncology, 13, 172–180.
- Elser, C., Siu, L. L., Winquist, E., et al. (2007). Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. Journal of Clinical Oncology, 25, 3766–3773.
- De Toro, J., Herschlik, L., Waldner, C., et al. (2015). Emerging roles of exosomes in normal and pathological conditions: New insights for diagnosis and therapeutic applications. Frontiers in Immunology, 6, 203.
- Marleau, A. M., Chen, C. S., Joyce, J. A., et al. (2012). Exosome removal as a therapeutic adjuvant in cancer. Journal of Translational Medicine, 10, 134.
- Tickner, J. A., Urquhart, A. J., Stephenson, S. A., et al. (2014). Functions and therapeutic roles of exosomes in cancer. Frontiers in Oncology, 4, 127.
- Ohno, S., Takanashi, M., Sudo, K., et al. (2013). Systemically injected exosomes targeted to EGFR deliver antitumour microRNA to breast cancer cells. Molecular Therapy, 21, 185–191.
- Qi, H., Liu, C., Long, L., et al. (2016). Blood exosomes endowed with magnetic and targeting properties for cancer therapy. ACS Nano, 10, 3323–3333.
- Johnsen, K. B., Gudbergsson, J. M., Skov, M. N., et al. (2014). A comprehensive overview of exosomes as drug delivery vehicles: Endogenous nanocarriers for targeted cancer therapy. Biochimica et Biophysica Acta, 1846, 75–87.
- Hannigan, A., & Wilson, J. B. (2010). Evaluation of LMP of Epstein-Barr virus as a therapeutic target by its inhibition. Molecular Cancer, 9, 184.


