细胞外囊泡外泌体在上皮性卵巢癌的应用
Application of Extracellular Vesicle Exosomes in Epithelial Ovarian Cancer
DOI: 10.12677/acm.2025.153676, PDF,   
作者: 韩佳楠*, 杨晓玲:内蒙古妇幼保健院,妇科,内蒙古 呼和浩特
关键词: 上皮性卵巢癌外泌体诊断治疗复发及预后Epithelial Ovarian Cancer Exosomes Diagnosis Treatment Recurrence and Prognosis
摘要: 在我国,卵巢癌年发病率居女性生殖系统肿瘤第3位,位于子宫颈癌和子宫体恶性肿瘤之后,呈逐年上升的趋势,而病死率位于女性生殖道恶性肿瘤之首,是严重威胁女性健康的恶性肿瘤。已有研究表明,EVs介导物质运输到近邻和远处细胞影响肿瘤发展的许多过程,包括促进血管生成,逃避免疫监视,侵袭转移,耐药等。外泌体已成为人类生物流体非侵入性液体活检中早期癌症诊断的新的候选者。本文将对细胞外囊泡外泌体在上皮性卵巢癌的诊断、治疗及预后方面的研究进展进行综述,以期望在上皮性卵巢癌患者的诊疗中提供参考。
Abstract: In China, the annual incidence rate of ovarian cancer ranks third in female reproductive system tumors, after cervical cancer and uterine body malignancies, showing a rising trend year by year, while the mortality rate ranks first in female reproductive tract malignancies, which is a serious threat to women’s health. Previous studies have shown that EVs mediate the transport of substances to neighboring and distant cells, affecting many processes of tumor development, including promoting angiogenesis, evading immune surveillance, invasion and metastasis, drug resistance, etc. Extracellular vesicles have emerged as a new candidate for early cancer diagnosis in non-invasive liquid biopsy of human biological fluids. This article will review the research progress of extracellular vesicle exosomes in the diagnosis, treatment, and prognosis of epithelial ovarian cancer, in order to provide reference for the diagnosis and treatment of epithelial ovarian cancer patients.
文章引用:韩佳楠, 杨晓玲. 细胞外囊泡外泌体在上皮性卵巢癌的应用[J]. 临床医学进展, 2025, 15(3): 764-771. https://doi.org/10.12677/acm.2025.153676

参考文献

[1] 刘宗超, 李哲轩, 张阳, 等. 2020全球癌症统计报告解读[J]. 肿瘤综合治疗电子杂志, 2021, 7(2): 1-13.
[2] Noone, A.M., Howlader, N., Krapcho, M., Miller, D., Brest, A., Yu, M., et al. (2018) SEER Cancer Statistics Review, 1975-2015. National Cancer Institute.
https://seer.cancer.gov/csr/1975_2015/
[3] Yang, C., Kim, H.S., Song, G. and Lim, W. (2019) The Potential Role of Exosomes Derived from Ovarian Cancer Cells for Diagnostic and Therapeutic Approaches. Journal of Cellular Physiology, 234, 21493-21503. [Google Scholar] [CrossRef] [PubMed]
[4] Elattar, A., Bryant, A., Winter-Roach, B.A., Hatem, M. and Naik, R. (2011) Optimal Primary Surgical Treatment for Advanced Epithelial Ovarian Cancer. Cochrane Database of Systematic Reviews, No. 8, CD007565. [Google Scholar] [CrossRef
[5] Kobayashi, H., Yamada, Y., Sado, T., Sakata, M., Yoshida, S., Kawaguchi, R., et al. (2008) A Randomized Study of Screening for Ovarian Cancer: A Multicenter Study in Japan. International Journal of Gynecological Cancer, 18, 414-420. [Google Scholar] [CrossRef] [PubMed]
[6] Menon, U., Gentry-Maharaj, A., Hallett, R., Ryan, A., Burnell, M., Sharma, A., et al. (2009) Sensitivity and Specificity of Multimodal and Ultrasound Screening for Ovarian Cancer, and Stage Distribution of Detected Cancers: Results of the Prevalence Screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). The Lancet Oncology, 10, 327-340. [Google Scholar] [CrossRef
[7] Prorok, P.C., Andriole, G.L., Bresalier, R.S., Buys, S.S., Chia, D., David Crawford, E., et al. (2000) Design of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Controlled Clinical Trials, 21, 273S-309S. [Google Scholar] [CrossRef] [PubMed]
[8] Buys, S.S. (2011) Effect of Screening on Ovarian Cancer Mortality: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA, 305, 2295-2303. [Google Scholar] [CrossRef] [PubMed]
[9] Mol, B.W.J., Bayram, N., Lijmer, J.G., Wiegerinck, M.A.H.M., Bongers, M.Y., van der Veen, F., et al. (1998) The Performance of CA-125 Measurement in the Detection of Endometriosis: A Meta-Analysis. Fertility and Sterility, 70, 1101-1108. [Google Scholar] [CrossRef] [PubMed]
[10] Topalak, O., Saygili, U., Soyturk, M., Karaca, N., Batur, Y., Uslu, T., et al. (2002) Serum, Pleural Effusion, and Ascites CA-125 Levels in Ovarian Cancer and Nonovarian Benign and Malignant Diseases: A Comparative Study. Gynecologic Oncology, 85, 108-113. [Google Scholar] [CrossRef] [PubMed]
[11] Shah, C.A., Lowe, K.A., Paley, P., Wallace, E., Anderson, G.L., McIntosh, M.W., et al. (2009) Influence of Ovarian Cancer Risk Status on the Diagnostic Performance of the Serum Biomarkers Mesothelin, HE4, and CA125. Cancer Epidemiology, Biomarkers & Prevention, 18, 1365-1372. [Google Scholar] [CrossRef] [PubMed]
[12] Moore, R.G., Miller, M.C., Eklund, E.E., Lu, K.H., Bast, R.C. and Lambert-Messerlian, G. (2012) Serum Levels of the Ovarian Cancer Biomarker HE4 Are Decreased in Pregnancy and Increase with Age. American Journal of Obstetrics and Gynecology, 206, 349.e1-349.e7. [Google Scholar] [CrossRef] [PubMed]
[13] Chang, X., Ye, X., Dong, L., Cheng, H., Cheng, Y., Zhu, L., et al. (2011) Human Epididymis Protein 4 (HE4) as a Serum Tumor Biomarker in Patients with Ovarian Carcinoma. International Journal of Gynecological Cancer, 21, 852-858. [Google Scholar] [CrossRef] [PubMed]
[14] Tian, Y., Wang, C., Cheng, L., Zhang, A., Liu, W., Guo, L., et al. (2015) Determination of Reference Intervals of Serum Levels of Human Epididymis Protein 4 (HE4) in Chinese Women. Journal of Ovarian Research, 8, Article No. 72. [Google Scholar] [CrossRef] [PubMed]
[15] Boukouris, S. and Mathivanan, S. (2015) Exosomes in Bodily Fluids Are a Highly Stable Resource of Disease Biomarkers. PROTEOMICS—Clinical Applications, 9, 358-367. [Google Scholar] [CrossRef] [PubMed]
[16] Salvador, S., Scott, S., Glanc, P., Eiriksson, L., Jang, J., Sebastianelli, A., et al. (2020) Guideline No. 403: Initial Investigation and Management of Adnexal Masses. Journal of Obstetrics and Gynaecology Canada, 42, 1021-1029.e3. [Google Scholar] [CrossRef] [PubMed]
[17] Mathieu, K.B., Bedi, D.G., Thrower, S.L., Qayyum, A. and Bast, R.C. (2018) Screening for Ovarian Cancer: Imaging Challenges and Opportunities for Improvement. Ultrasound in Obstetrics & Gynecology, 51, 293-303. [Google Scholar] [CrossRef] [PubMed]
[18] Pan, B. and Johnstone, R.M. (1983) Fate of the Transferrin Receptor during Maturation of Sheep Reticulocytes in vitro: Selective Externalization of the Receptor. Cell, 33, 967-978. [Google Scholar] [CrossRef] [PubMed]
[19] van Niel, G., D’Angelo, G. and Raposo, G. (2018) Shedding Light on the Cell Biology of Extracellular Vesicles. Nature Reviews Molecular Cell Biology, 19, 213-228. [Google Scholar] [CrossRef] [PubMed]
[20] Zhang, H. and Grizzle, W.E. (2014) Exosomes: A Novel Pathway of Local and Distant Intercellular Communication That Facilitates the Growth and Metastasis of Neoplastic Lesions. The American Journal of Pathology, 184, 28-41. [Google Scholar] [CrossRef] [PubMed]
[21] Beach, A., Zhang, H., Ratajczak, M.Z. and Kakar, S.S. (2014) Exosomes: An Overview of Biogenesis, Composition and Role in Ovarian Cancer. Journal of Ovarian Research, 7, Article No. 14. [Google Scholar] [CrossRef] [PubMed]
[22] Cocucci, E., Racchetti, G. and Meldolesi, J. (2009) Shedding Microvesicles: Artefacts No More. Trends in Cell Biology, 19, 43-51. [Google Scholar] [CrossRef] [PubMed]
[23] 兰霄霄, 周志阳, 徐欣欣, 等. 细胞外囊泡及其在卵巢癌诊治中的研究进展[J]. 温州医科大学学报, 2017, 47(12): 931-936.
[24] Van Doormaal, F.F., Kleinjan, A., Di Nisio, M., et al. (2009) Cell-Derived Microvesicles and Cancer. The Netherlands Journal of Medicine, 67, 266-273.
[25] Johnstone, R.M., Adam, M., Hammond, J.R., Orr, L. and Turbide, C. (1987) Vesicle Formation during Reticulocyte Maturation. Association of Plasma Membrane Activities with Released Vesicles (Exosomes). Journal of Biological Chemistry, 262, 9412-9420. [Google Scholar] [CrossRef] [PubMed]
[26] Keller, S., Sanderson, M.P., Stoeck, A. and Altevogt, P. (2006) Exosomes: From Biogenesis and Secretion to Biological Function. Immunology Letters, 107, 102-108. [Google Scholar] [CrossRef] [PubMed]
[27] Kowal, J., Tkach, M. and Théry, C. (2014) Biogenesis and Secretion of Exosomes. Current Opinion in Cell Biology, 29, 116-125. [Google Scholar] [CrossRef] [PubMed]
[28] Colombo, M., Raposo, G. and Théry, C. (2014) Biogenesis, Secretion, and Intercellular Interactions of Exosomes and Other Extracellular Vesicles. Annual Review of Cell and Developmental Biology, 30, 255-289. [Google Scholar] [CrossRef] [PubMed]
[29] Melo, S.A., Sugimoto, H., O’Connell, J.T., Kato, N., Villanueva, A., Vidal, A., et al. (2014) Cancer Exosomes Perform Cell-Independent MicroRNA Biogenesis and Promote Tumorigenesis. Cancer Cell, 26, 707-721. [Google Scholar] [CrossRef] [PubMed]
[30] Fong, M.Y., Zhou, W., Liu, L., Alontaga, A.Y., Chandra, M., Ashby, J., et al. (2015) Breast-Cancer-Secreted miR-122 Reprograms Glucose Metabolism in Premetastatic Niche to Promote Metastasis. Nature Cell Biology, 17, 183-194. [Google Scholar] [CrossRef] [PubMed]
[31] Li, W., Li, C., Zhou, T., Liu, X., Liu, X., Li, X., et al. (2017) Role of Exosomal Proteins in Cancer Diagnosis. Molecular Cancer, 16, Article No. 145. [Google Scholar] [CrossRef] [PubMed]
[32] Chevillet, J.R., Kang, Q., Ruf, I.K., Briggs, H.A., Vojtech, L.N., Hughes, S.M., et al. (2014) Quantitative and Stoichiometric Analysis of the MicroRNA Content of Exosomes. Proceedings of the National Academy of Sciences, 111, 14888-14893. [Google Scholar] [CrossRef] [PubMed]
[33] Escrevente, C., Keller, S., Altevogt, P. and Costa, J. (2011) Interaction and Uptake of Exosomes by Ovarian Cancer Cells. BMC Cancer, 11, Article No. 108. [Google Scholar] [CrossRef] [PubMed]
[34] Gray, H.J. and Garcia, R.L. (2019) Cancer of the Ovary, Fallopian Tube, and Peritoneum: Staging and Surgical Management. UpToDate.
[35] Zhang, W., Ou, X. and Wu, X. (2019) Proteomics Profiling of Plasma Exosomes in Epithelial Ovarian Cancer: A Potential Role in the Coagulation Cascade, Diagnosis and Prognosis. International Journal of Oncology, 54, 1719-1733. [Google Scholar] [CrossRef] [PubMed]
[36] Cho, M.S., Vasquez, H.G., Rupaimoole, R., Pradeep, S., Wu, S., Zand, B., et al. (2014) Autocrine Effects of Tumor-Derived Complement. Cell Reports, 6, 1085-1095. [Google Scholar] [CrossRef] [PubMed]
[37] Nunez-Cruz, S., Gimotty, P.A., Guerra, M.W., Connolly, D.C., Wu, Y., DeAngelis, R.A., et al. (2012) Genetic and Pharmacologic Inhibition of Complement Impairs Endothelial Cell Function and Ablates Ovarian Cancer Neovascularization. Neoplasia, 14, 994-1004. [Google Scholar] [CrossRef] [PubMed]
[38] Larsen, A.K., Escargueil, A.E. and Skladanowski, A. (2000) Resistance Mechanisms Associated with Altered Intracellular Distribution of Anticancer Agents. Pharmacology & Therapeutics, 85, 217-229. [Google Scholar] [CrossRef] [PubMed]
[39] Warren, L., Jardillier, J.C. and Ordentlich, P. (1991) Secretion of Lysosomal Enzymes by Drug-Sensitive and Multiple Drug-Resistant Cells. Cancer Research, 51, 1996-2001.
[40] Weiner‐Gorzel, K., Dempsey, E., Milewska, M., McGoldrick, A., Toh, V., Walsh, A., et al. (2015) Overexpression of the MicroRNA miR‐433 Promotes Resistance to Paclitaxel through the Induction of Cellular Senescence in Ovarian Cancer Cells. Cancer Medicine, 4, 745-758. [Google Scholar] [CrossRef] [PubMed]
[41] Yin, J., Yan, X., Yao, X., Zhang, Y., Shan, Y., Mao, N., et al. (2012) Secretion of Annexin A3 from Ovarian Cancer Cells and Its Association with Platinum Resistance in Ovarian Cancer Patients. Journal of Cellular and Molecular Medicine, 16, 337-348. [Google Scholar] [CrossRef] [PubMed]
[42] Dorayappan, K.D.P., Wanner, R., Wallbillich, J.J., Saini, U., Zingarelli, R., Suarez, A.A., et al. (2018) Hypoxia-Induced Exosomes Contribute to a More Aggressive and Chemoresistant Ovarian Cancer Phenotype: A Novel Mechanism Linking STAT3/Rab Proteins. Oncogene, 37, 3806-3821. [Google Scholar] [CrossRef] [PubMed]
[43] Arend, R., Westin, S.N. and Coleman, R.L. (2020) Decision Analysis for Secondline Maintenance Treatment of Platinum Sensitive Recurrent Ovarian Cancer: A Review. International Journal of Gynecological Cancer, 30, 684-694. [Google Scholar] [CrossRef] [PubMed]
[44] Rojas, V., Hirshfield, K., Ganesan, S. and Rodriguez-Rodriguez, L. (2016) Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment. International Journal of Molecular Sciences, 17, Article 2113. [Google Scholar] [CrossRef] [PubMed]
[45] Zhang, Y., Shi, J. and Li, C. (2019) Small Extracellular Vesicle Loading Systems in Cancer Therapy: Current Status and the Way Forward. Cytotherapy, 21, 1122-1136. [Google Scholar] [CrossRef] [PubMed]
[46] Kooijmans, S.A.A., Vader, P., van Dommelen, S.M., van Solinge, W.W. and Schiffelers, R.M. (2012) Exosome Mimetics: A Novel Class of Drug Delivery Systems. International Journal of Nanomedicine, 7, 1525-1541. [Google Scholar] [CrossRef] [PubMed]
[47] Zhang, X., Chen, J., Kang, Y., Hong, S., Zheng, Y., Sun, H., et al. (2013) Targeted Paclitaxel Nanoparticles Modified with Follicle-Stimulating Hormone Β 81-95 Peptide Show Effective Antitumor Activity against Ovarian Carcinoma. International Journal of Pharmaceutics, 453, 498-505. [Google Scholar] [CrossRef] [PubMed]
[48] Yue, Y., Li, J., Zhou, X., et al. (2017) Preparation of FSHβ Anchored Exosomes and Its Effect on Induced Killing of Ovarian Cancer Cell. Chinese Journal of Woman and Child Health Research, 28, 1601-1605.
[49] Wang, W., Wu, L., Li, C., Zhou, X., Liu, P., Jia, X., et al. (2019) Five Serum MicroRNAs for Detection and Predicting of Ovarian Cancer. European Journal of Obstetrics & Gynecology and Reproductive Biology: X, 3, Article 100017. [Google Scholar] [CrossRef] [PubMed]
[50] Bagnoli, M., Canevari, S., Califano, D., Losito, S., Maio, M.D., Raspagliesi, F., et al. (2016) Development and Validation of a MicroRNA-Based Signature (MiROvaR) to Predict Early Relapse or Progression of Epithelial Ovarian Cancer: A Cohort Study. The Lancet Oncology, 17, 1137-1146. [Google Scholar] [CrossRef] [PubMed]
[51] Ditto, A., De Cecco, L., Paolini, B., Alberti, P., Martinelli, F., Leone Roberti Maggiore, U., et al. (2022) Validation of MiROvaR, a MicroRNA-Based Predictor of Early Relapse in Early Stage Epithelial Ovarian Cancer as a New Strategy to Optimise Patients’ Prognostic Assessment. European Journal of Cancer, 161, 55-63. [Google Scholar] [CrossRef] [PubMed]
[52] Günel, T., Gumusoglu, E., Dogan, B., Ertem, F.B., Hosseini, M.K., Cevik, N., et al. (2018) Potential Biomarker of Circulating HSA-miR-1273g-3p Level for Detection of Recurrent Epithelial Ovarian Cancer. Archives of Gynecology and Obstetrics, 298, 1173-1180. [Google Scholar] [CrossRef] [PubMed]
[53] Alharbi, M., Sharma, S., Guanzon, D., Lai, A., Zuñiga, F., Shiddiky, M.J.A., et al. (2020) Mirna Signature in Small Extracellular Vesicles and Their Association with Platinum Resistance and Cancer Recurrence in Ovarian Cancer. Nanomedicine: Nanotechnology, Biology and Medicine, 28, Article 102207. [Google Scholar] [CrossRef] [PubMed]
[54] Meng, X., Müller, V., Milde-Langosch, K., Trillsch, F., Pantel, K. and Schwarzenbach, H. (2016) Diagnostic and Prognostic Relevance of Circulating Exosomal miR-373, miR-200a, miR-200b and miR-200c in Patients with Epithelial Ovarian Cancer. Oncotarget, 7, 16923-16935. [Google Scholar] [CrossRef] [PubMed]
[55] Amaria, R., Knisely, A., Vining, D., Kopetz, S., Overman, M.J., Javle, M., et al. (2024) Efficacy and Safety of Autologous Tumor-Infiltrating Lymphocytes in Recurrent or Refractory Ovarian Cancer, Colorectal Cancer, and Pancreatic Ductal Adenocarcinoma. Journal for ImmunoTherapy of Cancer, 12, e006822. [Google Scholar] [CrossRef] [PubMed]
[56] Vaksman, O., Tropé, C., Davidson, B. and Reich, R. (2014) Exosome-Derived miRNAs and Ovarian Carcinoma Progression. Carcinogenesis, 35, 2113-2120. [Google Scholar] [CrossRef] [PubMed]
[57] Cai, J., Gong, L., Li, G., Guo, J., Yi, X. and Wang, Z. (2021) Exosomes in Ovarian Cancer Ascites Promote Epithelial-Mesenchymal Transition of Ovarian Cancer Cells by Delivery of miR-6780b-5p. Cell Death & Disease, 12, Article No. 210. [Google Scholar] [CrossRef] [PubMed]