Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, Australia.
Subcell Biochem. 2021;97:211-245. doi: 10.1007/978-3-030-67171-6_9.
Chemotherapy represents the current mainstay therapeutic approach for most types of cancer. Despite the development of targeted chemotherapeutic strategies, the efficacy of anti-cancer drugs is severely limited by the development of drug resistance. Multidrug resistance (MDR) consists of the simultaneous resistance to various unrelated cytotoxic drugs and is one of the main causes of anticancer treatment failure. One of the principal mechanisms by which cancer cells become MDR involves the overexpression of ATP Binding Cassette (ABC) transporters, such as P-glycoprotein (P-gp), mediating the active efflux of cytotoxic molecules from the cytoplasm. Extracellular vesicles (EVs) are submicron lipid-enclosed vesicles that are released by all cells and which play a fundamental role in intercellular communication in physiological and pathological contexts. EVs have fundamental function at each step of cancer development and progression. They mediate the transmission of MDR through the transfer of vesicle cargo including functional ABC transporters as well as nucleic acids, proteins and lipids. Furthermore, EVs mediate MDR by sequestering anticancer drugs and stimulate cancer cell migration and invasion. EVs also mediate the communication with the tumour microenvironment and the immune system, resulting in increased angiogenesis, metastasis and immune evasion. All these actions contribute directly and indirectly to the development of chemoresistance and treatment failure. In this chapter, we describe the many roles EVs play in the acquisition and spread of chemoresistance in cancer. We also discuss possible uses of EVs as pharmacological targets to overcome EV-mediated drug resistance and the potential that the analysis of tumour-derived EVs offers as chemoresistance biomarkers.
化疗是目前大多数癌症类型的主要治疗方法。尽管已经开发了靶向化疗策略，但抗癌药物的疗效受到耐药性发展的严重限制。多药耐药性（MDR）包括对各种不相关细胞毒性药物的同时耐药性，是抗癌治疗失败的主要原因之一。癌细胞产生 MDR 的主要机制之一是 ATP 结合盒（ABC）转运蛋白的过度表达，如 P-糖蛋白（P-gp），介导细胞毒性分子从细胞质中的主动外排。细胞外囊泡（EVs）是亚微米脂质封闭的囊泡，所有细胞都会释放这些囊泡，并且在生理和病理环境中细胞间通讯中发挥着重要作用。EVs 在癌症发展和进展的每个阶段都具有基本功能。它们通过转移囊泡货物（包括功能性 ABC 转运蛋白以及核酸、蛋白质和脂质）来介导 MDR 的传递。此外，EVs 通过隔离抗癌药物并刺激癌细胞迁移和侵袭来介导 MDR。EVs 还介导与肿瘤微环境和免疫系统的通讯，导致血管生成、转移和免疫逃避增加。所有这些作用都直接或间接地导致了化疗耐药性的发展和治疗失败。在本章中，我们描述了 EVs 在癌症中获得和传播化疗耐药性方面所起的多种作用。我们还讨论了将 EV 作为药理学靶点来克服 EV 介导的耐药性的可能性，以及分析肿瘤衍生的 EV 作为化疗耐药性生物标志物的潜力。
