ABSTRACT

Evidence has been accumulating to indicate that extracellular vesicles (EVs), including exosomes, released by cancer cells can foster tumour progression. The molecular chaperones – CDC37, HSP90α and HSP90β play key roles in cancer progression including epithelial-mesenchymal transition (EMT), although their contribution to EVs-mediated cell–cell communication in tumour microenvironment has not been thoroughly examined. Here we show that triple depletion of the chaperone trio attenuates numerous cancer malignancy events exerted through EV release. Metastatic oral cancer-derived EVs (MEV) were enriched with HSP90α HSP90β and cancer-initiating cell marker CD326/EpCAM. Depletion of these chaperones individually induced compensatory increases in the other chaperones, whereas triple siRNA targeting of these molecules markedly diminished the levels of the chaperone trio and attenuated EMT. MEV were potent agents in initiating EMT in normal epithelial cells, a process that was attenuated by the triple chaperone depletion. The migration, invasion, and in vitro tumour initiation of oral cancer cells were significantly promoted by MEV, while triple depletion of CDC37/HSP90α/β reversed these MEV-driven malignancy events. In metastatic oral cancer patient-derived tumours, HSP90β was significantly accumulated in infiltrating tumour-associated macrophages (TAM) as compared to lower grade oral cancer cases. HSP90-enriched MEV-induced TAM polarization to an M2 phenotype, a transition known to support cancer progression, whereas the triple chaperone depletion attenuated this effect. Mechanistically, the triple chaperone depletion in metastatic oral cancer cells effectively reduced MEV transmission into macrophages. Hence, siRNA-mediated knockdown of the chaperone trio (CDC37/HSP90α/HSP90β) could potentially be a novel therapeutic strategy to attenuate several EV-driven malignancy events in the tumour microenvironment.

Abbreviations

CDC37: cell division control 37; EMT: epithelial-mesenchymal transmission; EV: extracellular vesicles; HNSCC: head and neck squamous cell carcinoma; HSP90: heat shock protein 90; TAM: tumour-associated macrophage

中文翻译：

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CDC37、HSP90-α 和 HSP90-β 的三重敲低可减少口腔癌中细胞外囊泡驱动的恶性肿瘤事件和巨噬细胞 M2 极化

摘要

越来越多的证据表明，癌细胞释放的细胞外囊泡（EV）（包括外泌体）可以促进肿瘤进展。分子伴侣——CDC37、HSP90α 和 HSP90β 在包括上皮间质转化 (EMT) 在内的癌症进展中起关键作用，尽管它们对肿瘤微环境中 EVs 介导的细胞间通讯的贡献尚未得到彻底检查。在这里，我们表明伴侣三重奏的三重消耗减弱了通过 EV 释放产生的许多癌症恶性肿瘤事件。转移性口腔癌衍生 EV (MEV) 富含 HSP90α HSP90β 和癌症起始细胞标志物 CD326/EpCAM。这些伴侣的消耗分别导致其他伴侣的补偿性增加，而这些分子的三重siRNA靶向显着降低了伴侣三重奏的水平并减弱了EMT。MEV 是在正常上皮细胞中启动 EMT 的有效药物，这一过程因三重伴侣耗尽而减弱。MEV 显着促进了口腔癌细胞的迁移、侵袭和体外肿瘤起始，而 CDC37/HSP90α/β 的三重耗竭逆转了这些 MEV 驱动的恶性肿瘤事件。在转移性口腔癌患者来源的肿瘤中，与较低级别的口腔癌病例相比，HSP90β 在浸润性肿瘤相关巨噬细胞 (TAM) 中显着积累。富含 HSP90 的 MEV 诱导的 TAM 极化为 M2 表型，这是一种已知支持癌症进展的转变，而三重伴侣的消耗减弱了这种效应。机械地，转移性口腔癌细胞中三重伴侣的消耗有效地减少了 MEV 向巨噬细胞的传递。因此，siRNA 介导的伴侣三重奏（CDC37/HSP90α/HSP90β）的敲低可能是一种新的治疗策略，可以减轻肿瘤微环境中几种 EV 驱动的恶性肿瘤事件。

缩写

CDC37：细胞分裂控制 37；EMT：上皮间质传递；EV：细胞外囊泡；HNSCC：头颈部鳞状细胞癌；HSP90：热休克蛋白90；TAM：肿瘤相关巨噬细胞