Table1_Extracellular vesicles from human breast cancer-resistant cells promote acquired drug resistance and pro-inflammatory macrophage response.docx

IntroductionBreast cancer is a significant public health problem around the world, ranking first in deaths due to cancer in females. The therapy to fight breast cancer involves different methods, including conventional chemotherapy. However, the acquired resistance that tumors develop during the treatment is still a central cause of cancer-associated deaths. One mechanism that induces drug resistance is cell communication via extracellular vesicles (EVs), which can carry efflux transporters and miRNA that increase sensitive cells’ survivability to chemotherapy.MethodsOur study investigates the transcription changes modulated by EVs from tamoxifen- and doxorubicin-resistant breast cancer cells in sensitive cells and how these changes may induce acquired drug resistance, inhibit apoptosis, and increase survivability in the sensitive cells. Additionally, we exposed human macrophages to resistant EVs to understand the influence of EVs on immune responses.ResultsOur results suggest that the acquired drug resistance is associated with the ability of resistant EVs to upregulate several transporter classes, which are directly related to the increase of cell viability and survival of sensitive cells exposed to EVs before a low-dose drug treatment. In addition, we show evidence that resistant EVs may downregulate immune system factors to evade detection and block cell death by apoptosis in sensitive breast cancer cells. Our data also reveals that human macrophages in contact with resistant EVs trigger a pro-inflammatory cytokine secretion profile, an effect that may be helpful for future immunotherapy studies.DiscussionThese findings are the first transcriptome-wide analysis of cells exposed to resistant EVs, supporting that resistant EVs are associated with the acquired drug resistance process during chemotherapy by modulating different aspects of sensitive cancer cells that coffer the chemoresistance.

全球范围内，乳腺癌是一项重大的公共卫生问题，在女性因癌症死亡原因中位居首位。对抗乳腺癌的治疗方法包括传统化疗等多种方法。然而，肿瘤在治疗过程中产生的获得性耐药性仍然是癌症相关死亡的主要原因之一。诱导药物耐药性的一种机制是通过细胞外囊泡（EVs）进行的细胞间通讯，这些囊泡可以携带外排转运蛋白和miRNA，从而增加敏感细胞对化疗的生存能力。研究方法：本研究调查了由 tamoxifen 和 doxorubicin 耐药性乳腺癌细胞分泌的 EVs 在敏感细胞中调节的转录变化，以及这些变化如何可能诱导获得性耐药性、抑制细胞凋亡并增加敏感细胞的生存能力。此外，我们还暴露人类巨噬细胞于耐药 EVs 中，以了解 EVs 对免疫反应的影响。研究结果：我们的结果表明，获得性耐药性与耐药 EVs 上调多种转运蛋白类别的能力相关，这些转运蛋白与暴露于 EVs 之前接受低剂量药物治疗时敏感细胞的细胞活力和生存能力的增加直接相关。此外，我们还发现耐药 EVs 可能下调免疫系统因素以逃避检测并阻断敏感乳腺癌细胞的细胞凋亡。我们的数据还显示，与耐药 EVs 接触的人类巨噬细胞引发促炎细胞因子分泌谱，这一效应可能有助于未来的免疫治疗研究。讨论：这些发现是首次对暴露于耐药 EVs 的细胞进行的转录组分析，支持了耐药 EVs 通过调节敏感癌细胞的不同方面，在化疗过程中与获得性耐药性过程相关的观点。