Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
Department of Medical Imaging, Hematology, and Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Front Immunol. 2024 Oct 15;15:1468229. doi: 10.3389/fimmu.2024.1468229. eCollection 2024.
Breast 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.
Our 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.
Our 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.
These 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.
乳腺癌是全球重大公共健康问题，在女性因癌症死亡的病例中，乳腺癌位居第一。治疗乳腺癌的方法包括常规化疗，但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。一种诱导耐药性的机制是通过细胞外囊泡（EVs）进行细胞间通讯，EVs 可以携带外排转运蛋白和 miRNA，从而增加化疗敏感细胞的存活能力。
我们的研究调查了来自他莫昔芬和阿霉素耐药乳腺癌细胞的 EVs 调节敏感细胞中转录变化的情况，以及这些变化如何诱导获得性耐药性、抑制细胞凋亡和增加敏感细胞的存活能力。此外，我们还将人巨噬细胞暴露于耐药 EVs 中，以了解 EVs 对免疫反应的影响。
我们的结果表明，获得性耐药性与耐药 EVs 上调几种转运蛋白类别的能力有关，这与在低剂量药物处理前暴露于 EVs 的敏感细胞的细胞活力和存活增加直接相关。此外，我们还证明耐药 EVs 可能下调免疫系统因子，以逃避检测并阻止敏感乳腺癌细胞的细胞凋亡。我们的数据还表明，与耐药 EVs 接触的人巨噬细胞会触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。
这些发现是首次对接触耐药 EVs 的细胞进行全转录组分析，支持耐药 EVs 通过调节敏感癌细胞的多个方面与化疗过程中的获得性耐药性过程相关，从而赋予其化疗耐药性。
