Abstract:
Hypoxia is a common feature of solid tumours and activates adaptation mechanisms in cancer cells that induce therapy resistance and has profound effects on cellular metabolism. As such, hypoxia is an important contributor to cancer progression and is associated with a poor prognosis. Metabolic alterations in cells within the tumour microenvironment support tumour growth via, amongst others, the suppression of immune reactions and the induction of angiogenesis. Recently, extracellular vesicles (EV) have emerged as important mediators of intercellular communication in support of cancer progression. Previously, we demonstrated the pro-angiogenic properties of hypoxic cancer cell derived EV. In this study, we investigate how (hypoxic) cancer cell derived EV mediate their effects. We demonstrate that cancer derived EV regulate cellular metabolism and protein synthesis in acceptor cells through increased activation of mTOR and AMPKα. Using metabolic tracer experiments, we demonstrate that EV stimulate glucose uptake in endothelial cells to fuel amino acid synthesis and stimulate amino acid uptake to increase protein synthesis. Despite alterations in cargo, we show that the effect of cancer derived EV on recipient cells is primarily determined by the EV producing cancer cell type rather than its oxygenation status.
摘要:
缺氧是实体瘤的常见特征,并激活癌细胞中的适应机制,从而诱导治疗抵抗并对细胞代谢产生深远的影响。因此,缺氧是导致癌症进展的重要因素,并且与不良预后相关。肿瘤微环境中细胞的代谢改变支持肿瘤生长,在其他人中,抑制免疫反应和诱导血管生成。最近,细胞外囊泡(EV)已成为支持癌症进展的细胞间通讯的重要介质。以前,我们证明了缺氧癌细胞来源的EV的促血管生成特性。在这项研究中,我们研究了(缺氧)癌细胞来源的EV如何介导其作用。我们证明,源自癌症的EV通过增加mTOR和AMPKα的激活来调节受体细胞中的细胞代谢和蛋白质合成。使用代谢示踪剂实验,我们证明EV刺激内皮细胞的葡萄糖摄取以促进氨基酸合成,并刺激氨基酸摄取以增加蛋白质合成。尽管货物有改动,我们表明,源自癌症的EV对受体细胞的影响主要取决于产生EV的癌细胞类型,而不是其氧合状态。