Extracellular vesicles (EVs) are emerging key protagonists in intercellular communication between adipocytes and breast cancer (BC) cells. Here, we described a new mechanism by which EVs released by mature adipocytes promoted breast cancer cell malignancy "in vitro" and "in vivo". We found that adipocyte-derived EVs enhanced growth, motility and invasion, stem cell-like properties, as well as specific traits of epithelial-to-mesenchymal transition in both estrogen receptor positive and triple negative BC cells. Of note, adipocyte-derived EVs aid breast tumor cells in lung metastatic colonization after tail-vein injection in mice. These EV-mediated effects occur via the induction of HIF-1α activity, since they were abrogated by the use of the HIF-1α inhibitor KC7F2 or in cells silenced for HIF-1α expression. Moreover, using an “ex vivo” model of obese adipocytes we found that the depletion of EVs counteracted the ability of obese adipocytes to sustain pro-invasive phenotype in BC cells. Interestingly, EVs released by undifferentiated adipocytes failed to induce aggressiveness and HIF-1α expression. These findings shed new light on the role of adipocyte-derived EVs in breast cancer progression, suggesting the possibility to target HIF-1α activity to block the harmful adipocyte-tumor cell dialogue, especially in obese settings.

细胞外囊泡（EV）是脂肪细胞和乳腺癌（BC）细胞之间细胞间通讯的新兴关键主角。在这里，我们描述了成熟脂肪细胞释放的EV在“体外”和“体内”促进乳腺癌细胞恶性的新机制。我们发现，脂肪细胞来源的 EV 增强了雌激素受体阳性和三阴性 BC 细胞的生长、运动和侵袭、干细胞样特性以及上皮间质转化的特定特征。值得注意的是，脂肪细胞来源的 EV 在小鼠尾静脉注射后有助于乳腺肿瘤细胞的肺转移定植。这些 EV 介导的效应是通过诱导 HIF-1α 活性而发生的，因为使用 HIF-1α 抑制剂 KC7F2 或在 HIF-1α 表达沉默的细胞中可以消除这些效应。此外，使用肥胖脂肪细胞的“离体”模型，我们发现 EV 的消耗抵消了肥胖脂肪细胞维持 BC 细胞中促侵袭表型的能力。有趣的是，未分化脂肪细胞释放的 EV 未能诱导攻击性和 HIF-1α 表达。这些发现为脂肪细胞衍生的 EV 在乳腺癌进展中的作用提供了新的线索，表明有可能靶向 HIF-1α 活性来阻止有害的脂肪细胞-肿瘤细胞对话，特别是在肥胖环境中。