Boston University-Boston Medical Center Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA.
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
Sci Signal. 2021 Nov 23;14(710):eabj2807. doi: 10.1126/scisignal.abj2807.
Obesity and metabolic diseases, such as insulin resistance and type 2 diabetes (T2D), are associated with metastatic breast cancer in postmenopausal women. Here, we investigated the critical cellular and molecular factors behind this link. We found that primary human adipocytes shed extracellular vesicles, specifically exosomes, that induced the expression of genes associated with epithelial-to-mesenchymal transition (EMT) and cancer stem–like cell (CSC) traits in cocultured breast cancer cell lines. Transcription of these genes was further increased in cells exposed to exosomes shed from T2D patient–derived adipocytes or insulin-resistant adipocytes and required the epigenetic reader proteins BRD2 and BRD4 in recipient cells. The thrombospondin family protein TSP5, which is associated with cancer, was more abundant in exosomes from T2D or insulin-resistant adipocytes and partially contributed to EMT in recipient cells. Bioinformatic analysis of breast cancer patient tissue showed that greater coexpression of (which encodes TSP5) and or correlated with poorer prognosis, specifically decreased distant metastasis–free survival. Our findings reveal a mechanism of exosome-mediated cross-talk between metabolically abnormal adipocytes and breast cancer cells that may promote tumor aggressiveness in patients with T2D.
肥胖和代谢疾病，如胰岛素抵抗和 2 型糖尿病（T2D），与绝经后妇女的转移性乳腺癌有关。在这里，我们研究了这一联系背后的关键细胞和分子因素。我们发现原代人脂肪细胞脱落细胞外囊泡，特别是外泌体，这些囊泡在共培养的乳腺癌细胞系中诱导与上皮间质转化（EMT）和癌症干细胞样细胞（CSC）特征相关的基因表达。这些基因在暴露于源自 T2D 患者或胰岛素抵抗脂肪细胞的外泌体的细胞中的转录进一步增加，并且需要受体内的表观遗传读取蛋白 BRD2 和 BRD4。与癌症相关的血栓素家族蛋白 TSP5 在源自 T2D 或胰岛素抵抗脂肪细胞的外泌体中更为丰富，并部分导致受体内的 EMT。对乳腺癌患者组织的生物信息学分析表明， （其编码 TSP5）与 或 表达水平更高与预后较差相关，特别是远处转移无复发生存率降低。我们的发现揭示了代谢异常脂肪细胞与乳腺癌细胞之间外泌体介导的串扰的机制，这可能会促进 T2D 患者肿瘤的侵袭性。
