Bertolini Irene, Perego Michela, Ghosh Jagadish C, Kossenkov Andrew V, Altieri Dario C
Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, 19104, USA.
Bioinformatics Shared Resource, The Wistar Institute, Philadelphia, PA, 19104, USA.
Oncogene. 2022 Apr;41(17):2520-2525. doi: 10.1038/s41388-022-02280-3. Epub 2022 Mar 30.
Small extracellular vesicles (sEV) contribute to the crosstalk between tumor cells and stroma, but the underlying signals are elusive. Here, we show that sEV generated by breast cancer cells in hypoxic (sEV), but not normoxic (sEV) conditions activate NFκB in recipient normal mammary epithelial cells. This increases the production and release of inflammatory cytokines, promotes mitochondrial dynamics leading to heightened cell motility and disrupts 3D mammary acini architecture with aberrant cell proliferation, reduced apoptosis and EMT. Mechanistically, Integrin-Linked Kinase packaged in sEV via HIF1α is sufficient to activate NFκB in the normal mammary epithelium, in vivo. Therefore, sEV activation of NFκB drives multiple oncogenic steps of inflammation, mitochondrial dynamics, and mammary gland morphogenesis in a breast cancer microenvironment.
小细胞外囊泡（sEV）有助于肿瘤细胞与基质之间的相互作用，但其潜在信号尚不清楚。在这里，我们表明，乳腺癌细胞在缺氧条件下产生的sEV（sEVhyp），而不是常氧条件下产生的sEV（sEVnorm），可激活受体正常乳腺上皮细胞中的NFκB。这会增加炎性细胞因子的产生和释放，促进线粒体动力学，导致细胞运动性增强，并通过异常细胞增殖、减少凋亡和上皮-间质转化破坏三维乳腺腺泡结构。从机制上讲，通过HIF1α包装在sEV中的整合素连接激酶足以在体内激活正常乳腺上皮中的NFκB。因此，sEV对NFκB的激活驱动了乳腺癌微环境中炎症、线粒体动力学和乳腺形态发生的多个致癌步骤。
