Extracellular Vesicles from Human Advanced-Stage Prostate Cancer Cells Modify the Inflammatory Response of Microenvironment-Residing Cells
Extracellular Vesicles from Human Advanced-Stage Prostate Cancer Cells Modify the Inflammatory Response of Microenvironment-Residing Cells
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DOI：
10.3390/cancers11091276
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发表时间：
2019-09-01
期刊：
影响因子：
5.2
通讯作者：
Bellezza, Ilaria
中科院分区：
文献类型：
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作者：
Mezzasoma, Letizia;Costanzi, Egidia;Bellezza, Ilaria
前列腺癌(Pca)的进展与微环境条件密切相关，肿瘤释放的胞外小泡(EVS)是细胞间通讯的重要介质，可改变微环境条件。然而，EVS在癌细胞和微环境驻留细胞之间的炎性串扰中的作用在很大程度上仍不清楚。为了评价EVS在肿瘤微环境中的作用，我们用晚期前列腺癌PC3分离的EVS(PC3-EVS)处理非癌前列腺癌细胞系pNT2。与EVS孵育24 h后，检测caspase-1介导的IL-1β成熟情况。此外，通过分析细胞因子的表达和PC3细胞的迁移和增殖情况，评估了PC3-EVS对分化的巨噬细胞THP-1细胞的影响。我们证明PC3细胞含有活跃的NLRP3-炎性小体级联反应，并分泌IL-1β。PC3-EV通过ERK1/2介导的溶酶体失稳和组织蛋白酶B的激活，影响pNT2的炎症反应，诱导caspase-1介导的IL-1β成熟。我们还证实了PC3-EVS在分化的THP-1细胞中诱导了功能性的样极化。我们的结果表明，癌症来源的EV在非癌症的前列腺细胞中诱导炎症反应，同时在免疫细胞中诱导免疫调节表型。这些明显相互矛盾的影响都致力于加强促进肿瘤的微环境。
Prostate cancer (PCa) progression is strictly associated with microenvironmental conditions, which can be modified by cancer-released extracellular vesicles (EVs), important mediators of cell-cell communication. However, the role of EVs in the inflammatory cross-talk between cancer cells and microenvironment-residing cells remains largely unknown. To evaluate the role of EVs in the tumour microenvironment, we treated the non-cancerous prostate cell line PNT2 with EVs isolated from advanced-stage prostate cancer PC3 (PC3-EVs). Caspase-1-mediated IL-1 beta maturation was evaluated after 24 h incubation with EVs. Moreover, the effect of PC3-EVs on differentiated macrophagic THP-1 cells was assessed by analyzing cytokine expression and PC3 cells migration and proliferation profiles. We illustrated that PC3 cells contain active NLRP3-inflammasome cascade and secrete IL-1 beta. PC3-EVs affect the PNT2 inflammatory response, inducing caspase-1-mediated IL-1 beta maturation via ERK1/2-mediated lysosomal destabilization and cathepsin B activation. We also verified that PC3-EVs induce a functional TAM-like polarization in differentiated THP-1 cells. Our results demonstrated that cancer-derived EVs induce an inflammatory response in non-cancerous prostate cells, while inducing an immunomodulatory phenotype in immune cells. These apparently contradictory effects are both committed to strengthening the tumour-promoting microenvironment