Expression of the αVβ3 integrin affects prostate cancer sEV cargo and density and promotes sEV pro-tumorigenic activity in vivo through a GPI-anchored receptor, NgR2

IF 15.5 1区 医学 Q1 CELL BIOLOGY Journal of Extracellular Vesicles Pub Date : 2024-08-06 DOI:10.1002/jev2.12482
Cecilia E. Verrillo, Fabio Quaglia, Christopher D. Shields, Stephen Lin, Andrew V. Kossenkov, Hsin-Yao Tang, David Speicher, Nicole M. Naranjo, Anna Testa, William K. Kelly, Qin Liu, Benjamin Leiby, Luca Musante, Khalid Sossey-Alaoui, Navneet Dogra, Tzu-Yi Chen, Dario C. Altieri, Lucia R. Languino
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Abstract

It is known that small extracellular vesicles (sEVs) are released from cancer cells and contribute to cancer progression via crosstalk with recipient cells. We have previously reported that sEVs expressing the αVβ3 integrin, a protein upregulated in aggressive neuroendocrine prostate cancer (NEPrCa), contribute to neuroendocrine differentiation (NED) in recipient cells. Here, we examine the impact of αVβ3 expression on sEV protein content, density and function. sEVs used in this study were isolated by iodixanol density gradients and characterized by nanoparticle tracking analysis, immunoblotting and single vesicle analysis. Our proteomic profile of sEVs containing αVβ3 shows downregulation of typical effectors involved in apoptosis and necrosis and an upregulation of tumour cell survival factors compared to control sEVs. We also show that the expression of αVβ3 in sEVs causes a distinct reposition of EV markers (Alix, CD81, CD9) to a low-density sEV subpopulation. This low-density reposition is independent of extracellular matrix (ECM) protein interactions with sEVs. This sEV subset contains αVβ3 and an αVβ3 downstream effector, NgR2, a novel marker for NEPrCa. We show that sEVs containing αVβ3 are loaded with higher amounts of NgR2 as compared to sEVs that do not express αVβ3. Mechanistically, we demonstrate that sEVs containing NgR2 do not affect the sEV marker profile, but when injected in vivo intratumorally, they promote tumour growth and induce NED. We show that sEVs expressing NgR2 increase the activation of focal adhesion kinase (FAK), a known promoter of cancer cell proliferation, in recipient cells. We also show that NgR2 mimics the effect of sEVs containing αVβ3 since it displays increased growth of NgR2 transfectants in vivo, as compared to control cells. Overall, our results describe the changes that occur in cargo, density and functions of cancer cell-derived sEVs containing the αVβ3 integrin and its effector, NgR2, without affecting the sEV tetraspanin profiles.

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αVβ3整合素的表达会影响前列腺癌sEV的载货量和密度,并通过GPI锚定受体NgR2促进体内sEV的促肿瘤活性。
众所周知,小细胞外囊泡(sEVs)从癌细胞中释放出来,并通过与受体细胞的串联促进癌症的发展。我们以前曾报道过,表达αVβ3整合素(一种在侵袭性神经内分泌前列腺癌(NEPrCa)中上调的蛋白质)的sEVs有助于受体细胞的神经内分泌分化(NED)。本研究采用碘克沙醇密度梯度分离 sEV,并通过纳米颗粒追踪分析、免疫印迹和单囊分析对其进行表征。与对照组相比,我们对含有αVβ3的sEVs进行的蛋白质组学分析表明,参与细胞凋亡和坏死的典型效应因子下调,而肿瘤细胞存活因子上调。我们还发现,在 sEVs 中表达 αVβ3 会导致 EV 标记(Alix、CD81、CD9)明显重新定位到低密度 sEV 亚群。这种低密度重新定位与细胞外基质(ECM)蛋白与 sEV 的相互作用无关。这种 sEV 亚群包含 αVβ3 和 αVβ3 下游效应物 NgR2,NgR2 是 NEPrCa 的新型标记物。我们发现,与不表达αVβ3的sEV相比,含有αVβ3的sEV负载了更多的NgR2。从机理上讲,我们证明了含有 NgR2 的 sEVs 不会影响 sEV 的标记特征,但当它们在体内肿瘤内注射时,会促进肿瘤生长并诱导 NED。我们的研究表明,表达 NgR2 的 sEV 会增加受体细胞中焦点粘附激酶(FAK)的活化,FAK 是一种已知的癌细胞增殖促进因子。我们还表明,NgR2 可模拟含有 αVβ3 的 sEVs 的效应,因为与对照细胞相比,NgR2 转染细胞在体内的生长速度加快。总之,我们的研究结果描述了含有αVβ3整合素及其效应物NgR2的癌细胞衍生sEV在货物、密度和功能方面发生的变化,而不影响sEV的四聚体概况。
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来源期刊
Journal of Extracellular Vesicles
Journal of Extracellular Vesicles Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
27.30
自引率
4.40%
发文量
115
审稿时长
12 weeks
期刊介绍: The Journal of Extracellular Vesicles is an open access research publication that focuses on extracellular vesicles, including microvesicles, exosomes, ectosomes, and apoptotic bodies. It serves as the official journal of the International Society for Extracellular Vesicles and aims to facilitate the exchange of data, ideas, and information pertaining to the chemistry, biology, and applications of extracellular vesicles. The journal covers various aspects such as the cellular and molecular mechanisms of extracellular vesicles biogenesis, technological advancements in their isolation, quantification, and characterization, the role and function of extracellular vesicles in biology, stem cell-derived extracellular vesicles and their biology, as well as the application of extracellular vesicles for pharmacological, immunological, or genetic therapies. The Journal of Extracellular Vesicles is widely recognized and indexed by numerous services, including Biological Abstracts, BIOSIS Previews, Chemical Abstracts Service (CAS), Current Contents/Life Sciences, Directory of Open Access Journals (DOAJ), Journal Citation Reports/Science Edition, Google Scholar, ProQuest Natural Science Collection, ProQuest SciTech Collection, SciTech Premium Collection, PubMed Central/PubMed, Science Citation Index Expanded, ScienceOpen, and Scopus.
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