胰腺癌细胞外囊泡通过IL-8/CCL2刺激雪旺细胞活化和神经周围侵袭。

In vitro models Pub Date : 2025-03-07 eCollection Date: 2025-02-01 DOI:10.1007/s44164-025-00083-w
Emory Gregory, Isabel Powers, Azemat Jamshidi-Parsian, Robert J Griffin, Younghye Song
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引用次数: 0

摘要

目的:胰腺导管腺癌(PDAC)仍然是癌症相关死亡的主要原因,而神经周围浸润(PNI),即癌细胞浸润神经,使大多数患者发生转移。PNI主要归因于雪旺细胞(SC),当被激活时,加速癌细胞向神经的迁移。然而,这种与癌症相关的重编程通常被低估了。此外,肿瘤细胞外囊泡(EV)促进癌症恶化已得到充分证实,但需要更多的研究来更好地了解它们在PNI中的作用。在这里,我们使用组织工程的体外平台和PANC-1和HPNE人类细胞系作为模型,评估了PDAC ev是否通过SC激活介导PNI。方法:NanoSight, Luminex®和蛋白质组学途径分析表征肿瘤(PANC-1)和健康细胞(HPNE) ev。将人雪旺样细胞(sNF96.2)包埋在脱细胞神经基质水凝胶中,然后用ev和货物功能阻断抗体处理。免疫荧光和Luminex®多重检测评估雪旺细胞活化。随后,将sNF96.2细胞与ev、PANC-1或HPNE细胞共培养;用sc条件培养基进行Transwell®侵袭试验,以确定体外PNI的机制。结果:PANC-1型EVs中白细胞介素-8 (IL-8)信号相关蛋白水平高于HPNE型EVs。在模拟神经的体外实验平台中,PANC-1 EVs通过细胞骨架标记改变和促肿瘤细胞因子(如趋化因子配体-2 (CCL2))的分泌,促进sNF96.2的激活。此外,IL-8/CCL2轴增强了PANC-1的侵袭性。结论:这些发现强调了PDAC ev在PNI中的潜在作用,需要继续进行临床前评估,增加生物多样性,以确定靶向IL-8/CCL2治疗PNI的有效性。补充信息:在线版本包含补充资料,提供地址:10.1007/s44164-025-00083-w。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pancreatic cancer extracellular vesicles stimulate Schwann cell activation and perineural invasion in vitro via IL-8/CCL2.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related deaths, and perineural invasion (PNI), in which cancer cells infiltrate nerves, enables metastasis in most patients. PNI is largely attributed to Schwann cells (SC) that, when activated, accelerate cancer cell migration towards nerves. However, this cancer-associated reprogramming is generally under-appreciated. Additionally, tumor extracellular vesicle (EV) facilitation of cancer aggravation is well documented, but more investigation is required to better understand their role in PNI. Here, we assessed whether PDAC EVs mediate PNI via SC activation using tissue-engineered in vitro platforms and PANC-1 and HPNE human cell lines as models.

Methods: NanoSight, Luminex®, and proteomic-pathway analyses characterized tumor (PANC-1) and healthy cell (HPNE) EVs. Human Schwann-like cells (sNF96.2) were embedded in decellularized nerve matrix hydrogels and then treated with EVs and a cargo-function-blocking antibody. Immunofluorescence and Luminex® multiplex assays assessed Schwann cell activation. Subsequently, sNF96.2 cells were co-cultured with EVs and either PANC-1 or HPNE cells; Transwell® invasion assays with SC-conditioned media were also conducted to establish a mechanism of in vitro PNI.

Results: PANC-1 EVs contained higher levels of interleukin-8 (IL-8) signaling-associated proteins than HPNE EVs. Within nerve-mimetic in vitro testbeds, PANC-1 EVs promoted sNF96.2 activation per cytoskeletal marker alterations and secretion of pro-tumorigenic cytokines, e.g., chemokine ligand-2 (CCL2), via IL-8 cargoes. Furthermore, the IL-8/CCL2 axis heightened PANC-1 invasiveness.

Conclusion: These findings highlight the potential role of PDAC EVs in PNI, which necessitates continued preclinical assessments with increased biodiversity to determine the efficacy of targeting IL-8/CCL2 for PNI.

Supplementary information: The online version contains supplementary material available at 10.1007/s44164-025-00083-w.

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