Tumor-neuroglia interaction promotes pancreatic cancer metastasis
Tumor-neuroglia interaction promotes pancreatic cancer metastasis
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肿瘤与神经胶质细胞相互作用促进胰腺癌转移
DOI：
10.7150/thno.42440
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Zhou, Quanbo
中科院分区：
文献类型：
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作者：
Su, Dan;Guo, Xiaofeng;Zhou, Quanbo
原理：外周神经系统（PNS）在肿瘤的生长和进展中起着重要作用。雪旺细胞（Schwann cells，SC）是PNS的主要胶质细胞，在多种恶性肿瘤中以接触依赖或非接触依赖的方式促进肿瘤转移。在本研究中，我们的目的是确定胰腺癌细胞和SC之间通过旁分泌信号传导的相互作用是否有助于癌症进展。研究方法：进行免疫荧光分析以揭示PDAC组织中SC的分布，并确定诊断为PDAC的患者的肿瘤内SC标记物水平的预后价值和临床病理相关性。进行了Transwell试验和伤口愈合试验，以研究SC条件培养基（SCM）、SC共培养物或共培养CM对胰腺癌细胞迁移和侵袭能力的影响。利用实时定量逆转录聚合酶链反应（qRT-PCR）、酶联免疫吸附试验（ELISA）、蛋白质印迹、免疫荧光、免疫组织化学、siRNA介导的基因干扰和体内小鼠模型证实了SC诱导癌细胞迁移和侵袭的机制。结果如下：组织样本的免疫荧光分析显示，有两种不同类型的SC分布在肿瘤微环境中，其存在与PDAC患者的几个临床病理特征和总生存率相关。虽然SCM对肿瘤细胞的运动性和侵袭性没有影响，但与SC和共培养的CM共培养都增强了胰腺癌细胞的迁移和侵袭。从机制上讲，通过与胰腺癌细胞共培养诱导的SC来源的白细胞介素6（IL 6）通过激活癌细胞中的STAT 3信号传导增强癌细胞的迁移和侵袭，而IL 6中和或STAT 3下调则消除了这些作用。此外，肿瘤细胞分泌的白细胞介素1β（IL 1 β）激活了SC中的核因子（NF）-κ B通路，导致细胞因子（包括IL 6）的产生增加，而抑制IL 1 β-IL 1 R1轴导致NF-κ B信号通路失活，下调SC中细胞因子的表达。干扰肿瘤-神经胶质细胞的串扰阻碍了体内癌细胞的传播。结论：雪旺细胞广泛分布于PDAC肿瘤微环境中，高水平的肿瘤内SC标志物可作为PDAC患者生存不良的独立预后因素。肿瘤-神经胶质细胞的相互作用对于SC获得肿瘤促进表型是必不可少的。靶向肿瘤-神经胶质细胞的相互作用可能是治疗PDAC的一个有前途的策略。
Rationale: The peripheral nervous system (PNS) plays an important role in tumor growth and progression. Schwann cells (SCs), the main glia cells of the PNS, augment cancer metastasis in contact-dependent or contact-independent manner in various malignancies. In the present study, we aimed to determine whether interplay between pancreatic cancer cells and SCs via paracrine signaling contributes to cancer progression. Methods: Immunofluorescence analysis was performed to reveal the distribution of SCs in PDAC tissues and to determine the prognostic value and clinicopathological relevance of the level of intra‑tumoral SC markers for patients diagnosed with PDAC. Transwell assays and wound healing assays were carried out to investigate the influence of SC conditioned medium (SCM), SC co‑culture, or co-cultured CM on the migratory and invasive abilities of pancreatic cancer cells. The mechanism of SCs induced cancer cells migration and invasion was confirmed using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assays (ELISAs), western blotting, immunofluorescence, immunohistochemistry, siRNA-mediated gene interference, and an in vivo mouse model. Results: Immunofluorescence analysis of tissue samples revealed that there were two different types of SCs distributed in the tumor microenvironment, the presence of which correlated with several clinicopathological characteristics and overall survival for patients with PDAC. Although SCM had no impact on the motility and invasiveness of tumor cells, both co-cultivation with SCs and co‑cultured CM enhanced pancreatic cancer cell migration and invasion. Mechanistically, SC‑derived Interleukin 6 (IL6), which was induced by co-culture with pancreatic cancer cells, augmented cancer cell migration and invasion by activating STAT3 signaling in cancer cells, while IL6 neutralization or STAT3 downregulation abrogated these effects. Furthermore, Interleukin 1β (IL1β), secreted by tumor cells, activated the nuclear actor (NF)-kappa B pathway in SCs, resulting in increased cytokines production, including IL6, while inhibiting the IL1β-IL1R1 axis led to inactivation of NF-kappa B signaling and downregulated cytokines expression in SCs. Interfering with tumor-neuroglia crosstalk impeded cancer cell dissemination in vivo. Conclusion: Schwann cells were extensively distributed in the PDAC tumor microenvironment and high level of intra-tumoral SC markers could serve as an independent prognostic factor for poor survival of patients with PDAC. The tumor-neuroglia interaction is indispensable for SCs to acquire a tumor-facilitating phenotype. Targeting the tumor-neuroglia interplay might be a promising strategy to treat PDAC.