Department of Pain Management, Tianjin First Center Hospital , Tianjin, China.
Department of Anesthesiology, Tianjin Medical University NanKai Hospital , Tianjin, China.
Bioengineered. 2020 Dec;11(1):661-678. doi: 10.1080/21655979.2020.1771068.
Neuropathic pain associated with cancers was caused by tumor itself or tumor therapy, which was aggravated by sensitizing nociceptor sensory neurons. The tumor microenvironment contributed to tumorigenesis, tumor progress, tumor metastasis, tumor immune resistance, tumor chemotherapy, and tumor immunotherapy. In the current study, we explored the contributions of the infiltrated dendritic cells insulted by Wnt1 in tumor microenvironment to neuropathic pain associated with cancers. The different transcriptome of infiltrated dendritic cells from lung adenocarcinoma and from juxtatumor indicated that thousands of genes were up-regulated by the tumor microenvironment, some of which were enriched in pain pathway. The paracrine factors such as TNF, WNT10A, PDGFA, and NRG1 were also elevated in tumor-infiltrating dendritic cells. The receptors of paracrine factors were highly expressed on dorsal root ganglia (DRG), and not altered in pain conditions. Single-cell RNA-seq data unveiled that TNFSF1 was expressed in neurons, microglial cells, and endothelial cells. PDGFRA was only expressed in microglial cells. ERBB3 was only expressed in neurons. FZD1 and 3 were extensively expressed in various cells. The components composed of signaling pathways associated with the above paracrine factors participated in pain networks. The transcription factors activated by paracrine factor signaling regulated the expression of genes associated with pain. TNF, WNT10A, and PDGFA were extensively expressed in multiple cancers, but their expression in patients did not distribute normally. These data indicated that infiltrated dendritic cells in tumor microenvironment promoted neuropathic pain by sensitizing nociceptor sensory neurons via paracrine factors. Blockage of paracrine factor signaling might alleviate cancer pain.
与癌症相关的神经性疼痛是由肿瘤本身或肿瘤治疗引起的，它会加剧伤害感受器感觉神经元的致敏作用。肿瘤微环境有助于肿瘤发生、肿瘤进展、肿瘤转移、肿瘤免疫抵抗、肿瘤化疗和肿瘤免疫治疗。在本研究中，我们探讨了肿瘤微环境中受 Wnt1 侵袭的浸润树突状细胞对与癌症相关的神经性疼痛的贡献。来自肺腺癌和肿瘤周围的浸润树突状细胞的不同转录组表明，数千个基因受到肿瘤微环境的上调，其中一些基因富集在疼痛通路中。旁分泌因子如 TNF、WNT10A、PDGFA 和 NRG1 也在肿瘤浸润树突状细胞中升高。旁分泌因子的受体在背根神经节（DRG）上高表达，在疼痛状态下没有改变。单细胞 RNA-seq 数据揭示了 TNFSF1 在神经元、小胶质细胞和内皮细胞中表达。PDGFRA 仅在小胶质细胞中表达。ERBB3 仅在神经元中表达。FZD1 和 3 在各种细胞中广泛表达。与上述旁分泌因子相关的信号通路组成部分参与了疼痛网络。旁分泌因子信号激活的转录因子调节与疼痛相关的基因表达。TNF、WNT10A 和 PDGFA 在多种癌症中广泛表达，但它们在患者中的表达分布不正常。这些数据表明，肿瘤微环境中的浸润树突状细胞通过旁分泌因子使伤害感受器感觉神经元致敏，从而促进神经性疼痛。阻断旁分泌因子信号可能会缓解癌症疼痛。
