Institute of Clinical Pharmacology, University Hospital Goethe University Frankfurt, 60590 Frankfurt, Germany.
Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD), 60596 Frankfurt/Main, Germany.
Cells. 2020 Jan 29;9(2):320. doi: 10.3390/cells9020320.
Cancer-induced pain occurs frequently in patients when tumors or their metastases grow in the proximity of nerves. Although this cancer-induced pain states poses an important therapeutical problem, the underlying pathomechanisms are not understood. Here, we implanted adenocarcinoma, fibrosarcoma and melanoma tumor cells in proximity of the sciatic nerve. All three tumor types caused mechanical hypersensitivity, thermal hyposensitivity and neuronal damage. Surprisingly the onset of the hypersensitivity was independent of physical contact of the nerve with the tumors and did not depend on infiltration of cancer cells in the sciatic nerve. However, macrophages and dendritic cells appeared on the outside of the sciatic nerves with the onset of the hypersensitivity. At the same time point downregulation of perineural tight junction proteins was observed, which was later followed by the appearance of microlesions. Fitting to the changes in the epi-/perineurium, a dramatic decrease of triglycerides and acylcarnitines in the sciatic nerves as well as an altered localization and appearance of epineural adipocytes was seen. In summary, the data show an inflammation at the sciatic nerves as well as an increased perineural and epineural permeability. Thus, interventions aiming to suppress inflammatory processes at the sciatic nerve or preserving peri- and epineural integrity may present new approaches for the treatment of tumor-induced pain.
癌症引起的疼痛常发生于肿瘤或其转移灶生长接近神经的患者中。尽管这种癌症引起的疼痛状态构成了一个重要的治疗学问题，但潜在的病理机制尚不清楚。在这里，我们将腺癌、纤维肉瘤和黑色素瘤肿瘤细胞植入坐骨神经附近。这三种肿瘤类型都导致了机械性超敏反应、热低敏反应和神经元损伤。令人惊讶的是，超敏反应的发生与神经与肿瘤的物理接触无关，也不依赖于癌细胞在坐骨神经中的浸润。然而，在超敏反应发生时，巨噬细胞和树突状细胞出现在坐骨神经的外部。同时，观察到神经周围紧密连接蛋白的下调，随后出现微小损伤。与神经外膜和神经内膜的变化相吻合的是，坐骨神经中的甘油三酯和酰基辅酶 A 显著减少，以及神经外膜脂肪细胞的定位和外观发生改变。总之，这些数据显示坐骨神经发生炎症，以及神经周围和神经内膜通透性增加。因此，旨在抑制坐骨神经炎症过程或维持神经周围和神经内膜完整性的干预措施可能为治疗肿瘤引起的疼痛提供新的方法。
