School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia.
Integrated Cancer Research Center, Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia.
Cancer Res. 2020 Jul 1;80(13):2940-2955. doi: 10.1158/0008-5472.CAN-19-2331. Epub 2020 Apr 28.
For the constellation of neurologic disorders known as chemotherapy-induced peripheral neuropathy, mechanistic understanding and treatment remain deficient. Here, we present the first evidence that chronic sensory neuropathy depends on nonlinear interactions between cancer and chemotherapy. Global transcriptional profiling of dorsal root ganglia revealed differential expression, notably in regulators of neuronal excitability, metabolism, and inflammatory responses, all of which were unpredictable from effects observed with either chemotherapy or cancer alone. Systemic interactions between cancer and chemotherapy also determined the extent of deficits in sensory encoding and ion channel protein expression by single mechanosensory neurons, with the potassium ion channel Kv3.3 emerging as one potential contributor to sensory neuron dysfunction. Validated measures of sensorimotor behavior in awake, behaving animals revealed dysfunction after chronic chemotherapy treatment was exacerbated by cancer. Notably, errors in precise forelimb placement emerged as a novel behavioral deficit unpredicted by our previous study of chemotherapy alone. These original findings identify novel contributors to peripheral neuropathy and emphasize the fundamental dependence of neuropathy on the systemic interaction between chemotherapy and cancer. SIGNIFICANCE: These findings highlight the need to account for pathobiological interactions between cancer and chemotherapy as a major contributor to neuropathy and will have significant and immediate impact on future investigations in this field.
对于被称为化疗诱导性周围神经病的一系列神经紊乱疾病，其发病机制和治疗方法仍然存在不足。在这里，我们首次提出了证据，证明慢性感觉神经病变依赖于癌症和化疗之间的非线性相互作用。背根神经节的全基因组转录组分析显示出差异表达，特别是在神经元兴奋性、代谢和炎症反应的调节剂方面，所有这些都无法从单独使用化疗或癌症观察到的效果来预测。癌症和化疗之间的全身相互作用也决定了单个机械感觉神经元感觉编码和离子通道蛋白表达缺陷的程度，其中钾离子通道 Kv3.3 成为感觉神经元功能障碍的一个潜在贡献者。在清醒、行为活跃的动物中，经过验证的感觉运动行为测量方法显示，慢性化疗治疗后的功能障碍在癌症的作用下进一步恶化。值得注意的是，精确前肢放置的错误作为一种新的行为缺陷出现，这是我们之前单独研究化疗所没有预测到的。这些新发现确定了周围神经病变的新贡献因素，并强调了神经病学依赖于化疗和癌症之间的全身相互作用的基本原理。意义：这些发现强调了需要考虑癌症和化疗之间的病理生物学相互作用作为导致神经病变的主要因素，这将对该领域未来的研究产生重大而直接的影响。
