Functional consequences of sensory neuronal invasion in oral cancer pain and carcinogenesis

项目总结 口腔癌痛是由癌分泌介质激活初级传入神经元引起的。我的 以前的工作表明，4-硝基喹啉-1-氧化物(4NQO)诱导的小鼠舌癌- 癌变表现为伤害性行为和三叉神经节神经元(TGNs)支配舌部 变得极度兴奋。口腔癌细胞还分泌神经营养因子，诱导神经元萌发成 癌症，而支配癌症的TGNs释放的局部神经递质与 致癌。我假设口腔癌和感觉神经元相互作用，因此，口腔癌 诱导神经元敏化、发芽和可塑性，传出神经元活动促进口腔 致癌。为了支持我的假设，我使用口腔癌异种移植模型证明了 轴突切断抑制了口腔鳞状细胞癌在后爪的生长。来检验我的假设并 为我的独立研究生涯做好准备，我建议在K99阶段获得高分辨率的技能 显微镜、定量分析、癌细胞生物学和口腔组织病理学。具体地说，我将描述 支配口腔的感觉神经的类型、分布、萌发特点及其随时间的发展 4NQO致癌过程中的微环境(目标1)。在目标2中，我将确定倒数 体外细胞培养对神经元-癌症交流的影响。我建议在R00中使用这些技能，以 研究初级传入神经元在口腔癌痛和癌变中的差异性影响 抑制口腔癌小鼠肿瘤诱导的神经元萌发和TGN亚群的消融 模特。成功完成拟议的实验和培训计划将进一步加深我的知识 感觉神经元和癌症之间的关系，以及发展我需要的技能 独立研究生涯。

PROJECT SUMMARY Oral cancer pain results from activation of primary afferent neurons by cancer-secreted mediators. My previous work demonstrated that mice bearing tongue cancers induced by 4-nitroquinoline-1-oxide (4NQO)- carcinogenesis exhibit nociceptive behavior and trigeminal ganglia neurons (TGNs) innervating the tongue become hyperexcitable. Oral cancer cells also secrete neurotrophic factors that induce neuronal sprouting into the cancer, while local neurotransmitter release from TGNs innervating the cancer has been linked to carcinogenesis. I hypothesize that oral cancer and sensory neurons interact, such that, oral cancer induces sensitization, sprouting and plasticity in neurons, and efferent neuronal activity promotes oral carcinogenesis. In support of my hypothesis, I demonstrated, using an oral cancer xenograft model that nerve axotomy suppressed oral squamous cell carcinoma growth in the hindpaw. To test my hypothesis and to prepare me for an independent research career, I propose in the K99 phase to gain skills in high-resolution microscopy, quantitative analysis, cancer cell biology and oral histopathology. Specifically, I will characterize the type, distribution, sprouting features and development over time of sensory nerves innervating the oral cancer microenvironment during 4NQO-carcinogenesis (Aim 1). In Aim 2, I will determine the reciprocal impact of neuron-cancer communication using cell cultures in vitro. I propose to use these skills in the R00, to study the differential impact of primary afferent neurons on oral cancer pain and carcinogenesis through inhibition of cancer-induced neuronal sprouting and ablation of TGN subpopulations in an oral cancer mouse model. The successful completion of the proposed experiments and training program will further my knowledge in the relationship between sensory neurons and cancer, as well as develop skills I need to pursue an independent research career.