TRPV1 nociceptors in oral carcinogenesis and pain

项目摘要 口腔癌疼痛比其他所有癌症都严重。转移性口腔癌患者经历 最大的痛苦口腔癌激活神经元并产生疼痛;然而，伤害性感受器对口腔癌的影响可能与疼痛有关。 癌症在很大程度上是未知的。口腔癌和神经元之间相互作用的机制， 这种相互作用如何促进癌症和疼痛尚不清楚。长期目标是改善管理 口腔癌患者和阿片类药物通过识别癌症微环境的成分， 治疗癌症和口腔癌疼痛的可行靶点。本申请的总体目标是（i）阐明 瞬时受体电位通道（TRPV 1）表型和分布 神经支配疼痛和转移性口腔癌的神经元，（ii）测量TRPV 1+的致敏和活化 通过口腔癌分泌的介质来确定TRPV 1+神经元对口腔癌的作用，以及（iii）确定TRPV 1+神经元对口腔癌的作用。 致癌作用中心假设是口腔癌释放介质，包括介质中携带的介质， 细胞外囊泡（EV），其敏化并激活诱发口腔癌疼痛的伤害感受器。癌症- 引发的伤害感受器反过来又促进癌症。该项目的基本原理是， 癌症-神经相互作用提供了开发治疗口腔癌和口腔癌的方法的机会。 癌症疼痛，从而减少阿片类药物的使用。中心假设将通过追求三个具体的测试 目的：1）确定口腔癌神经支配的类型和密度与疼痛和转移的关系; 2） 研究三叉神经（TG）神经元对癌痛介质的敏感性; 3）研究癌症 癌症的促进激活和致敏TRPV 1+神经元，并评估阻止癌症的潜力， 通过拮抗感觉神经肽、降钙素基因相关肽的信号传导来减轻癌症疼痛 （CGRP）。在第一个目标下，将在回顾性患者中评估癌症的神经支配 已知疼痛和淋巴结状态的队列，并测试辣椒素（TRPV 1激动剂）敏感性， 将在前瞻性入选的口腔癌患者中进行疼痛测量。对于第二个目标，A 与疼痛和转移相关的基因和来自EV的miRNA将作为疼痛介质进行研究。为 第三个目的是使用小鼠口腔癌发生模型来研究TRPV 1丰度的影响。 对癌症发病率和表型的影响，CGRP信号传导对癌症促进的影响，以及 用于治疗和预防口腔癌和口腔癌疼痛的CGRP/CGRP受体疗法。研究 建议是创新的，因为它是基于两个新的发现，关于口腔癌疼痛：（1）新发现的 在来自报告高水平疼痛的患者的转移性癌症中过表达的推定的癌症疼痛介质， 和（2）EV参与癌症诱导的伤害性行为。所提出的研究是有意义的 因为这些研究将为评估CGRP和CGRP受体靶向的临床试验奠定基础， FDA批准用于治疗偏头痛的治疗方法，用于治疗癌症和减轻癌症疼痛。

Project Summary Oral cancer pain is more severe than all other cancers. Patients with metastatic oral cancer experience the greatest pain. Oral cancers activate neurons and produce pain; however, the effect of nociceptors on oral cancer is largely unknown. The mechanisms of reciprocal interaction between oral cancer and neurons, and how the interactions promote cancer and pain, are not known. The long-term goal is to improve management of oral cancer patients and obviate opioids by identifying components of the cancer microenvironment that are viable targets to treat cancer and oral cancer pain. The overall objectives for this application are to (i) elucidate the phenotype and distribution of transient receptor potential channel, vanilloid subfamily member (TRPV1) + neurons innervating painful and metastatic oral cancers, (ii) measure sensitization and activation of TRPV1+ neurons by mediators secreted by oral cancer, and (iii) determine the contribution of TRPV1+ neurons to oral carcinogenesis. The central hypothesis is that oral cancers release mediators, including mediators carried in extracellular vesicles (EVs) that sensitize and activate nociceptors inducing oral cancer pain. The cancer- primed nociceptors, in turn, promote cancer. The rationale for the project is that identification of components of the cancer-nerve interaction provides the opportunity to develop approaches to treat oral cancer and oral cancer pain, thereby reducing use of opioids. The central hypothesis will be tested by pursuing three specific aims: 1) Determine the type and density of innervation in oral cancers in relation to pain and metastasis; 2) Investigate sensitization of trigeminal (TG) neurons by cancer pain mediators; and, 3) Investigate cancer promotion by cancer activated and sensitized TRPV1+ neurons and evaluate the potential to stop cancer and alleviate cancer pain by antagonizing signaling via the sensory neuropeptide, calcitonin gene related peptide (CGRP). Under the first aim, neuronal innervation of the cancer will be evaluated in a retrospective patient cohort with known pain and nodal status, and testing for capsaicin (TRPV1 agonist) sensitivity and measurement of pain will be performed in prospectively enrolled oral cancer patients. For the second aim, a gene associated with pain and metastasis and miRNAs from EVs will be investigated as pain mediators. For the third aim a mouse oral carcinogenesis model will be used to investigate the impact of TRPV1 abundance on cancer incidence and phenotype, the impact of CGRP signaling on cancer promotion, and the potential for CGRP/CGRP receptor therapies for treating and preventing oral cancer and oral cancer pain. The research proposed is innovative because it is based on two new findings regarding oral cancer pain: (1) newly identified putative cancer pain mediators overexpressed in metastatic cancers from patients reporting high levels of pain, and (2) involvement of EVs in cancer induced nociceptive behavior. The proposed research is significant because these studies will lay the foundation for clinical trials to assess CGRP and CGRP receptor targeted therapies, which are FDA-approved for migraine, to treat cancer and attenuate cancer pain.