TRPV1 nociceptors in oral carcinogenesis and pain

项目摘要 口腔癌疼痛比所有其他癌症都要严重。转移性口腔癌患者经历了 最大的痛苦。口腔癌激活神经元产生疼痛；然而，伤害性感受器对口腔的影响 癌症在很大程度上是未知的。口腔癌与神经元相互作用的机制，以及 这种相互作用是如何促进癌症和疼痛的，目前尚不清楚。长期目标是改善管理 通过识别癌症微环境的成分来识别口腔癌患者并避免阿片类药物 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 瞬时受体电位通道香草素亚家族成员(TRPV1)+的表型和分布 支配疼痛和转移性口腔癌的神经元：(II)测定TRPV1+的敏化和激活 口腔癌分泌的介质对神经元的影响，以及(Iii)确定TRPV1+神经元对口腔的贡献 致癌。中心假设是口腔癌释放介质，包括携带进来的介质。 细胞外小泡(EVS)，敏化并激活引起口腔癌疼痛的伤害性感受器。癌症- 预置的伤害性感受器反过来会促进癌症。该项目理由是确定了以下组成部分 癌症与神经的相互作用为开发治疗口腔癌和口腔癌的方法提供了机会。 癌症疼痛，从而减少阿片类药物的使用。核心假设将通过追求三个具体的 目的：1)确定口腔癌的神经支配类型和密度与疼痛和转移的关系；2) 研究癌症疼痛介质对三叉神经(TG)神经元的敏化作用；以及，3)研究癌症 癌症激活和致敏TRPV1+神经元的促进作用，并评估阻止癌症和 通过感觉神经肽、降钙素基因相关肽拮抗信号通路减轻癌痛 (CGRP)。在第一个目标下，癌症的神经元神经支配将在一名回顾性患者中进行评估。 已知疼痛和结节状态的队列，以及辣椒素(TRPV1激动剂)敏感性和 疼痛测量将在预期入选的口腔癌患者中进行。对于第二个目的，一个 与疼痛和转移相关的基因和来自EV的miRNAs将作为疼痛介质进行研究。为 第三个目的是利用小鼠口腔癌变模型来研究TRPV1丰度的影响。 对癌症发病率和表型的影响，降钙素基因相关肽信号对癌症促进的影响，以及 治疗和预防口腔癌和口腔癌疼痛的CGRP/CGRP受体疗法。这项研究 提出的是创新的，因为它基于关于口腔癌疼痛的两个新发现：(1)新发现 可能的癌症疼痛介质在报告高疼痛水平的转移性癌症中过度表达， (2)EVS参与肿瘤的伤害性行为。这项拟议的研究具有重要意义 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批准的治疗偏头痛的疗法，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.