Schwann cell activation in oral cancer perineurial invasion and neuropathic pain

项目摘要/摘要 口腔癌患者患有疼痛，口腔功能受损。口腔癌疼痛的始发和维持在 并在癌症进展过程中恶化。神经周围侵袭(PNI)，定义为癌症侵袭， 在神经周围或沿着神经，与疼痛严重程度增加和预后不良相关。治疗方案的选择 痛苦是有限的。目前还没有针对PNI的靶向治疗方法。目前对口腔癌痛的研究主要集中在 癌症介质对初级传入神经元的影响。由PNI引起的神经病理性疼痛是罕见的 机械地处理。雪旺细胞(SCs)是支持外周血的最常见的细胞类型 神经，还没有被定义为口腔癌的PNI和疼痛。我们发现口腔癌诱导SC激活，a 众所周知，干细胞对神经损伤的反应。口腔癌细胞和干细胞相互促进增殖， 迁徙和入侵。口腔癌激活的干细胞培养上清可诱导小鼠伤害性行为。 我们发现口腔癌细胞富含可溶性的肿瘤坏死因子(STNF)，这是一种主要的 正常的细胞因子。已知sTNF可激活干细胞并介导神经病理性疼痛。受体的主要功能 STNF为TNFR1。我们假设sTNF通过TNFR1激活SCs促进口腔癌PNI和 神经性疼痛。我们的假设是基于我们对患者、细胞培养和动物模型的观察。 口腔癌和PNI。这项建议将结合肿瘤学、病理学、电生理学、细胞 生物学、神经超微结构、动物行为和统计学以：目的1.评估SC 口腔癌中的激活、SC TNFR1表达、PNI和疼痛目的2.表征sTNF的作用 中和或SC TNFR1基因缺失治疗口腔癌痛。我们将确定sTNF-TNFR1是否 介导SC激活，导致SC释放伤害性介质，和/或伴随 髓鞘/轴突异常，导致伤害性感受器过敏和神经病理性疼痛。目标3.描述 STNF中和或SC-TNFR1基因缺失对口腔癌PNI的影响我们将测试sTNF- TNFR1介导的SC激活促进SCs与口腔黏膜间的增殖、迁移和侵袭 癌细胞，促进PNI。我们的目标是阐明SC激活的机制，并测试 控制SC激活以减少口腔癌PNI和疼痛的治疗潜力。了解供应链如何 导致口腔癌PNI和神经病理性疼痛可能揭示新的机会和策略来中断 口腔癌的这些并发症。

PROJECT SUMMARY/ABSTRACT Oral cancer patients suffer from pain with impaired oral function. Oral cancer pain is initiated and maintained in the periphery and worsens during cancer progression. Perineural invasion (PNI), defined as cancer invading in, around, or along the nerve, correlates with increased pain severity and poor prognosis. Treatment options for pain are limited. No targeted treatments for PNI exist. Current research on oral cancer pain mainly focuses on the effect of cancer mediators on primary afferent neurons. Neuropathic pain caused by PNI is rarely addressed mechanistically. The role of Schwann cells (SCs), the most prevalent cell type supporting peripheral nerves, has not been defined in oral cancer PNI and pain. We found that oral cancer induces SC activation, a well-known response of SCs to nerve injury. Oral cancer cells and SCs mutually promote proliferation, migration, and invasion. Supernatant from oral cancer-activated SCs induces nociceptive behaviors in mice. We found that oral cancer cells are enriched with the soluble form of tumor necrosis factor (sTNF), a master regular of cytokines. sTNF is known to activate SCs and mediates neuropathic pain. The primary receptor for sTNF is TNFR1. We hypothesize that sTNF activates SCs through TNFR1 to promote oral cancer PNI and neuropathic pain. Our hypothesis is based on our observations in patients, cell culture and animal models of oral cancer and PNI. This proposal will combine expertise from oncology, pathology, electrophysiology, cell biology, nerve ultrastructure, animal behavior, and statistics to: Aim 1. Evaluate associations between SC activation, SC TNFR1 expression, PNI, and pain in human oral cancer. Aim 2. Characterize the effect of sTNF neutralization or SC TNFR1 gene deletion on oral cancer pain. We will determine whether sTNF-TNFR1 mediates SC activation, which causes SCs to release nociceptive mediators, and/or is accompanied by myelin/axon abnormalities, resulting in nociceptor hypersensitivity and neuropathic pain. Aim 3. Characterize the effect of sTNF neutralization or SC TNFR1 gene deletion on oral cancer PNI. We will test whether sTNF- TNFR1 mediated SC activation facilitates proliferation, migration, and invasiveness between SCs and oral cancer cells, promoting PNI. Our objective is to elucidate the mechanism of SC activation and to test the therapeutic potential of controlling SC activation to reduce oral cancer PNI and pain. Understanding how SCs contribute to oral cancer PNI and neuropathic pain may reveal new opportunities and strategies to interrupt these co-morbidities of oral cancer.