Schwann cell activation in oral cancer perineurial invasion and neuropathic pain

雪旺细胞激活在口腔癌神经周围侵犯和神经性疼痛中的作用

• 批准号: 10597995
• 负责人: Yi Ye
• 金额: $ 37.86万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597995
• 关键词: Address; Afferent Neurons; Animal Behavior; Animal Model; Axon; Behavior; Cancer Cell Growth; Cancer Patient; Cell Culture Techniques; Cells; Cellular biology; Clinical Trials; Coculture Techniques; Colon Carcinoma; Data; Disease Progression; Electrophysiology (science); Etiology; Functional disorder; Gene Deletion; Goals; Grant; Growth; Human; Hypersensitivity; Immune System Diseases; Impairment; Interruption; Invaded; Knowledge; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Mechanics; Mediating; Mediator; Modeling; Mus; Myelin; Nerve; Nerve Degeneration; Nerve Regeneration; Neuroglia; Neurons; Nociception; Nociceptors; Oncology; Opioid; Oral; Pain; Pain Clinics; Pain management; Pathology; Patients; Peripheral; Peripheral Nerves; Process; Prognosis; Proliferating; Quality of life; Recombinants; Reporting; Research; Role; Schwann Cells; Severities; TNF gene; Testing; Tissues; Tropism; Tumor Necrosis Factor Receptor; axon injury; cancer cell; cancer invasiveness; cancer pain; carcinogenesis; cell type; comorbidity; cytokine; improved; in vivo; inhibitor; intense pain; malignant mouth neoplasm; migration; myelination; nerve injury; nervous system disorder; novel strategies; novel therapeutics; oral pain; overexpression; painful neuropathy; perineural; receptor; receptor expression; repaired; response; response to injury; side effect; statistics; therapeutic evaluation; tumor; tumor progression

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.

项目总结/摘要 口腔癌患者遭受口腔功能受损的疼痛。口腔癌疼痛是在 在癌症发展过程中的外周和外周。神经周围浸润（PNI），定义为癌细胞浸润， 在神经周围或沿着，与增加的疼痛严重性和不良预后相关。的治疗选择 疼痛是有限的。目前还没有针对PNI的靶向治疗方法。目前对口腔癌疼痛的研究主要集中在 癌介质对初级传入神经元的影响。PNI引起的神经病理性疼痛很少 机械地处理。雪旺细胞（SC）是支持外周血淋巴细胞增殖的最常见的细胞类型， 神经，尚未在口腔癌PNI和疼痛中定义。我们发现口腔癌诱导SC活化， 众所周知的SC对神经损伤的反应。口腔癌细胞与SC相互促进增殖， 迁徙和入侵口腔癌激活的干细胞上清液诱导小鼠伤害性行为 我们发现口腔癌细胞富含可溶性肿瘤坏死因子（sTNF）， 调节细胞因子。已知sTNF激活SC并介导神经性疼痛。的主要受体 sTNF是TNFR 1。我们假设sTNF通过TNFR 1激活SC，促进口腔癌PNI， 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。该提案将联合收割机结合肿瘤学、病理学、电生理学、细胞 生物学，神经超微结构，动物行为学和统计学：目的1。评估SC之间的关联 激活，SC TNFR 1表达，PNI和人类口腔癌中的疼痛。目标二。表征sTNF的作用 中和或SC TNFR 1基因缺失对口腔癌疼痛的影响。我们将确定sTNF-TNFR 1 介导SC激活，其导致SC释放伤害感受介质，和/或伴随 髓鞘/轴突异常，导致伤害感受器超敏反应和神经性疼痛。目标3。表征 sTNF中和或SC TNFR 1基因缺失对口腔癌PNI的影响。我们将测试sTNF- TNFR 1介导的SC活化促进SC和口腔粘膜之间的增殖、迁移和侵袭。 癌细胞，促进PNI。我们的目的是阐明SC激活的机制，并测试SC激活的机制。 控制SC活化以减少口腔癌PNI和疼痛的治疗潜力。了解SC如何 有助于口腔癌PNI和神经性疼痛可能揭示新的机会和策略，中断 这些口腔癌的并发症。