The Role of Peripheral Brain-Derived Neurotrophic Factor (BDNF) Signaling in Oral Cancer Pain

外周脑源性神经营养因子 (BDNF) 信号在口腔癌疼痛中的作用

• 批准号: 10217097
• 负责人: Shivani B Ruparel
• 金额: $ 36.22万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217097
• 关键词: Address; Afferent Neurons; Analgesics; Anatomy; Animals; Apoptosis; Behavior; Behavioral; Behavioral Assay; Biochemical; Brain-Derived Neurotrophic Factor; Cancer Patient; Cells; Chemoresistance; Clinical; Data; Development; Effectiveness; Electrophysiology (science); Environment; Female; Fiber; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; Hypersensitivity; In Situ; Knowledge; Malignant Epithelial Cell; Malignant Neoplasms; Mechanics; Mediating; Medical; Methods; Modeling; Molecular; Morbidity - disease rate; Mouth Neoplasms; Mus; Nerve; Nerve Fibers; Neurotrophic Tyrosine Kinase Receptor Type 2; Nociceptors; Pain; Pain management; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Play; Preparation; Quality of life; Receptor Activation; Recombinants; Regulation; Reporting; Research Project Grants; Role; Sensory; Signal Pathway; Signal Transduction; Site; Symptoms; Techniques; Testing; Tongue; Tongue Neoplasms; afferent nerve; base; cancer cell; cancer pain; cancer therapy; clinically relevant; effective therapy; efficacious treatment; epithelial to mesenchymal transition; experimental study; follow-up; head and neck cancer patient; in vivo; innovation; lingual nerve; male; malignant mouth neoplasm; malignant tongue neoplasm; mouth squamous cell carcinoma; neoplastic cell; novel; opiate tolerance; pain model; prevent; receptor; sex; sexual dimorphism; side effect; transcriptional coactivator p75; tumor; tumor progression

Project Summary Numerous studies have indicated that pain is the top ranked symptom in head and neck cancer (HNC) patients. However, available treatments are limited and associated with severe side effects adding substantially to the burden of having cancer. Thus, there is a critical need for novel analgesics. However, there is a large gap in knowledge for oral cancer pain mechanisms and thus pain control is often incomplete. Because pain in oral cancer occurs even before a tumor becomes clinically apparent, this cardinal symptom indicates that cancer cells control the activities of surrounding nociceptors at the site of the tumor. The objective here is to study a novel mechanism for oral cancer pain by which tumor cells interact with sensory neurons at the orthotopic site. Our central hypothesis is that Brain-derived neurotrophic factor (BDNF) is released from oral squamous cell carcinoma (OSCC) cells and activates adjacent sensory fibers, contributing to OSCC-induced pain. This hypothesis is based on compelling preliminary data demonstrating that BDNF levels are elevated in oral tumor in mice and that antagonizing the BDNF receptor reverses pain-like behaviors in vivo. We will employ behavioral, biochemical, anatomical methods as well as electrophysiological analysis of lingual nerve fibers that allows studying tumor-nerve interactions in situ, to study the aims: Aim 1: Determine whether OSCC-released BDNF contributes to oral cancer pain. Using superfusion techniques, electrophysiology and behavioral assays, this aim will determine the release of BDNF from tongue tumor as well as test whether released BDNF regulate surrounding nerve fibers activities in the tongue and produce pain-like behaviors in vivo. Results from male and female mice will be compared to determine BDNF- induced sexually dimorphic effects. Aim 2: Determine whether TrkB and p75 receptors (p75R) play a role in BDNF mediated peripheral oral cancer pain. The effects of pharmacological and molecular inhibition on the TrkB and p75 receptors in sensory neurons will be determined with electrophysiologic recordings. Follow-up experiments will test the effect of application of recombinant human BDNF on sensory fiber activities in naïve animals. Sex-dependent differences will also be determined. Aim 3: Determine downstream BDNF signaling pathways in mediating oral cancer pain. Using male and female mice, this aim will employ anatomical and electrophysiological methods to identify the downstream pathways of TrkB and the p75 receptor that may play a role in BDNF-induced oral cancer pain. Collectively, experiments proposed herein provide critical and comprehensive tests of the central hypothesis. The translational significance of this project is strengthened by the use of human cancer cells and a clinically relevant orthotopic model that mimics patient symptoms as well as the novel electrophysiology method to study tumor-nerve interaction at the very site of tumor development. RELEVANCE: It is often very difficult to treat pain from oral cancer with available medications due to limited effectiveness or rapid development of tolerance. We propose a highly novel mechanism that will evaluate the peripheral role of BDNF signaling in oral cancer pain. The research project addresses a significant medical problem with an innovative hypothesis and newly developed experimental methods. Moreover, there is a strong rationale for the focus of this application, as BDNF signaling is known to trigger pain and contribute to tumor progression and chemoresistance in head and neck cancer.

项目摘要 大量研究表明，疼痛是头颈癌（HNC）的首要症状 患者然而，可用的治疗方法是有限的，并与严重的副作用有关， 与癌症的负担有很大的关系。因此，迫切需要新型镇痛剂。但 在口腔癌疼痛机制的知识方面存在很大的差距，因此疼痛控制通常是不完全的。 因为口腔癌的疼痛甚至在肿瘤临床表现出来之前就已经发生了， 表明癌细胞控制肿瘤部位周围伤害感受器的活动。的 目的研究口腔癌疼痛的一种新机制，即肿瘤细胞与感觉神经系统相互作用， 原位神经元。我们的中心假设是脑源性神经营养因子（BDNF）是 从口腔鳞状细胞癌（OSCC）细胞释放并激活邻近的感觉纤维， OSCC引起的疼痛。这一假设是基于令人信服的初步数据，表明BDNF 在小鼠口腔肿瘤中，BDNF水平升高，拮抗BDNF受体可逆转疼痛样行为 in vivo.我们将采用行为，生物化学，解剖学方法以及电生理学分析， 舌神经纤维，允许原位研究肿瘤-神经相互作用，研究目的： 目的1：确定OSCC释放的BDNF是否有助于口腔癌疼痛。使用灌注 技术，电生理学和行为测定，这一目标将确定BDNF从舌的释放 肿瘤以及测试是否释放BDNF调节周围的神经纤维活动的舌头， 在体内产生类似疼痛的行为。将比较雄性和雌性小鼠的结果，以确定BDNF- 诱导性二型效应。 目的2：确定TrkB和p75受体（p75 R）是否在BDNF介导的周围型口腔癌中发挥作用 痛苦药理学和分子抑制对感觉神经元中TrkB和p75受体的影响 神经元将通过电生理记录来确定。后续实验将测试 重组人BDNF在幼稚动物感觉纤维活动中的应用。性别依赖 也将确定差异。 目的3：确定BDNF下游信号通路在口腔癌疼痛中的作用。使用雄性和 雌性小鼠，这一目标将采用解剖学和电生理学方法来确定下游 TrkB和p75受体的通路可能在BDNF诱导的口腔癌疼痛中发挥作用。 总的来说，本文提出的实验提供了对中枢神经系统的关键和全面的测试。 假说.该项目的转化意义通过使用人类癌细胞得到加强， 临床相关的原位模型，模拟患者症状以及新的电生理学 方法来研究肿瘤神经相互作用的肿瘤发展的非常网站。 相关性：由于口腔癌的局限性， 有效性或耐受性的快速发展。我们提出了一个非常新颖的机制，将评估 BDNF信号在口腔癌疼痛中的外周作用该研究项目解决了一个重要的医学问题， 问题与创新的假设和新开发的实验方法。而且，还有一个 这一应用的重点是强有力的理由，因为已知BDNF信号传导会引发疼痛，并有助于 肿瘤进展和头颈癌的化疗耐药性。

项目成果

Characterization of sensory neuronal subtypes innervating mouse tongue.

• DOI: 10.1371/journal.pone.0207069
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wu P;Arris D;Grayson M;Hung CN;Ruparel S
• 通讯作者: Ruparel S

Oral squamous cell carcinoma-released brain-derived neurotrophic factor contributes to oral cancer pain by peripheral tropomyosin receptor kinase B activation.

• DOI: 10.1097/j.pain.0000000000002382
• 发表时间: 2022-03-01
• 期刊: Pain
• 影响因子: 7.4
• 作者: Grayson M;Arris D;Wu P;Merlo J;Ibrahim T;Fang-Mei C;Valenzuela V;Ganatra S;Ruparel S
• 通讯作者: Ruparel S