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

项目摘要 大量研究表明，疼痛是头颈癌(HNC)的首要症状。 病人。然而，可用的治疗方法是有限的，并与严重的副作用增加相关。 大大增加了罹患癌症的负担。因此，迫切需要新型止痛药。然而，在那里 对口腔癌疼痛机制的认识存在很大差距，因此疼痛控制往往是不完整的。 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，这一主要症状 表明癌细胞控制着肿瘤部位周围伤害性感受器的活动。这个 摘要目的研究口腔癌痛的一种新机制，即肿瘤细胞与感觉的相互作用。 原位的神经元。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)细胞释放出来，激活邻近的感觉纤维，有助于 口腔鳞癌引起的疼痛。这一假说是基于令人信服的初步数据证明BDNF 小鼠口腔肿瘤中水平升高，拮抗BDNF受体可逆转痛样行为 在活体内。我们将使用行为、生化、解剖学方法以及电生理分析 舌神经纤维允许在原位研究肿瘤与神经的相互作用，以研究目的： 目的1：确定口腔鳞状细胞癌释放的脑源性神经营养因子是否参与口腔癌疼痛。使用灌流 技术、电生理和行为分析，这一目标将决定BDNF从舌头释放 以及检测释放的BDNF是否调节舌头周围神经纤维的活动和 在体内产生类似疼痛的行为。雄性和雌性小鼠的结果将进行比较，以确定BDNF- 诱导性二态效应。 目的2：探讨TrkB和p75受体(P75R)在脑源性神经营养因子介导的周围型口腔癌中的作用 疼痛。药物和分子抑制对感觉神经元TrkB和p75受体的影响 神经元将通过电生理记录来确定。后续实验将检验该药的效果。 重组人脑源性神经营养因子在幼稚动物感觉神经活性中的应用。性依赖 分歧也将被确定。 目的3：探讨BDNF下游信号通路在口腔癌痛中的作用。使用凸形和 雌性小鼠，这一目标将使用解剖学和电生理学方法来识别下游 TrkB和p75受体的通路可能在BDNF诱导的口腔癌痛中起作用。 总的来说，这里提出的实验提供了对中央处理器的关键和全面的测试 假设。这个项目的翻译意义通过使用人类癌细胞和 一种临床相关的模拟患者症状的原位模型以及新的电生理学 方法研究肿瘤发生部位的肿瘤-神经相互作用。 相关性：由于有限的药物治疗口腔癌引起的疼痛通常是非常困难的 耐受性的有效性或快速发展。我们提出了一种非常新颖的机制来评估 脑源性神经营养因子信号在口腔癌痛中的外周作用。该研究项目解决了一个重要的医学问题 一个创新的假说和新开发的实验方法存在问题。此外，还有一个 这一应用的重点是强有力的理由，因为BDNF信号已知会触发疼痛并有助于 头颈癌的肿瘤进展和化疗耐药。

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.