Role of Neurogenic Inflammation in Pancreatic Cancer

神经源性炎症在胰腺癌中的作用

• 批准号: 8721899
• 负责人: BRIAN M DAVIS
• 金额: $ 38.35万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721899
• 关键词: Ablation; Affect; Afferent Neurons; Appearance; Attenuated; Automobile Driving; Blood; Blood Circulation; Brain-Derived Neurotrophic Factor; Calcitonin Gene-Related Peptide; Cells; Clinical; Conditioned Culture Media; Data; Development; Diagnosis; Disease; Disease Progression; Distant; Edema; Electrophysiology (science); Epithelial Cells; Exposure to; Fiber; Gene Expression; Genes; Genetic; Genetically Engineered Mouse; Glutamates; Growth Factor; Human; Hypersensitivity; Immune system; Individual; Inflammation; Inflammatory; Label; Laboratories; Lead; Lesion; Link; Liver; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Methodology; Methods; Modeling; Mus; Nature; Nerve Growth Factor Receptors; Nerve Growth Factors; Nervous system structure; Neurogenic Inflammation; Neurons; Nodose Ganglion; Organ; Pancreas; Pancreatectomy; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Patients; Physicians; Play; Premalignant; Process; Production; Property; Risk; Role; Sensory; Signal Transduction; Staging; Substance P; TRP channel; Testing; Time; Tissues; United States; Up-Regulation; Western Blotting; acute pancreatitis; afferent nerve; base; chronic pancreatitis; cytokine; glial cell-line derived neurotrophic factor; high risk; mouse model; neurotrophic factor; neutralizing antibody; novel; pancreatic neoplasm; patch clamp; prevent; prophylactic; public health relevance; relating to nervous system; research study; response; spinal nerve posterior root; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC), like many cancers, has a major inflammatory component that is integral to disease progression. In humans, patients with familial chronic pancreatitis (CP) have a 53-fold increase in their risk for PDAC [92] and 40% go on to develop pancreatic cancer [63]. The link between CP and PDAC is so strong that physicians often recommend prophylactic pancreatectomy for patients with severe CP. The mechanistic link between pancreatic inflammation and cancer is not known. However, studies by our laboratories and others indicate that inflammation accelerates the disease, driving maturation of precancerous lesions into frank cancer [40, 41]. Furthermore, in a genetically engineered mouse model (GEM) of PDAC, pancreatic inflammation increased dissemination of pancreatic cells into the blood and liver [78]. Experiments in our labs show that pancreatic inflammation can be regulated by the nervous system. The importance of "neurogenic inflammation" is supported by studies that show ablation or silencing of pancreatic afferents attenuates/prevents acute and chronic pancreatitis [45, 67, 81, 82]. PDAC converts the pancreas into a tissue that produces pathological levels of neurotrophic factors that cause hypersensitivity and sprouting of sensory neuron terminals and this likely underlie disease-related neurogenic inflammation. Importantly, preliminary data from our lab indicate that growth factor upregulation begins early in the disease process, even before the appearance of frank cancer (Preliminary Data). These observations in combination with the role that inflammation appears to play in progression of PDAC leads to the central hypothesis of this application: PDAC-generated neurotrophic factors induce neurogenic inflammation that drives PDAC progression. This hypothesis will be tested in the following specific aims: Aim 1: Determine the effect of PDAC-produced neurotrophic factors on pancreatic afferents (dorsal root and nodose ganglion neurons) and whether blocking these growth factors attenuates the release of neurogenic inflammatory molecules. Aim 2: Determine the contribution of neurogenic inflammation to PDAC progression and tumor growth. These studies will directly test the role of the nervous system in PDAC. Three different methodologies will be tested for their ability to block neurogenic inflammation and slow/halt disease progression. Each of these methods is either currently available or in development for use in the clinical setting. If successful, any of these approaches could be used for patients with high-risk for PDAC or those in which the disease is already diagnosed.

描述（由申请人提供）：胰腺导管腺癌 (PDAC) 与许多癌症一样，具有主要的炎症成分，这是疾病进展不可或缺的一部分。在人类中，家族性慢性胰腺炎 (CP) 患者患 PDAC 的风险增加 53 倍 [92]，并且 40% 的患者会继续发展为胰腺癌 [63]。 CP 和 PDAC 之间的联系如此紧密，以至于医生经常建议对严重 CP 患者进行预防性胰腺切除术。胰腺炎症和癌症之间的机制联系尚不清楚。然而，我们实验室和其他机构的研究表明，炎症会加速疾病的发展，促使癌前病变成熟为癌症 [40, 41]。此外，在 PDAC 基因工程小鼠模型 (GEM) 中，胰腺炎症增加了胰腺细胞向血液和肝脏的扩散 [78]。 我们实验室的实验表明，胰腺炎症可以受到神经系统的调节。 “神经源性炎症”的重要性得到了研究的支持，这些研究表明胰腺传入神经的消融或沉默可以减轻/预防急性和慢性胰腺炎[45,67,81,82]。 PDAC 将胰腺转化为一种组织，产生病理水平的神经营养因子，导致感觉神经元末梢过敏和发芽，这可能是与疾病相关的神经源性炎症的基础。重要的是，我们实验室的初步数据表明，生长因子上调在疾病过程的早期就开始了，甚至在癌症出现之前就开始了（初步数据）。这些观察结果与炎症在 PDAC 进展中所起的作用相结合，得出了本申请的中心假设：PDAC 产生的神经营养因子诱导神经源性炎症，从而驱动 PDAC 进展。该假设将在以下具体目标中得到检验： 目标 1：确定 PDAC 产生的神经营养因子对胰腺传入神经（背根和结状神经节神经元）的影响，以及阻断这些生长因子是否会减弱神经源性炎症分子的释放。 目标 2：确定神经源性炎症对 PDAC 进展和肿瘤生长的影响。 这些研究将直接测试神经系统在 PDAC 中的作用。将测试三种不同的方法阻止神经源性炎症和减缓/阻止疾病进展的能力。这些方法中的每一种都是目前可用的或正在开发用于临床环境。如果成功的话，这些方法中的任何一种都可以用于患有以下疾病的患者： PDAC 的高风险人群或已诊断出该疾病的人群。