Role of Neurogenic Inflammation in Pancreatic Cancer

描述(申请人提供)：胰腺导管腺癌(PDAC)，像许多癌症一样，有一个主要的炎性成分，是疾病发展不可或缺的组成部分。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]，40%继续发展为胰腺癌[63]。CP和PDAC之间的联系是如此强烈，以至于医生经常建议对严重CP的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，我们的实验室和其他机构的研究表明，炎症会加速疾病，促使癌前病变成熟为直肠癌[40，41]。此外，在PDAC的基因工程小鼠模型(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，胰腺炎症可以由神经系统调节。有研究表明，切除或沉默胰腺传入可以减轻/预防急性和慢性胰腺炎[45，67，81，82]，这支持了“神经源性炎症”的重要性。PDAC将胰腺转化为产生病理水平的神经营养因子的组织，这些神经营养因子导致感觉神经元终末的过敏和萌发，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，甚至在直肠癌出现之前(初步数据)。这些观察结合炎症似乎在PDAC进展中所起的作用，导致了这一应用的中心假说：PDAC产生的神经营养因子诱导神经源性炎症，从而推动PDAC进展。这一假设将在以下具体目标中得到检验： 目的：研究PDAC产生的神经营养因子对胰腺传入(背根和结节神经节神经元)的影响，以及阻断这些生长因子是否能减少神经源性炎症分子的释放。 目的2：确定神经源性炎症在PDAC进展和肿瘤生长中的作用。 这些研究将直接测试神经系统在PDAC中的作用。将对三种不同的方法进行测试，以确定它们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中，可用于临床环境。如果成功，这些方法中的任何一种都可以用于患有 对PDAC或那些已经被诊断出疾病的人来说是高风险的。

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.