Role of Neurogenic Inflammation in Pancreatic Cancer

描述（由申请人提供）：胰腺导管腺癌（PDAC），像许多癌症一样，具有疾病进展不可或缺的主要炎症成分。在人类中，家族性慢性胰腺炎（CP）患者发生PDAC的风险增加53倍[92]，40%的患者发展为胰腺癌[63]。胰腺炎和PDAC之间的联系是如此紧密，以至于医生经常建议对严重胰腺炎患者进行预防性胰腺切除术。胰腺炎和癌症之间的机制联系尚不清楚。然而，我们实验室和其他实验室的研究表明，炎症加速了疾病，推动癌前病变成熟为直接癌症[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传播[78]。

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.