High fat diet stimulates pancreatic cancer through the actions of Cholecystokinin

高脂肪饮食通过胆囊收缩素的作用刺激胰腺癌

• 批准号: 8969907
• 负责人: Jill P Smith
• 金额: $ 20.04万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-06 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8969907
• 关键词: Adipocytes; Age; Animal Model; Animals; Bile fluid; Bioavailable; Biological Availability; Blood; C57BL/6 Mouse; Cancer Etiology; Cells; Cessation of life; Cholecystokinin; Cholecystokinin Receptor; Clinic; Colon Carcinoma; Contracts; Country; Development; Diabetes Mellitus; Diet; Dietary Fats; Digestion; Engineering; Enzymes; Epidemic; Epidemiologic Studies; Epithelial; Fatty acid glycerol esters; Functional disorder; Gallbladder; Genetic Engineering; Glucose; Goals; Growth; Growth Factor; Hormones; Human; Hyperphagia; Immunocompetent; Incidence; Inflammation; Ingestion; Insulin; Investigation; Islet Cell; Islets of Langerhans; KRAS2 gene; Knowledge; Lead; Leptin; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Messenger RNA; Modeling; Morbid Obesity; Mus; Mutate; Neoplasm Metastasis; Neoplasms; Non obese; Nude Mice; Obese Mice; Obesity; Oral; Pancreas; Pancreatic Intraepithelial Neoplasia; Pancreatitis; Pathway interactions; Patients; Peptides; Physiological; Play; Premalignant; Production; Randomized; Reporting; Research Personnel; Risk; Risk Factors; Role; Testing; Time; Transgenic Mice; Transgenic Organisms; Translating; Transplantation; United States; Weight; Xenograft procedure; cancer cell; carcinogenesis; chronic pancreatitis; driving force; feeding; gastrointestinal; high risk; improved; malignant breast neoplasm; mouse model; neoplastic cell; novel; pancreatic cancer cells; pancreatic juice; pancreatic neoplasm; prevent; public health relevance; receptor; research study; response; subcutaneous; translational study; tumor

 DESCRIPTION (provided by applicant): Epidemiologic studies have shown that the incidence of pancreatic cancer is greater in countries that consume diets high in fat. Furthermore, obesity has been reported as a risk factor for the development of pancreatic cancer. Many factors have been associated with the relationship of diet or obesity and pancreatic cancer including leptin, glucose dysregulation, insulin growth factor (IGF), and inflammation. This project is unique in that we aim to show that dietary fat promotes growth of pancreatic cancer by the actions of the gastrointestinal trophic peptide cholecystokinin (CCK) on its receptor. Under physiologic conditions, CCK is released in response to dietary fat in order to stimulate secretion of pancreatic digestive enzymes, regulate insulin, and contract the gall bladder through the CCK receptor. We have demonstrated the presence of CCK receptors on early precancerous pancreatic epithelial neoplasias (PanINs) and CCK receptor blockade completely halts progression of these precursor lesions to form cancer in a transgenic KRAS murine model. CCK receptors are also abundantly over-expressed in cancer where they are involved in stimulating growth. Obese animals have been shown to have 500-fold greater CCK levels and also an enhanced growth rate of xenografted pancreatic cancer. We have also shown that mice bearing either subcutaneous or orthotopic pancreatic cancers, had significantly larger tumors and more metastases when fed a diet high in fat compared to mice on a low fat or normal diet. This growth stimulatory effect of pancreatic cancer by a high fat diet was blocked with concomitant administration of a CCK receptor antagonist suggesting the CCK: CCK-receptor pathway as an important, if not the key factor, in dietary-fat associated pancreatic cancer. It is hypothesized that dietary fat stimulates CCK release which promotes growth of pancreatic cancer through its mitogenic actions on the CCK receptor. In order to test this hypothesis we will perform the following specific aims: 1) Examine the role of the CCK: CCK-receptor axis on growth and metastasis of an orthotopically transplanted pancreatic cancer in a syngeneic (species specific) immunocompetent murine model by pharmacologic blockade, and 2) Examine the role of the CCK: CCK-receptor axis on growth and metastasis of pancreatic cancer in genetically engineered models that either lack the CCK receptor or the CCK peptide. Since CCK receptor antagonists are available and have oral bioavailability, results of this project may be readily translated to the clinic. These investigations if successful will facilitate in our understanding o the risks that lead to pancreatic cancer and will provide potential novel therapies to inhibit or prevent growth and metastases in patients with pancreatic cancer.

 描述（由申请人提供）：流行病学研究表明，饮食中脂肪含量高的国家胰腺癌的发病率较高。此外，肥胖已被报道为胰腺癌发展的风险因素。许多因素与饮食或肥胖和胰腺癌的关系有关，包括瘦素、葡萄糖调节异常、胰岛素生长因子（IGF）和炎症。该项目的独特之处在于，我们的目标是表明膳食脂肪通过胃肠营养肽胆囊收缩素（CCK）对其受体的作用促进胰腺癌的生长。在生理条件下，CCK响应于膳食脂肪而释放，以刺激胰腺消化酶的分泌，调节胰岛素，并通过CCK受体收缩胆囊。我们已经证明了CCK受体在早期癌前胰腺上皮瘤变（PanIN）中的存在，并且CCK受体阻断剂完全阻止了转基因KRAS小鼠模型中这些前体病变形成癌症的进展。CCK受体在癌症中也大量过度表达，它们参与刺激生长。肥胖动物的CCK水平高出500倍，异种移植胰腺癌的生长速度也加快。我们还表明，与低脂或正常饮食的小鼠相比，皮下或原位胰腺癌小鼠在喂食高脂肪饮食时具有显著更大的肿瘤和更多的转移。这种高脂饮食对胰腺癌的生长刺激作用被CCK受体拮抗剂的伴随给药阻断，这表明CCK：CCK受体途径是饮食-脂肪相关胰腺癌中的重要因素，如果不是关键因素的话。据推测，膳食脂肪刺激CCK释放，通过其对CCK受体的促有丝分裂作用促进胰腺癌的生长。为了验证这一假设，我们将进行以下具体目标：1）检查CCK：CCK-受体轴在同基因胰腺癌原位移植的生长和转移中的作用。（物种特异性）免疫活性鼠模型，和2）检查CCK的作用：CCK-受体轴在缺乏CCK受体或CCK肽的基因工程模型中对胰腺癌生长和转移的影响由于CCK受体拮抗剂是可用的，并具有口服生物利用度，该项目的结果可以很容易地转化为临床。这些研究如果成功，将有助于我们了解导致胰腺癌的风险，并将提供潜在的新疗法来抑制或预防胰腺癌患者的生长和转移。