Effect of high fat diet on pancreatic cancer in IKKa deficient mice

高脂肪饮食对 IKKa 缺陷小鼠胰腺癌的影响

• 批准号: 8446306
• 负责人: Ning Li
• 金额: $ 7.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446306
• 关键词: Affect; Alleles; Antioxidants; Architecture; Attenuated; Autophagocytosis; CDKN2A gene; Cells; Chemicals; Code; Consumption; DNA Damage; Defect; Detection; Development; Diet; Dietary Intervention; Disease; Energy Intake; Epithelial Cells; Etiology; Event; Exocrine pancreas; Exposure to; Fatty acid glycerol esters; Fibrosis; Freezing; Genes; Genomic Instability; Goals; Individual; Induced Mutation; Inflammation; Inflammatory; Interleukin-6; KRAS2 gene; Lasers; Lead; Lesion; MADH4 gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Modeling; Molecular Chaperones; Mus; Mutation; Nature; Nuclear Atypia; Obesity; Oncogenes; Oxidative Stress; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pancreatitis; Paraffin Embedding; Pathology; Phosphotransferases; Premalignant; Prevention; Prevention strategy; Reactive Oxygen Species; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Signal Pathway; Staging; Staining method; Stains; TNF gene; TP53 gene; Testing; Therapeutic; Tumor Suppressor Genes; Tumor Suppressor Proteins; base; cancer risk; cytokine; endoplasmic reticulum stress; feeding; high risk; improved; inflammatory marker; inhibiting antibody; interest; mouse model; neoplastic; pancreatic tumorigenesis; prevent; research study; response; therapeutic target

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is characterized by invasiveness, rapid progression and resistance to conventional and targeted therapeutics, which make it one of the most incurable and deadliest cancers. Prevention, detection and eradication of premalignant lesions that give rise to PDAC are of great importance and may be the only approaches towards the successful treatment of this incurable disease. Pancreatic intraepithelial neoplasia (PanIN) is the major precursor lesion for PDAC and has been classified as PanIN1, PanIN2 and PanIN3, based on cellular architecture and nuclear atypia. KRAS2 mutational activation is an early event found in 90% of PanIN lesions and is followed by loss of different tumor suppressors, including CDK2A/INK4A, SMAD4 and TP53. Obesity is positively associated with elevated (2.6-fold) PDAC risk, but the mechanisms by which obesity promotes pancreatic cancer development are not fully understood. Recently, I have made an interesting and exciting finding that mice, termed Ikk?+/?pan, in which one Ikk? allele, coding for I?B kinase ? (IKK?), has been deleted in pancreatic epithelial cells, are phenotypically normal but develop PanIN lesions after 4 months on a high-fat diet (HFD). This model is unique, as it is the only one in which high caloric intake and obesity lead to neoplastic changes in the pancreas without deliberate introduction of a Kras oncogene. The complete loss of IKK? expression in pancreatic epithelial cells results in development of spontaneous fibrosis and pancreatitis in lean mice, pathologies that are associated with early cellular defects of diminished autophagic maturation and endoplasmic reticulum (ER) stress, that lead to increased accumulation of reactive oxygen species (ROS) in IKK?-deficient cells. It is therefore likely that consumption of HFD may cause similar defects in Ikk?+/Dpan mice that are haploin sufficient for IKK?, thereby resulting in ROS accumulation and subsequent genomic instability and inflammation that promote PanIN development and progression. Our specific aims are: 1) Identify mechanisms by which obesity induces PanIN lesion formation in Ikk?+/?pan mice and accelerates their malignant progression. 2) Determine whether HFD-induced suppression of autophagy is sufficient for inducing PanIN lesion development and malignant progression. The overall goals of these aims are to further improve the Ikk?+/?pan model for PanIN induction by HFD, use this model to identify potential pharmacological and dietary interventions that prevent PanIN induction and malignant progression and develop an IKK?-independent model for PanIN induction by elevated caloric intake/HFD.

描述(申请人提供)：胰腺导管腺癌(PDAC)的特点是侵袭性，进展迅速，对传统和靶向治疗方法耐药，使其成为最无法治愈和最致命的癌症之一。预防、检测和根除引起PDAC的癌前病变是非常重要的，可能是成功治疗这种不治之症的唯一途径。胰腺上皮内瘤变(Panin)是PDAC的主要前驱病变，根据细胞结构和核异型性分为PanIN1、PanIN2和PanIN3。KRAS2突变激活是在90%的Panin病变中发现的早期事件，随后是不同的肿瘤抑制因子的丢失，包括CDK2A/Ink4a、Smad4和TP53。肥胖与PDAC风险增加(2.6倍)呈正相关，但肥胖促进胰腺癌发展的机制尚不完全清楚。最近，我有一个有趣和令人兴奋的发现，小鼠，命名为ikk？+/？PAN，在哪一个ikk？等位基因，编码I、B激酶？(IKK？)，在胰腺上皮细胞中已被删除，表型正常，但在高脂饮食(HFD)4个月后出现Panin病变。这个模型是独一无二的，因为它是唯一一个在没有刻意引入Kras癌基因的情况下，高卡路里摄入量和肥胖导致胰腺肿瘤变化的模型。完全失去ikk？胰腺上皮细胞的表达导致瘦小鼠的自发性纤维化和胰腺炎的发展，这些病理与自噬成熟减少和内质网(ER)应激的早期细胞缺陷有关，导致IKK？缺陷细胞中活性氧物种(ROS)的积累增加。因此，摄入HFD可能会在IKK？+/DPAN小鼠中引起类似的缺陷，单倍体对IKK？足够，从而导致ROS积累和随后的基因组不稳定和炎症，促进Panin的发展和进展。我们的具体目标是：1)明确肥胖诱导IKK+/？PAN小鼠Panin病变形成并加速其恶性进展的机制。2)确定HFD诱导的自噬抑制是否足以诱导Panin病变的发展和恶性进展。这些目标的总体目标是进一步完善HFD诱导Panin的IKK+/PAN模型，利用该模型识别潜在的阻止Panin诱导和恶性进展的药物和饮食干预措施，并开发一个通过增加热量摄入/HFD诱导Panin的IKK？非依赖模型。