A novel murine model for metastatic islet cell pancreas cancer

描述(申请人提供)：本提案是对PA-08-208“胰腺癌的初步研究(R21)”的回应，该提案旨在“促进跨多学科的创新研究，以更好地了解胰腺癌的生物学、病因、检测、预防和治疗。”胰腺癌研究中的一个主要问题是缺乏临床相关的动物模型来更真实地复制人类疾病。在这里，我们建议对我们偶然建立的胰岛细胞癌的强大动物模型进行详细的表征，该模型是由于细胞特异性地删除了胰腺肾素表达的细胞室内的Rb和P53基因座而产生的。初步评估表明，该模型具有转移性胰岛细胞癌的特征，高水平表达胰高血糖素。它以高外显性出现，就像它的人类等价物一样，表现出深刻的转移扩散到临床相关部位，导致4-5个月死亡。我们认为进一步鉴定和验证这一模型是很重要的，因为它表现出独特的特征，将有助于更好地了解胰岛细胞的发育、肾素-血管紧张素系统在其中的作用、胰岛细胞的癌变以及相关的转移过程。在目前的建议中，我们将首次寻求确定胰腺个体发育过程中肾素表达的时空窗口，利用转基因报告构建和直接免疫组织化学方法检测肾素和胰岛标记物；通过监测组织学特征、增生、血管特征和肿瘤表达谱(S)来表征胰腺原发肿瘤(S)的发生和发展，同时通过磁共振成像和血清分析无创性地监测肿瘤生长、肝酶紊乱和相关生理参数；并使用组织病理学来表征转移扩散的时间和谱。将通过比较基因组杂交(CGH)对正常胰岛细胞、随机出现的原发肿瘤和肝转移瘤中肾素表达细胞的直系后代进行初步评估，目的是识别与这些过程相关的潜在遗传特征。提出了将肾素的表达与特定的胰岛细胞瘤联系起来的组织假说。总体而言，这些数据将导致一种新的转移性胰腺癌模型，该模型可用于测试新的治疗方法，并将有助于更全面地了解胰岛细胞癌。

DESCRIPTION (provided by applicant): The present proposal is in response to PA -08-208, 'Pilot Studies in Pancreatic Cancer (R21)' which seeks to 'promote innovative research across multiple disciplines for a better understanding of the biology, etiology, detection, prevention and treatment of pancreatic cancer.' A major problem in pancreatic cancer research is the lack of clinically relevant animal models that can more faithfully replicate human disease. Here we propose to undertake a detailed characterization of a robust animal model for pancreatic islet cell cancer that we have serendipitously created as a result of cell-specifically deleting floxed Rb and p53 loci within the renin-expressing cell compartment of pancreas. Preliminary assessments suggest the model has the hallmarks of a metastatic islet cell carcinoma that expresses high levels of glucagon. It arises with high penetrance and, just like its human equivalent, exhibits profound metastatic spread to clinically relevant sites resulting in death by 4-5 months. We believe it is important to characterize and validate this model further as it exhibits unique features which will foster better understanding of pancreatic islet cell development, the role of the renin- angiotensin system therein, islet cell carcinogenesis, and the associated metastatic process. In the current proposal we will seek, for the first time, to identify the spatial-temporal windows of renin expression during pancreas ontogeny, utilizing transgenic reporter constructs and direct immunohistochemical assays for renin and pancreatic islet markers; characterize the initiation and progression of neoplasia of the primary tumor(s) in pancreas by monitoring histological features, hyperplasia, vascularization characteristics and the tumor expression profile(s), while monitoring noninvasively via MRI and serum analysis tumor growth, liver enzyme perturbations and relevant physiological parameters; and characterize the timing and spectrum of metastatic spread using histopathology. A preliminary assessment will be made by comparative genome hybridization (CGH) of lineal descendents of the renin-expressing cell as found in normal pancreatic islet cells, the stochastically arising primary tumors, and liver metastases with the aim of identifying potential genetic signatures associated with these processes. An organizing hypothesis linking the expression of renin to the specific islet cell neoplasia is put forth. Overall, these data will result in a newly characterized model of metastatic pancreas cancer that can be used for testing of novel therapeutics and will contribute to a more complete understanding of islet cell cancers.