A novel murine model for metastatic islet cell pancreas cancer

描述（由申请人提供）：本提案是对PA -08-208“胰腺癌试点研究（R21）”的回应，该提案旨在“促进跨学科的创新研究，以更好地了解胰腺癌的生物学，病因学，检测，预防和治疗”。胰腺癌研究的一个主要问题是缺乏临床相关的动物模型，可以更忠实地复制人类疾病。在这里，我们建议对一个强大的胰岛细胞癌动物模型进行详细的表征，这个模型是我们偶然创建的，它是由于细胞特异性地删除了胰腺肾素表达细胞腔室中固定的Rb和p53位点。初步评估表明，该模型具有转移性胰岛细胞癌的特征，表达高水平的胰高血糖素。它具有高外显率，就像其人类等效物一样，表现出向临床相关部位的深度转移扩散，导致4-5个月死亡。我们认为进一步表征和验证该模型很重要，因为它具有独特的特征，将有助于更好地理解胰岛细胞的发育、肾素-血管紧张素系统的作用、胰岛细胞的癌变和相关的转移过程。在目前的提案中，我们将首次利用转基因报告构建和肾素和胰岛标志物的直接免疫组化分析，寻求确定胰腺个体发育过程中肾素表达的时空窗口；通过监测胰腺原发肿瘤的组织学特征、增生、血管化特征和肿瘤表达谱来描述肿瘤的发生和进展，同时通过MRI和血清分析无创监测肿瘤生长、肝酶扰动和相关生理参数；并利用组织病理学表征转移扩散的时间和频谱。将通过比较基因组杂交（CGH）对正常胰岛细胞、随机产生的原发性肿瘤和肝转移中肾素表达细胞的直系后代进行初步评估，目的是确定与这些过程相关的潜在遗传特征。提出了肾素的表达与胰岛细胞特异性肿瘤形成有关的组织假说。总的来说，这些数据将导致转移性胰腺癌的新特征模型，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.