A novel murine model for metastatic islet cell pancreas cancer

转移性胰岛细胞胰腺癌的新型小鼠模型

• 批准号: 8435352
• 负责人: KENNETH W GROSS
• 金额: $ 18.85万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435352
• 关键词: Adult; Age-Months; Animal Model; Animals; Biological Assay; Biology; Cell Proliferation; Cell model; Cells; Cessation of life; Characteristics; Data; Detection; Development; Discipline; Disease; Endocrine; Endocrine Gland Neoplasms; Enzymes; Etiology; Exhibits; Fostering; Genetic; Glucagon; Glucagonoma; Growth; Histopathology; Hormones; Human; Hyperplasia; Immunohistochemistry; Infiltration; Insulin; Investigation; Islet Cell; Islets of Langerhans; Kinetics; Link; Liver; Location; Lung; Magnetic Resonance Imaging; Malignant neoplasm of pancreas; Metabolism; Metastatic Lesion; Metastatic Neoplasm to the Liver; Modeling; Molecular Profiling; Monitor; Mus; Neoplasm Metastasis; Neoplasms; Neoplastic Processes; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Endocrine Carcinoma; Pancreatic Hormones; Penetrance; Physiological; Pilot Projects; Plasma; Population; Prevention; Primary Lesion; Primary Neoplasm; Process; Proteins; Renin; Renin-Angiotensin System; Reporter; Research; Role; S-Phase Fraction; Serum; Site; Surveys; Symptoms; Syndrome; Testing; Time; Tissues; Transcript; Transgenic Model; Transgenic Organisms; Tumor Burden; Tumor Suppressor Proteins; Vascularization; anticancer research; carcinogenesis; cell type; clinically relevant; comparative genomic hybridization; glucose metabolism; histogenesis; human disease; immunocytochemistry; innovation; interest; islet; lymph nodes; metastatic process; neoplastic cell; novel; novel therapeutics; pancreatic neoplasm; promoter; response; time use; tumor; tumor growth; tumor initiation; tumor progression

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.

描述（由申请人提供）：本提案是对PA -08-208的“胰腺癌试点研究（R21）”的回应，该研究试图“促进跨多个学科的创新研究，以更好地理解生物学，病因，检测，预防和治疗胰腺癌”。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，这些模型可以更忠实地复制人类疾病。在这里，我们建议对胰岛细胞癌的健壮动物模型进行详细的特征，我们是由于细胞特异性删除的Floxed RB和p53基因座在胰腺的肾素表达细胞室内偶然产生的。初步评估表明，该模型具有转移性胰岛癌的标志，该癌表达了高水平的胰高血糖素。它具有很高的渗透率，就像它的人类同等学历一样，它表现出深刻的转移性传播到临床相关的部位，导致死亡4-5个月。我们认为，进一步表征和验证该模型非常重要，因为它表现出独特的特征，这些特征将更好地理解胰岛细胞的发育，其中肾素血管紧张素系统，胰岛细胞致癌作用以及相关的转移过程。在当前的建议中，我们将首次寻求胰腺个体发育过程中肾素表达的空间窗口，利用转基因报告构建体和直接的肾素和胰岛胰岛标记的直接免疫组织化学测定。通过监测组织学特征，增生，血管化特征和肿瘤表达谱（S），同时通过MRI和血清分析肿瘤分析生长，肝酶促疗法和相关的生理学参数来表征胰腺中原发性肿瘤（S）肿瘤（S）的起始和进展。并表征使用组织病理学的转移扩散的时间和频谱。通过在正常胰腺胰岛细胞中发现的表达肾素表达细胞的线性后代的比较基因组杂交（CGH）将进行初步评估，随机产生的原发性肿瘤以及肝转移酶，旨在鉴定与这些过程相关的潜在遗传学特征的目的。提出了将肾素表达与特定胰岛细胞肿瘤联系起来的组织假设。总体而言，这些数据将导致新表征的转移性胰腺癌模型，可用于测试新型疗法，并有助于对胰岛细胞癌的更完整地了解。