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: 8229338
• 负责人: KENNETH W GROSS
• 金额: $ 21.96万
• 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 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8229338
• 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. PUBLIC HEALTH RELEVANCE: While endocrine tumors of the pancreas are relatively rare there remains considerable interest in these entities because of the complexity of the tumor spectrum and the uncertain histogenesis underlying their specific origins. Unfortunately, representative animal models that enable a more thorough investigation of the etiology of the disease process are few. Because of the tremendous need for clinically relevant models of various pancreatic cancers, particularly ones that metastasize to clinically relevant locations, we believe it is important to characterize and validate this model further.

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，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，我们建议对一个稳健的胰岛细胞癌动物模型进行详细的表征，该模型是我们通过细胞特异性删除胰腺表达血管紧张素的细胞区室中的floxed Rb和p53基因座而偶然创建的。初步评估表明，该模型具有表达高水平胰高血糖素的转移性胰岛细胞癌的特征。它以高转移率出现，并且就像其人类等同物一样，表现出严重的转移性扩散到临床相关部位，导致4-5个月死亡。我们认为，重要的是进一步表征和验证该模型，因为它表现出独特的特征，这将促进更好地理解胰岛细胞发育，其中的肾素-血管紧张素系统的作用，胰岛细胞癌变，以及相关的转移过程。在目前的建议中，我们将寻求，第一次，以确定在胰腺发育过程中的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测定肾素和胰岛标志物;通过监测组织学特征，增生，血管化特征和肿瘤表达谱，同时通过MRI和血清分析非侵入性地监测肿瘤生长、肝酶扰动和相关生理参数;并使用组织病理学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、随机发生的原发性肿瘤和肝转移中发现的表达肾素的细胞的直系后代进行初步评估，目的是鉴定与这些过程相关的潜在遗传特征。提出了一个组织化假说，将肾素的表达与特定的胰岛细胞瘤联系起来。总的来说，这些数据将产生一种新的转移性胰腺癌模型，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。 公共卫生相关性：虽然胰腺内分泌肿瘤相对罕见，但由于肿瘤谱的复杂性和其特定起源的不确定组织发生，对这些实体仍有相当大的兴趣。不幸的是，代表性的动物模型，使一个更彻底的调查病因的疾病过程是很少的。由于对各种胰腺癌的临床相关模型的巨大需求，特别是转移到临床相关位置的模型，我们认为进一步表征和验证该模型是重要的。