Mutant mouse models of exocrine pancreatic cancer

外分泌胰腺癌突变小鼠模型

• 批准号: 7498542
• 负责人: David A Tuveson
• 金额: $ 20.99万
• 依托单位: CANCER RESEARCH UNITED KINGDOM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7498542
• 关键词: Alleles; Animal Cancer Model; Complex; Condition; Development; Disease; Ductal; Early Diagnosis; Engineering; Epithelial Cells; Human; In Vitro; Intraductal Hyperplasia; Invasive; Islet Cell; Islets of Langerhans; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Modeling; Molecular; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Oncogenic; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pathway interactions; Relative (related person); Role; Signal Transduction; Specimen; Staging; Stem cells; Tumor Suppressor Genes; Viral; base; human disease; in vivo; mutant mouse model; notch protein; novel; recombinase; tumor progression; tumorigenesis

Ductal pancreatic adenocarcinoma is almost uniformly lethal and cannot be effectively detected at early stages. Virtually all cases of pancreatic cancer and preneoplastic ductal hyperplasias contain oncogenic K- ras mutations, suggesting its importance in this disease. Animal models of cancer that faithfully recapitulate the cognate human condition afford the opportunity to explore the molecular basis of cancer, develop early detection strategies, and evaluate novel therapies. Although mutant mice predisposed to the development of exocrine pancreatic cancer have been previously described, none develop ductal pancreatic adenocarcinoma resembling the human disease. In order to construct a more relevant murine model of ductal pancreatic cancer, we have engineered a mutant mouse strain that harbors an endogenous, conditionally-expressed, oncogenic K-ras G12D allele. By crossing this strain with mouse strains that express Cre recombinase in the pancreas, we observe preneoplastic pancreatic ductal lesions (PanlN) that strikingly resemble those seen in humans. Here, we will investigate the cellular compartments that are capable of initiating pancreatic cancer, determine the relative importance of the two tumor suppressor genes in the Ink4a/ARF locus with regards to tumor progression, and evaluate the role of Notch signaling and MMP7 function in the development of PanlN and PDA. The availability of a suitable murine model of pancreatic ductal adenocarcinoma will allow a detailed assessment of the molecular and cellular features present in discrete stages of tumorigenesis. Such studies are essentially impossible in human pancreatic cancer specimens since they are invariably detected only at very late stages. Information gained from this murine model should facilitate further understanding of human pancreatic cancer.

胰腺导管腺癌几乎是一致致命的，不能在早期有效地检测到。 阶段几乎所有的胰腺癌和癌前导管增生病例都含有致癌的K- ras突变，提示其在该疾病中的重要性。癌症的动物模型忠实地再现了 同源人类条件提供了探索癌症的分子基础，早期发展， 检测策略，并评估新的疗法。虽然突变小鼠倾向于发展 外分泌胰腺癌以前曾被描述过，但没有发展成胰腺导管癌。 类似人类疾病的腺癌。为了构建更相关的小鼠模型， 胰腺导管癌，我们已经设计了一种突变小鼠品系， 条件性表达的致癌K-ras G12 D等位基因。通过将这种品系与 在胰腺表达Cre重组酶的情况下，我们观察到癌前胰腺导管病变（PanIN）， 与人类惊人的相似在这里，我们将研究细胞室， 能够引发胰腺癌，决定了两个肿瘤抑制基因的相对重要性， 在Ink 4a/ARF基因座中与肿瘤进展有关，并评估Notch信号传导的作用， MMP 7在PanIN和PDA的发展中的作用。合适的小鼠模型的可用性 胰腺导管腺癌的分子和细胞特征的详细评估 存在于肿瘤发生的不同阶段。这样的研究在人类胰腺中基本上是不可能的。 癌症标本，因为它们总是只在非常晚期才被发现。由此获得的信息 小鼠模型有助于进一步了解人胰腺癌。