Mutant mouse models of exocrine pancreatic cancer

导管型胰腺癌几乎都是致命的，不能在早期有效地发现。 各阶段。几乎所有胰腺癌和癌前导管增生症的病例中都含有致癌K- RAS基因突变，提示其在本病中的重要性。如实概括的癌症动物模型 相似的人类状况为探索癌症的分子基础提供了机会，早期发展 检测策略，并评估新的疗法。尽管突变的小鼠容易发展为 胰腺外分泌癌已有报道，无一例发展为导管性胰腺癌。 类似于人类疾病的腺癌。为了构建一种更相关的小鼠模型 导管胰腺癌，我们已经培育了一种突变的小鼠品系，它含有内源性的， 有条件表达的致癌K-ras G12D等位基因。通过将这种品系与 在胰腺中表达Cre重组酶，我们观察到癌前病变(PanLN) 与在人类身上看到的惊人地相似。在这里，我们将研究细胞隔间 能够启动胰腺癌，确定两个肿瘤抑制基因的相对重要性 在Ink4a/ARF基因座与肿瘤进展有关，并评估Notch信号和 MMP7在PanlN和PDA发展中的作用。一种合适的小鼠模型的可用性 胰腺导管腺癌将允许对分子和细胞特征进行详细的评估。 处于肿瘤发生的离散阶段。这样的研究在人类胰腺基本上是不可能的。 癌症标本，因为它们总是在很晚的阶段才被发现。从这一点上获得的信息 小鼠模型应有助于进一步了解人类胰腺癌。

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.