Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma
Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma
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DOI：
10.1101/gad.1158703
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发表时间：
2003-12-15
影响因子：
10.5
通讯作者：
DePinho, RA
中科院分区：
文献类型：
--
作者：
Aguirre, AJ;Bardeesy, N;DePinho, RA
胰腺导管腺癌是人类最致命的恶性肿瘤之一。在这里，我们评估了两个标志性突变在小鼠中的协同作用，这些突变被设计成维持胰腺特异性CRE介导的突变Kras等位基因(Kras(G12D))的激活和条件性Ink4a/Arf肿瘤抑制等位基因的缺失。Kras(G12D)单独的表型影响主要局限于局灶性癌前导管病变的发展，称为胰腺上皮内肿瘤(Panins)，而Ink4a/Arf的单独失活未能在胰腺产生任何肿瘤病变。同时，Kras(G12D)表达和Ink4a/Arf缺乏导致Panin病变较早出现，这些肿瘤迅速进展为高侵袭性和转移性癌症，导致所有病例在11周内死亡。这些肿瘤的演变与人类疾病有惊人的相似之处，具有增生性间质成分和导管病变，有发展到低分化状态的倾向。在小鼠身上的这些发现为广泛接受的人类胰腺癌模型提供了实验支持，在该模型中，激活的KRAS起到启动Panin病变的作用，而Ink4a/ARF肿瘤抑制因子发挥作用来抑制这些Panin病变向致命的导管腺癌的恶性转化。这种忠实的小鼠模型可能允许对与人类疾病有关的遗传损伤进行系统分析，并作为识别早期疾病标志物和有效测试新疗法的平台。
Pancreatic ductal adenocarcinoma ranks among the most lethal of human malignancies. Here, we assess the cooperative interactions of two signature mutations in mice engineered to sustain pancreas-specific Cre-mediated activation of a mutant Kras allele (Kras(G12D)) and deletion of a conditional Ink4a/Arf tumor suppressor allele. The phenotypic impact of Kras(G12D) alone was limited primarily to the development of focal premalignant ductal lesions, termed pancreatic intraepithelial neoplasias (PanINs), whereas the sole inactivation of Ink4a/Arf failed to produce any neoplastic lesions in the pancreas. In combination, Kras(G12D) expression and Ink4a/Arf deficiency resulted in an earlier appearance, of PanIN lesions and these neoplasms progressed rapidly to highly invasive and metastatic cancers, resulting in death in all cases by 11 weeks. The evolution of these tumors bears striking resemblance to the human disease, possessing a proliferative stromal component and ductal lesions with a propensity to advance to a poorly differentiated state. These findings in the mouse provide experimental support for the widely accepted model of human pancreatic adenocarcinoma in which activated KRAS serves to initiate PanIN lesions, and the INK4A/ARF tumor suppressors function to constrain the malignant conversion of these PanIN lesions into lethal ductal adenocarcinoma. This faithful mouse model may permit the systematic analysis of genetic lesions implicated in the human disease and serve as a platform for the identification of early disease markers and for the efficient testing of novel therapies.