Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes
Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes
复制标题
DOI：
10.1101/gad.947701
复制
发表时间：
2001-12-15
影响因子：
10.5
通讯作者：
Varmus, HE
中科院分区：
文献类型：
--
作者：
Fisher, GH;Wellen, SL;Varmus, HE
为了研究激活的K-Ras基因在肺腺癌的发生和维持中的作用，我们开发了在II型肺细胞中强力霉素控制下表达鼠K-Ras 4 b（G12 D）的转基因小鼠。早在用强力霉素诱导后7天就观察到肺泡II型肺细胞的局灶性增殖性病变;诱导两个月后，肺中含有腺瘤和腺癌，在后期阶段有胸膜的局灶性浸润。去除强力霉素引起突变K-Ras RNA水平的快速升高，并伴随早期增殖性病变和肿瘤的凋亡消退。停药后三天肿瘤负荷显著降低，一个月后肿瘤检测不到。当用p53基因或Ink 4A/Arf基因座缺陷的动物进行类似的实验时，肿瘤发生得更快（多西环素暴露1个月内），表现出更明显的恶性组织学特征;然而，当去除诱导剂时，这些肿瘤也迅速消退，这意味着突变K-Ras的持续产生对于在肿瘤抑制基因不存在以及存在的情况下维持肿瘤细胞的活力是必需的。我们还表明，这些肺部肿瘤的外观和消退可以很容易地监测麻醉转基因动物的磁共振成像。
To investigate the role of an activated K-Ras gene in the initiation and maintenance of lung adenocarcinomas, we developed transgenic mice that express murine K-Ras4b(G12D) under the control of doxycycline in type II pneumocytes. Focal proliferative lesions of alveolar type II pneumocytes were observed as early as seven days after induction with doxycycline; after two months of induction, the lungs contained adenomas and adenocarcinomas, with focal invasion of the pleura at later stages. Removal of doxycycline caused a rapid fan in levels of mutant K-Ras RNA and concomitant apoptotic regression of both the early proliferative lesions and the tumors. Tumor burden was dramatically decreased by three days after withdrawal, and tumors were undetectable after one month. When similar experiments were performed with animals deficient in either the p53 gene or the Ink4A/Arf locus, tumors arose more quickly (within one month of exposure to doxycycline) and displayed more obvious histological features of malignancy; nevertheless, these tumors also regressed rapidly when the inducer was removed, implying that continued production of mutant K-Ras is necessary to maintain the viability of tumor cells in the absence as well as the presence of tumor suppressor genes. We also show that the appearance and regression of these pulmonary tumors can be readily monitored in anesthetized transgenic animals by magnetic resonance imaging.