Introduction of oncogenes into mammary glands in vivo with an avian retroviral vector initiates and promotes carcinogenesis in mouse models
Introduction of oncogenes into mammary glands in vivo with an avian retroviral vector initiates and promotes carcinogenesis in mouse models
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DOI：
10.1073/pnas.0608607103
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发表时间：
2006-11-14
影响因子：
11.1
通讯作者：
Li, Yi
中科院分区：
文献类型：
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作者：
Du, Zhijun;Podsypanina, Katrina;Li, Yi
我们采用了禽白血病病毒 RCAS（有复制能力的禽肉瘤白血病病毒 LTR 剪接受体）介导的体细胞基因转移技术，将癌基因引入转基因禽 A 亚型受体基因 tva 的小鼠乳腺细胞中，并受小鼠乳腺肿瘤病毒 (MMTV) 启动子的控制。导管内滴注携带多瘤中T抗原（PyMT）基因（RCAS-PyMT）的RCAS载体，可在3周内在MMTV-tva转基因小鼠受感染的乳腺中诱导多个寡克隆肿瘤。这些肿瘤从相对较小的感染细胞池中快速出现（通过携带 GFP 基因的 RCAS 感染，估计每个腺体大约有 2 x 10(3) 个细胞；RCAS-GFP），同时伴随着高比例的 Ki67、Cyclin D1 和 c-Myc 阳性细胞，这意味着强大的增殖能力。此外，与 MMTV-PyMT 小鼠中产生的肿瘤相比，肿瘤表现出更大的细胞异质性，表明 RCAS-PyMT 转化了相对不成熟的细胞类型。与未感染的双转基因动物中观察到的情况相比，用携带激活的 Neu 癌基因的 RCAS 病毒感染 MMTV-Wnt-1 和 MMTV-tva 转基因小鼠，显着增强了肿瘤形成。我们得出的结论是，用逆转录病毒载体感染乳腺是筛选候选癌基因启动或促进小鼠乳腺癌发生能力的有效方法。
We have adapted the avian leukosis virus RCAS (replication-competent avian sarcoma-leukosis virus LTR splice acceptor)-mediated somatic gene transfer technique to introduce oncogenes into mammary cells in mice transgenic for the avian subgroup A receptor gene, tva, under control of the mouse mammary tumor virus (MMTV) promoter. Intraductal instillation of an RCAS vector carrying the polyoma middle T antigen (PyMT) gene (RCAS-PyMT) induced multiple, oligoclonal tumors within 3 weeks in infected mammary glands of MMTV-tva transgenic mice. The rapid appearance of these tumors from a relatively small pool of infected cells (estimated to be approximate to 2 x 10(3) cells per gland by infection with RCAS carrying a GFP gene; RCAS-GFP) was accompanied by a high fraction of cells positive for Ki67, Cyclin D1, and c-Myc, implying strong proliferation competence. Furthermore, the tumors displayed greater cellular heterogeneity than did tumors arising in MMTV-PyMT mice, suggesting that RCAS-PyMT transforms a relatively immature cell type. Infection of mice transgenic for both MMTV-Wnt-1 and MMTV-tva with RCAS virus carrying an activated Neu oncogene dramatically enhanced tumor formation over what is observed in uninfected bitransgenic animals. We conclude that infection of mammary glands with retrovirus vectors is an efficient means to screen candidate oncogenes for their capacity to initiate or promote mammary carcinogenesis in the mouse.