Type I Insulin-like Growth Factor Receptor Induces Pulmonary Tumorigenesis
Type I Insulin-like Growth Factor Receptor Induces Pulmonary Tumorigenesis
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DOI：
10.1593/neo.09310
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发表时间：
2009-07-01
期刊：
影响因子：
4.8
通讯作者：
Moorehead, Roger A.
中科院分区：
文献类型：
--
作者：
Linnerth, Nicolle M.;Siwicky, Megan;Moorehead, Roger A.
尽管I型胰岛素样生长因子受体（IGF-IR）在超过80%的人类肺肿瘤中高度表达，但尚未建立肺中IGF-IR过表达的转基因模型。我们制作了两种新型转基因小鼠模型，其中IGF-IR在肺II型肺泡细胞（表面活性蛋白C [SPC]-IGFIR）或Clara细胞（CCSP-IGFIR）中以强力霉素诱导的方式过表达。IGF-IR在任一细胞类型中的过表达引起多灶性腺瘤性肺泡增生伴乳头状和实性腺瘤。这些肿瘤在大多数肿瘤细胞中表达甲状腺转录因子1和Kruppel样因子5。与我们先前对小鼠乳腺肿瘤病毒-IGF-II转基因小鼠中发生的肺肿瘤的研究类似，SPC-IGFIR和CCSP-IGFIR转基因小鼠中发生的肺肿瘤表达高水平的环磷酸腺苷反应元件结合蛋白，其主要定位于细胞核。尽管升高的IGF-IR表达可以引发肺肿瘤发展，但是肿瘤可以变得不依赖于IGF 1 R信号传导，因为在已建立的肿瘤中IGF-IR下调在一些但不是全部肿瘤中产生肿瘤消退。这些发现暗示IGF-IR是肺肿瘤发生的重要起始物，并表明SPC-IGFIR和CCSP-IGF-IR转基因小鼠可用于进一步了解人类肺癌和IGF-IR在这种疾病中的作用。
Despite the type I insulin-like growth factor receptor (IGF-IR) being highly expressed in more than 80% of human lung tumors, a transgenic model of IGF-IR overexpression in the lung has not been created. We produced two novel transgenic mouse models in which IGF-IR is overexpressed in either lung type II alveolar cells (surfactant protein C [SPC]-IGFIR) or Clara cells (CCSP-IGFIR) in a doxycycline-inducible manner. Overexpression of IGF-IR in either cell type caused multifocal adenomatous alveolar hyperplasia with papillary and solid adenomas. These tumors expressed thyroid transcription factor 1 and Kruppel-like factor 5 in most tumor cells. Similar to our previous work with lung tumors that developed in the mouse mammary tumor virus-IGF-II transgenic mice, the lung tumors that develop in the SPC-IGFIR and CCSP-IGFIR transgenic mice expressed high levels of the cyclic adenosine monophosphate response element binding protein that was localized primarily to the nucleus. Although elevated IGF-IR expression can initiate lung tumor development, tumors can become independent of IGFIR signaling as IGF-IR down-regulation in established tumors produced tumor regression in some, but not all, of the tumors. These findings implicate IGF-IR as an important initiator of lung tumorigenesis and suggest that the SPC-IGFIR and CCSP-IGF-IR transgenic mice can be used to further our understanding of human lung cancer and the role IGF-IR plays in this disease.