Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2151837 | Neoplasia | 2009 | 11 Pages |
Abstract
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 IGF-IR 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-IGFIR transgenic mice can be used to further our understanding of human lung cancer and the role IGF-IR plays in this disease.
Keywords
IGFtype I insulin-like growth factor receptorBronchioalveolar stem cellrtTAKlf5CCSPIGFBPIGF-IRAAHTTF-1CREBBASCSPCMMTVSCLCReverse tetracycline transactivatorNSCLCSmall cell lung cancerNon-small cell lung cancerTREkruppel-like factor 5Thyroid transcription factor 1tetracycline response elementInsulin-like growth factorMouse mammary tumor virusinsulin-like growth factor binding proteincyclic adenosine monophosphate response element binding proteinClara cell secretory proteinsurfactant protein C
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Authors
Nicolle M. Linnerth, Megan D. Siwicky, Craig I. Campbell, Katrina L.M. Watson, James J. Petrik, Jeffrey A. Whitsett, Roger A. Moorehead,