Type I insulin-like growth factor receptor induces pulmonary tumorigenesis.
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.
Linnerth
Nicolle M
NM
Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Ontario, Canada.
Siwicky
Megan D
MD
Campbell
Craig I
CI
Watson
Katrina L M
KL
Petrik
James J
JJ
Whitsett
Jeffrey A
JA
Moorehead
Roger A
RA
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics*; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D014598:Uteroglobin / Q000235:genetics
C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse; D014598:Uteroglobin; D017526:Receptor, IGF Type 1