The function of IGF-IR in NNK-mediated lung tumorigenesis.
The type I insulin-like growth factor receptor (IGF-IR) is associated with many different types of cancer and it has been found to be involved in many aspects of the malignant phenotype, such as mitogenesis, survival, transformation and metastasis. This receptor has been observed to be overexpressed in the majority of lung cancer cell lines and human lung tumor biopsies. Two doxycycline-inducible transgenic mouse models in which the human IGF-IR was overexpressed in either the Clara cells or the type II alveolar cells of the lung were used in this study to examine the interaction between the nicotine derivative, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and the IGF-IR. NNK was injected into both of the transgenic mouse models that overexpress human IGF-IR in the lung tissue in order to determine whether IGF-IR overexpression would affect NNK-induced tumorigenesis. No significant differences in the overall tumor burden were found between mice overexpressing the IGF-IR transgene that were treated with NNK and those that were not, however NNK-treated mice expressing high levels of IGF-IR transgene developed larger tumors than mice expressing high levels of IGF-IR transgene that did not receive NNK injections. In addition, endogenous murine IGF-IR was found to be expressed at high levels in the tumors that developed in the wild type, NNK injected mice suggesting that NNK induces lung tumors through inducing endogenous IGF-IR expression.
Siwicky
Megan D
MD
Department of Biomedical Sciences, Ontario Veterinary College, 50 Stone Road East, University of Guelph, Guelph, ON, Canada N1G2W1.
Petrik
James J
JJ
Moorehead
Roger A
RA
D000818:Animals; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009602:Nitrosamines; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects
D002273:Carcinogens; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D017526:Receptor, IGF Type 1