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Elevated Epithelial Insulin-like Growth Factor Expression Is a Risk Factor for Lung Cancer Development

Departments of ¹ Thoracic/Head and Neck Medical Oncology, ² Biostatistics, and ³ Pathology, The University of Texas M.D. Anderson Cancer Center; ⁴ The University of Texas Graduate School of Biomedical Sciences, Houston, Texas; and ⁵ Department of Medicine, Denver Veterans Affairs Medical Center, University of Colorado Denver, Denver, Colorado

Requests for reprints: Ho-Young Lee, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-0769; Fax: 713-792-0430; E-mail: hlee{at}mdanderson.org.

Key Words: IGF • IGF-IR • lung cancer • cigarette smoking • carcinogenesis

Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling has been implicated in several human neoplasms. However, the role of serum levels of IGFs in lung cancer risk is controversial. We assessed the role of tissue-derived IGFs in lung carcinogenesis. We found that IGF-I and IGF-II levels in bronchial tissue specimens containing high-grade dysplasia were significantly higher than in those containing normal epithelium, hyperplasia, and squamous metaplasia. Derivatives of human bronchial epithelial cell lines with activation mutation in KRAS(V12) or loss of p53 overexpressed IGF-I and IGF-II. The transformed characteristics of these cells were significantly suppressed by inactivation of IGF-IR or inhibition of IGF-I or IGF-II expression but enhanced by overexpression of IGF-IR or exposure to the tobacco carcinogens (TC) 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone and benzo(a)pyrene. We further determined the role of IGF-IR signaling in lung tumorigenesis by determining the antitumor activities of the selective IGF-IR tyrosine kinase inhibitor cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo [1,5-a]pyrazin-8-ylamine using an in vitro progressive cell system and an in vivo mouse model with a lung-specific IGF-I transgene after exposure to TCs, including 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone plus benzo(a)pyrene. Our results show that airway epithelial cells produce IGFs in an autocrine or paracrine manner, and these IGFs act jointly with TCs to enhance lung carcinogenesis. Furthermore, the use of selective IGF-IR inhibitors may be a rational approach to controlling lung cancer. [Cancer Res 2009;69(18):7439–48]

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				Correction: Elevated Epithelial Insulin-Like Growth Factor Expression Is a RiskFactor for Lung Cancer Development Cancer Res., October 15, 2009; 69(20): 8216 - 8216. [Full Text] [PDF]