Abstract
Insulin-like growth factor 1 receptor (IGF-1R) signaling has been implicated in several human neoplasms. However, the role of serum levels of insulin-like growth factors (IGFs) in lung cancer risk is controversial. Our study assessed the role of tissue-derived IGFs in lung carcinogenesis. We found that IGF-1 and IGF-2 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, genetic changes frequently observed during lung carcinogenesis, overexpressed IGF-1 and IGF-2. Tobacco carcinogen (TC) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) enhanced transformed characteristics of these cells, which were significantly suppressed by the inhibiting the action of IGF-1, IGF-2, or the insulin-like growth factor receptor (IGFR). We further determined the role of IGF expression in lung tumorigenesis using a mouse model with a lung-specific IGF-1 transgene after exposure to TCs, including urethane or NNK plus benzo[a]pyrene (BaP). Finally, we demonstrated antitumor activities of the selective IGF-1R 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 (PQIP) in IGF-1 transgenic mice carrying NNK/BaP-induced lung tumors. Our results demonstrate that airway epithelial cells produce IGFs in an autocrine manner, and these IGFs act jointly with TCs to stimulate lung carcinogenesis. Thus, the use of selective IGF-1R inhibitors may be a rational approach to controlling lung cancer. This work was supported by National Institutes of Health grants R01 CA109520 and CA100816-01A1 (to H.-Y. Lee); and in part: by U.S. Department of Defense grant W81XWH-04-1-0142-01-VITAL (to W.K. Hong); M. D. Anderson Cancer Center Specialized Programs of Research Excellence Grant in head and neck cancer P50 CA58187 (to W.K. Hong); and a Department of Veterans Affairs Merit Review Grant (both to Y.E.M.).
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 793.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO