Insulin-like growth factors (IGF) and its receptor (IGF-1R) signaling have been implicated in the development of various human cancers. IGF-binding protein (IGFBP-3), a major regulator of IGF signaling, either suppresses or enhances the actions of IGFs. Accordingly, circulating levels of IGF-1 and IGFBP-3 have been linked to the risk of various human cancers, with the most compelling data seen in breast, colon, and prostate cancers. However, prior studies have had inconsistent findings, regarding the role of circulating levels of IGFs and IGFBP-3 in lung cancer risk. Our study assessed the role of the IGF axis in lung cancer development by determining the incidence and growth of spontaneous and carcinogen-induced lung tumors in genetically modified mice, which convey lung-specific human IGF-1 transgenic expression (IGFTg)and/or germ-line null mutations of IGFBP3 (BP3+/+, BP3+/-and BP3-/-). The circulating IGFBP-3 level was significantly decreased in BP3+/- (50%)and BP3-/-mice (undetectable) compared to that in BP3+/+mice. The circulating mouse IGF-1 level was concurrently decreased in the BP3+/-(80%) and BP3-/-(50%) mice compared to that in BP3+/+. The mice carrying lung-specific IGF-1 transgene and/or loss of the IGFBP-3 gene (BP3+/-, BP3-/-, BP3+/+;IGFTg, BP3+/-;IGFTg, and BP3-/-;IGFTg) developed spontaneous lung adenocarcinomas (AC). Surprisingly, among those mice, the BP3+/-; IGFTgmice had the greatest levels of pIGF-1R in the lungs and the highest incidence and multiplicity of overall tumors and ACs. To further evaluate the role of IGFBP-3 in progression to malignant lung tumors, tobacco carcinogen (TC) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was exposed to those mice. While the overall tumor incidence did not vary among the genotypes, the BP3+/-; IGFTgmice had the highest incidence, and multiplicity of ACs, revealing enhancement of tumor progression by the NNK exposure. The observation that the degree of IGF-1R activation and lung tumor development in BP3+/-; IGFTg mice were greater than those in BP3-/-;IGFTg mice suggests the Janus effect of IGFBP3 in lung cancer development (stabilizer and suppressor of the IGF signaling). Further, the lower blood level IGF-1with severer phenotype in BP3+/-; IGFTgmice compared to thosein BP3+/+;IGFTgsuggest the importance of tissue-derived IGFs, rather than circulating IGFs, in activation of the IGF-1R signaling and lung cancer development. This work was supported by National Institutes of Health grants R01 CA109520 and CA100816-01A1 (to H.-Y. Lee).

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 795.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO