Lung cancer is the leading cause of cancer-related mortality worldwide, and 85% of lung cancers are associated with tobacco use. Activating mutations in K-ras have been identified in ~25% of lung adenocarcinomas and are found predominantly in smokers. We previously demonstrated that reducing systemic IGF-1 levels, by treatment with the anti-diabetic drug metformin or by liver-specific ablation of the IGF-1 gene, decreases tumorigenesis in mouse models of k-ras-driven lung cancer. Since preclinical and clinical studies suggest that diet composition is the best predictor of systemic IGF-1 levels, we hypothesized that diets high in fat or carbohydrates might increase systemic IGF-1 levels and promote lung tumorigenesis.
To assess the effect of diet, C57Bl/6J and A/J mice were fed standard cereal diet, high-carbohydrate diet, or high-fat diet (HFD) for 12 weeks starting at nine weeks of age, after which plasma and tissue samples were collected. The HFD increased levels of IGF-1 and insulin in both strains of mice, and increased the weights of C57BL/6J, but not A/J mice. In contrast, the high-carbohydrate diet did not increase the weights or circulating levels of IGF-1/insulin in either strain of mice.
Since insulin and IGF-I were induced more with HFD, we investigated the impact of HFD on lung tumorigenesis using two mouse models of Kras-mutant lung cancer. In the first, genetically engineered C57BL/6LA2 mice were fed a cereal diet or HFD for 10 weeks starting at weaning. Lung tumor multiplicity and tumor burden increased 2.7-fold compared to littermates fed a cereal diet. In the second model, lung tumorigenesis was initiated in 6 week old A/J mice by three weekly IP injections of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) that invariably causes Kras mutations. . One week after the last NNK injection, mice were randomized to cereal or HFD for 10 weeks. Mice on HFD had a 40% increase in lung tumor multiplicity and a 60% increase in lung tumor burden. These studies show that a HFD promotes lung tumor growth caused by a mutation commonly observed in smokers. Conversely, the results imply that dietary modification could slow the progression of tumorigensis due to smoking related genetic changes in lung epithelium. Further, chemopreventative drugs, such as metformin, may have enhanced efficacy in a HFD model due to the associated increases in levels of insulin and/or IGF-I. Finally, understanding the long term effects of HFD could identify new targets for cancer prevention.
Citation Format: Jeffrey W. Norris, Regan M. Memmott, Kristin Lastwika, Phillip Dennis. A high-fat diet, but not obesity, promotes tumorigenesis in two mouse models of k-ras-driven lung cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B23.