Abstract 4330: A high-fat diet promotes tumorigenesis in two mouse models of K-ras-driven lung cancer

Abstract

Lung cancer is the leading cause of cancer-related mortality worldwide, and 85% of lung cancer cases are associated with tobacco use. Within this group, activating mutations in K-ras have been identified in ∼25% of lung adenocarcinomas. Using a mouse model of k-ras-driven lung tumorigenesis, we previously demonstrated that deletion of the IGF-1 gene or reduction of systemic IGF-1 levels using the antidiabetic drug metformin markedly reduced tumor burden. Since preclinical and clinical studies suggest that diet composition is the best predictor of IGF-1 levels, we hypothesized that diets high in fat or carbohydrate would promote lung tumorigenesis by increasing systemic IGF-1 levels. To assess the effect of diet on systemic IGF-1 levels, 9 week old C57Bl/6J and A/J mice were fed standard cereal, high-carbohydrate, or high-fat (HFD) diets for 12 weeks. At the conclusion of the study plasma, liver, and lung samples were collected. Compared to the cereal-fed control mice, IGF-1 and insulin levels were increased in both strains of mice only with HFD. Average body weight only increased for the C57Bl/6J group that was fed HFD. We investigated the effect of HFD on lung tumorigenesis using two mouse models of lung cancer. In the first, C57Bl/6LA2 mice, which are genetically modified with a K-ras mutation present in human smokers, were fed either cereal diet or HFD for 10 weeks following weaning. Lung tumor burden in the mice fed HFD was increased 2.7-fold compared to littermates fed cereal diet. In the second model, the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone (NNK) was given by IP injection to A/J mice beginning at 6 weeks of age. This carcinogen causes lung tumor formation by inducing K-ras mutations. Following once weekly injections of NNK for 3 weeks, the mice were randomized to cereal diet or HFD. 10 weeks later, mice fed HFD were found to have a 60% increase in lung tumor burden. In both studies, there was no relationship between the final body weight of the mice and tumor burden. These studies show that HFD promotes lung tumor growth resulting from a mutation commonly observed in smokers. Therefore, dietary modification may slow the progression of tumorigenesis resulting from smoking-related genetic changes through IGF-1. Chemopreventative drugs, like metformin, may also have greater efficacy in a HFD model due to the increased insulin and IGF-1 associated with this model. Finally, understanding the molecular mechanisms by which HFD promotes tumor growth may help to identify new targets for cancer prevention. Citation Format: Jeffrey Norris, Krista Pearman, Regan Memmott, Kristin Lastwika, Joell Gills, Phillip Dennis. A high-fat diet promotes tumorigenesis in two mouse models of K-ras-driven lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4330.