|RUST, BRET - Washington State University
|SUNDARAM, SNEHA - Covance Laboratories
Submitted to: Nutrition and Metabolic Insights
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/15/2022
Publication Date: 7/29/2022
Citation: Yan, L., Rust, B.M., Sundaram, S., Picklo, M.J., Bukowski, M.R. 2022. Alteration in plasma metabolome in high-fat diet-fed monocyte chemotactic protein-1 knockout mice bearing pulmonary metastasis of Lewis lung carcinoma. Nutrition and Metabolic Insights. 107. Article 109051. https://doi.org/10.1016/j.jnutbio.2022.109051.
Interpretive Summary: Cancer growth is an aggressive process that demands excessive amounts of nutrients and energy to support its rapid growth. Lung cancer is the leading cancer for both men and women in the U.S. Like most cancers, the development and growth of lung cancer can be affected by dietary factors. For example, obesity induced by high dietary fat intake, increases the risk of lung cancer. To understand the metabolism of lung cancer, we compared metabolic profiles between lung cancer from cancer-bearing mice and the healthy lung tissue from non-cancer-bearing mice fed a low-fat control diet or an obesogenic, high-fat diet. The metabolic profile of lung cancer differed from that of the healthy lung tissue. This is mainly reflected in alterations in protein and sugar metabolism. Furthermore, the high-fat diet induced elevation of lipids (for example, cholesterol) in the healthy lung tissue but not in lung cancer. This suggests an accelerated utilization or metabolism of lipids by the cancer cells, which may be responsible, at least partly, for the aggressiveness of lung cancer. Findings from this study can be useful in designing targeted studies for prevention and treatment of lung cancer.
Technical Abstract: Metastasis is the most devastating aspect of cancer. This study tested the hypothesis that the metastatic metabolome differs from that of host organs by using the spontaneous metastasis model of Lewis lung carcinoma (LLC). In a 2x2 design, male C57BL/6 mice with or without a subcutaneous LLC inoculation were fed the AIN93G standard diet or a high-fat diet (HFD) for 12 weeks. At the end of the study, lung metastases from injected mice and the lungs from non-injected mice were harvested for metabolomic analysis. Gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) identified 91 metabolites, 70 of which differed among the four groups. Pathway and network analyses along with discriminant analysis demonstrated that amino acid and carbohydrate metabolism were altered the most in LLC metastases compared to the lungs. A 60% decrease in glutamine and a 25-fold elevation in sorbitol were observed in metastases. Cholesterol and its metabolite dihydrocholesterol were 50% lower in metastases than in the lungs. The HFD elevated arachidonic acid and its precursor linoleic acid in the lungs of non-LLC-bearing mice, reflecting the dietary fatty acid composition of the HFD. This elevation did not occur in metastases from HFD-fed LLC-bearing mice, suggesting alterations in lipid metabolism during LLC metastatic progression. Differences in the metabolomes between LLC pulmonary metastases and the normal healthy lungs can be useful in designing targeted studies for prevention and treatment of metastasis using this spontaneous metastasis model.