Abstract 45: Role of microenvironment on alterations in cancer metabolism using metabolic profiling

Abstract Endothelial, fibroblast cells, and extracellular matrix play a major role in progression, growth and spread of cancers. The extent to which each plays a role in metabolic adaptations in cancer metabolism is unknown. Because of the unique signature of metabolites in endothelial and fibroblasts when compared with epithelial cancer cell metabolism, metabolic profiling is an ideal approach to study induced metabolic changes in cancer cells during cocultures with fibroblasts and endothelia cells. Additionally, interaction of extracellular matrix with cancer cells has been shown to play a key role in cancer invasion and dissemination. In current work, we study the role of microenvironment (various cell types and extracellular matrix proteins) on alterations and adaptations of cancer metabolism. Metabolic profiling of various cancer cells (lung, prostate, breast, and ovarian) in coculture with fibroblasts and endothelial cells was done using metabolic flux analysis in various extracellular matrix environments (collagen coating, collagen gel, and matrigel). Metabolic flux analysis (MFA) refers to a methodology whereby intracellular fluxes (i.e. conversion rates of metabolites through individual reactions) are calculated using a stoichiometric model for the major intracellular reactions and applying mass balances around intracellular metabolites. MFA is a powerful approach for understanding and comparing different metabolic states, and offer insights into the functional capabilities of a metabolic network. The power of this approach is that it takes into account a large set of measurements as well as the complex inter-dependence among the various pathways due to the sharing of a common pool of co-factors such as NADH, NADPH, thus providing a more complete and integrated picture of the metabolic state than isolated measurements relevant to a few pathways. Our findings using quantification of 82 metabolites pertaining to central carbon and nitrogen metabolism provided clues as to which pathways relevant to glycolysis, the pentose phosphate pathway, the TCA and urea cycles, lipid cycle, and amino acid and nucleotide metabolisms, may be altered by endothelial and fibroblasts in cancer cells, resulting in identification of dominant factors which regulate cancer cell metabolism. During extracellular matrix cultures, amino acid supplementation, irrespective of extracellular matrix type, induced dramatic changes. Amino acid supplementation also significantly increased the TCA cycle flux at the level of citrate synthase and oxidized 96% to 97% of the fatty acid-derived acetyl-CoA to CO2. The information we gain elucidates the critical role of microenvironment and nutritional supplementation in cancer metabolism and allows development of therapeutics for modulating the communication between cancer and its microenvironment to prevent cancer invasion and dissemination. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 45.