Abstract 1886: Metabolic alterations associated with pancreatic cancer-induced cachexia.

Abstract Cachexia, a metabolic syndrome, leads to loss of muscle weight and fat tissues. Cancer-induced cachexia accounts for nearly 20% of all cancer-related deaths and is most prevalent in patients with gastric, pancreatic, colon and lung cancer. Although association of cachexia with various types of cancers has been known for a long time, the molecular mechanism of cancer-induced cachexia is still not well understood. Better understanding of the cancer-related cachexia syndrome may provide novel therapeutic targets and improved health care for cancer patients. By culturing differentiated C2C12 and 3T3-L1 cells in the presence of pancreatic adenocarcinoma cell or immortalized epithelial cell supernatants, we established cell culture-based cachexia model systems to investigate the depletion of muscle mass and fatty acid storage. Progressive physiological and biochemical alterations during muscle fibre breakdown and adipocyte fat depletion were assayed by utilizing western blotting, real-time PCR and cell imaging. We then investigated metabolomic alterations in C2C12 and 3T3-L1 cell lines in response to the cachectic factors secreted by the tumor cells. We performed differential metabolomic analyses on tumor cell supernatant-treated or control treated differentiated C2C12 muscle fibers and 3T3-L1-derived adipocytes by utilizing 2D 1H-13C HSQC NMR technique. Alterations in metabolic pathways were also investigated by evaluating the expression of metabolic genes in the corresponding pathways by performing quantitative real-time PCR. To obtain further insights into the metabolic alterations that trigger cachexia, we extended our studies to in vivo mouse orthotopic xenograft models and investigated alterations in metabolic gene expression and metabolite flux in muscle and fat tissues of tumor-bearing mice. Our results identify crucial nodes in metabolite flux that can be targeted to regulate cell growth, proliferation, and turnover in muscle and fat tissues during cancer-induced cachexia. Citation Format: Surendra K. Shukla, Pankaj K. Singh. Metabolic alterations associated with pancreatic cancer-induced cachexia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1886. doi:10.1158/1538-7445.AM2013-1886