Abstract 2510: Interrogating liver metabolic stress due to cancer-induced cachexia

Abstract

Abstract Cancer-induced cachexia accounts for approximately 20% of all cancer deaths 1. In pancreatic cancer, the syndrome affects nearly 80% of patients 2,3. Cachectic patients experience a wide range of symptoms affecting the function of several organs such as muscle, liver, brain, and heart, that decrease quality of life and worsen prognosis. A major characteristic of cachexia is the accelerated skeletal muscle and fat storage wasting causing nutrient mobilization both directly as lipid and amino acids, and indirectly as glucose derived from the exploitation of liver gluconeogenesis that reaches the tumor through the bloodstream4. Patients with cachexia develop a wide range of metabolic stress from increased proteins and fat tissue burning resulting in increased energy expenditure. Here, for the first time, we have performed high-resolution quantitative 1H magnetic resonance spectroscopy (MRS) of liver tissue obtained from normal, noncachectic and cachectic mice bearing PDAC that are cachectic (Pa04C) and noncachectic (Panc1). A significant reduction in liver weight and significant changes in 1H MRS derived metabolite profiles were detected with cachexia. Human pancreatic cancer cell lines, Panc1 and Pa04C, were used for the study. Six to 8 week old male severe combined immunodeficient mice were inoculated in the right flank with cancer cells (5×106) and in the right hind leg muscle with reporter myoblasts (2×106) to monitor the development of cachexia in mice5. Live animal optical imaging was done using a Xenogen IVIS® Spectrum (PerkinElmer) optical scanner. Dual phase solvent extraction was performed on liver tissue to extract water soluble metabolites. All 1H MR spectra were acquired on an Avance 750 MHz Bruker NMR spectrometer. We found, for the first time, that the liver in Pa04C tumor bearing mice underwent a profound weight loss; although Panc1 tumor bearing mice showed some liver weight loss this was not as profound as observed with Pa04C tumors. Significant decreases in lactate, glucose and glutathione were observed in cachectic mouse liver compared to noncachectic mouse liver, and the liver from healthy control mice. The significant decrease of these metabolites in cachectic livers may reflect increased utilization of glucose, lactate and glutathione by the tumor or other organs during the cachexia cascade4. These results provide new insights into changes in liver metabolism during cachexia, and support investigating metabolic strategies such as supplementing glutathione or glucose to reduce cachexia associated morbidity.