Brain metabolites in cholinergic and glutamatergic pathways are altered by pancreatic cancer cachexia

Abstract

Background Cachexia is a major cause of morbidity in pancreatic ductal adenocarcinoma (PDAC) patients. Our purpose was to understand the impact of PDAC-induced cachexia on brain metabolism in PDAC xenograft studies, to gain new insights into the causes of cachexia-induced morbidity. Changes in mouse and human plasma metabolites were characterized to identify underlying causes of brain metabolic changes. Methods We quantified metabolites, detected with high-resolution 1 H magnetic resonance spectroscopy, in the brain and plasma of normal mice (n = 10) and mice bearing cachexia (n = 10) or non-cachexia (n = 9) inducing PDAC xenografts as well as in human plasma obtained from normal individuals (n = 24) and from individuals with benign pancreatic disease (n = 20) and PDAC (n = 20). Statistical significance was defined as a P value ≤0.05. Results The brain metabolic signature of cachexia-inducing PDAC was characterized by a significant depletion of choline of À27% and À21% as well as increases of glutamine of 13% and 9% and formate of 21% and 14%, relative to normal controls and non-cachectic tumour-bearing mice, respectively. Good to moderate correlations with percent weight change were found for choline (r = 0.70), glutamine (r = À0.58), and formate (r = À0.43). Significant choline depletion of À38% and À30%, relative to normal controls and non-cachectic tumour-bearing mice, respectively, detected in the plasma of cachectic mice likely contributed to decreased brain choline in cachectic mice. Similarly, relative to normal controls and patients with benign disease, choline levels in human plasma samples of PDAC patients were significantly lower by À12% and À20% respectively. A comparison of plasma metabolites from PDAC patients with and without weight loss identified significant changes in glutamine metabolism. Conclusions Disturbances in metabolites of the choline/cholinergic and glutamine/glutamate/glutamatergic neurotransmitter pathways may contribute to morbidity. Metabolic normalization may provide strategies to reduce morbidity. The human plasma metabolite changes observed may lead to the development of companion diagnostic markers to detect PDAC and PDAC-induced cachexia.

Review of the endocrine organ–like tumor hypothesis of cancer cachexia in pancreatic ductal adenocarcinoma

“…The utilization of BCAAs by PDAC can result in plasma BCAA depletion during late-stage PDAC. Similar observations have been reported for glutamate, in which the plasma levels of glutamate and the glutamine/glutamate (Q/E) ratio are significantly reduced in cachectic patients and animal models compared with their healthy counterparts ( 83 , 99 ). Glutamine metabolism is a primary source of nitrogen and carbon, contributing to macromolecular synthesis and redox balance ( 83 ).…”

GEO data mining and TCGA analysis reveal altered branched chain amino acid metabolism in pancreatic cancer patients

“…Metabolic pathways are increasingly being appreciated in tumor intervention [ 27 , 28 ]. With the aim to clarify the relationship between BCAA metabolism and PDAC development, we utilize the open accessed databases (GEO and TCGA) to address some of the most concerned issues.…”

Cancer insights from magnetic resonance spectroscopy of cells and excised tumors

“…The potential of 1 H MRS and 31 P MRS of serum metabolite markers to detect cancer has been evaluated in different tumor types, including prostate, pancreas, lung, and renal cancers, and leukemia. 103,111,127,131 Metabolomic profiles in serum from lung cancer patients were found to predict overall survival. Prolonged survival was associated with increased glutamine, valine, and glycine, and reduced glutamate and lipids.…”

“…Biofluids are easily accessible, providing an attractive option for cancer screening, especially for cancers with no available screening method. The potential of 1 H MRS and 31 P MRS of serum metabolite markers to detect cancer has been evaluated in different tumor types, including prostate, pancreas, lung, and renal cancers, and leukemia 103,111,127,131 …”

“…Analysis of serum from individuals with acute myeloid leukemia and acute lymphoblastic leukemia identified alterations in metabolic pathways that included glycolysis, TCA cycle, lipoprotein metabolism, and choline and fatty acid metabolism in these two subtypes of acute leukemia 127 . In pancreatic cancer, lower plasma choline levels were observed in patients with PDAC compared with those in normal subjects and with those in patients with benign pancreatic disease 103 . 31 P MRS was applied to plasma samples to assess the systemic phospholipid profile in renal cell carcinoma patients 131 .…”