TY - JOUR
T1 - Brain metabolites in cholinergic and glutamatergic pathways are altered by pancreatic cancer cachexia
AU - Winnard, Paul T.
AU - Bharti, Santosh Kumar
AU - Sharma, Raj Kumar
AU - Krishnamachary, Balaji
AU - Mironchik, Yelena
AU - Penet, Marie France
AU - Goggins, Michael G.
AU - Maitra, Anirban
AU - Kamel, Ihab
AU - Horton, Karen M.
AU - Jacobs, Michael A.
AU - Bhujwalla, Zaver M.
N1 - Funding Information:
This work was supported by National Institutes of Health R35 CA209960, R01 CA193365, R01 CA82337, and U01 CA210170. We thank Mr Gary Cromwell for tumour inoculations and Ms Flonne Wildes for her assistance with the studies. The authors certify that they comply with the ethical guidelines for publishing in the Journal of Cachexia, Sarcopenia and Muscle: update 2019.48
Funding Information:
This work was supported by National Institutes of Health R35 CA209960, R01 CA193365, R01 CA82337, and U01 CA210170.
Publisher Copyright:
© 2020 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders
PY - 2020/12
Y1 - 2020/12
N2 - 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 1H 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 −27% and −21% 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 = −0.58), and formate (r = −0.43). Significant choline depletion of −38% and −30%, 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 −12% and −20% 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.
AB - 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 1H 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 −27% and −21% 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 = −0.58), and formate (r = −0.43). Significant choline depletion of −38% and −30%, 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 −12% and −20% 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.
KW - Brain and plasma H MR spectroscopy
KW - Cachexia
KW - Human pancreatic cancer xenografts
KW - Human plasma
KW - Metabolites
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U2 - 10.1002/jcsm.12621
DO - 10.1002/jcsm.12621
M3 - Article
C2 - 33006443
AN - SCOPUS:85091753479
VL - 11
SP - 1487
EP - 1500
JO - Journal of Cachexia, Sarcopenia and Muscle
JF - Journal of Cachexia, Sarcopenia and Muscle
SN - 2190-5991
IS - 6
ER -