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Cell Metab. 2018 Nov 6;28(5):793-800.e2. doi: 10.1016/j.cmet.2018.07.020. Epub 2018 Aug 23.

Isotope Tracing of Human Clear Cell Renal Cell Carcinomas Demonstrates Suppressed Glucose Oxidation In Vivo.

Author information

1
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, TX, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: kevin.courtney@utsouthwestern.edu.
2
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
3
Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
4
Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
5
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
6
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
7
Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
8
Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
9
Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
10
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Veterans Affairs North Texas Healthcare System, Dallas, TX, USA.
11
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
12
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: elizabeth.maher@utsouthwestern.edu.

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common form of human kidney cancer. Histological and molecular analyses suggest that ccRCCs have significantly altered metabolism. Recent human studies of lung cancer and intracranial malignancies demonstrated an unexpected preservation of carbohydrate oxidation in the tricarboxylic acid (TCA) cycle. To test the capacity of ccRCC to oxidize substrates in the TCA cycle, we infused 13C-labeled fuels in ccRCC patients and compared labeling patterns in tumors and adjacent kidney. After infusion with [U-13C]glucose, ccRCCs displayed enhanced glycolytic intermediate labeling, suppressed pyruvate dehydrogenase flow, and reduced TCA cycle labeling, consistent with the Warburg effect. Comparing 13C labeling among ccRCC, brain, and lung tumors revealed striking differences. Primary ccRCC tumors demonstrated the highest enrichment in glycolytic intermediates and lowest enrichment in TCA cycle intermediates. Among human tumors analyzed by intraoperative 13C infusions, ccRCC is the first to demonstrate a convincing shift toward glycolytic metabolism.

KEYWORDS:

cancer metabolism; clear cell renal cell carcinoma; human cancer; kidney cancer; mass spectrometry; nuclear magnetic resonance spectroscopy (NMR); stable isotope tracing

PMID:
30146487
PMCID:
PMC6221993
[Available on 2019-11-06]
DOI:
10.1016/j.cmet.2018.07.020

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