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

Kevin D Courtney; Divya Bezwada; Tomoyuki Mashimo; Kumar Pichumani; Vamsidhara Vemireddy; Alexander M Funk; Jennifer Wimberly; Sarah S McNeil; Payal Kapur; Yair Lotan; Vitaly Margulis; Jeffrey A Cadeddu; Ivan Pedrosa; Ralph J DeBerardinis; Craig R Malloy; Robert M Bachoo; Elizabeth A Maher

doi:10.1016/j.cmet.2018.07.020

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

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

Authors

Kevin D Courtney¹, Divya Bezwada², Tomoyuki Mashimo³, Kumar Pichumani⁴, Vamsidhara Vemireddy⁵, Alexander M Funk⁴, Jennifer Wimberly⁶, Sarah S McNeil⁷, Payal Kapur⁸, Yair Lotan⁶, Vitaly Margulis⁶, Jeffrey A Cadeddu⁶, Ivan Pedrosa⁹, Ralph J DeBerardinis², Craig R Malloy¹⁰, Robert M Bachoo¹¹, Elizabeth A Maher¹²

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Aged
Carbon Isotopes / metabolism
Carcinoma, Renal Cell / metabolism*
Carcinoma, Renal Cell / pathology
Citric Acid Cycle
Glucose / metabolism*
Glycolysis
Humans
Kidney / metabolism
Kidney / pathology
Kidney Neoplasms / metabolism*
Kidney Neoplasms / pathology
Middle Aged
Oxidation-Reduction

Substances

Carbon Isotopes
Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding