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Hyperpolarized 13C-Pyruvate Metabolism as a Surrogate for Tumor Grade and Poor Outcome in Renal Cell Carcinoma—A Proof of Principle Study

1
Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge CB2 0QQ, UK
2
Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, UK
3
Department of Radiology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
4
Department of Urology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
5
Department of Endocrinology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
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Department of Oncology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
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Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK
8
Wellcome Sanger Institute, Hinxton CB10 1RQ, UK
9
Department of Pathology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Simone Maurea
Cancers 2022, 14(2), 335; https://doi.org/10.3390/cancers14020335
Received: 15 November 2021 / Revised: 4 January 2022 / Accepted: 6 January 2022 / Published: 11 January 2022
(This article belongs to the Special Issue Imaging Cancer Metabolism)
We evaluated renal cancer with varying aggressive appearances on histology, using an emerging form of non-invasive metabolic MRI. This imaging technique assesses the uptake and metabolism of a breakdown product of glucose (pyruvate) labelled with hyperpolarized carbon-13. We show that pyruvate metabolism is dependent on the aggressiveness of an individual tumor and we provide a mechanism for this finding from tissue analysis of molecules influencing pyruvate metabolism, suggesting a role for its membrane transporter.
Differentiating aggressive clear cell renal cell carcinoma (ccRCC) from indolent lesions is challenging using conventional imaging. This work prospectively compared the metabolic imaging phenotype of renal tumors using carbon-13 MRI following injection of hyperpolarized [1-13C]pyruvate (HP-13C-MRI) and validated these findings with histopathology. Nine patients with treatment-naïve renal tumors (6 ccRCCs, 1 liposarcoma, 1 pheochromocytoma, 1 oncocytoma) underwent pre-operative HP-13C-MRI and conventional proton (1H) MRI. Multi-regional tissue samples were collected using patient-specific 3D-printed tumor molds for spatial registration between imaging and molecular analysis. The apparent exchange rate constant (kPL) between 13C-pyruvate and 13C-lactate was calculated. Immunohistochemistry for the pyruvate transporter (MCT1) from 44 multi-regional samples, as well as associations between MCT1 expression and outcome in the TCGA-KIRC dataset, were investigated. Increasing kPL in ccRCC was correlated with increasing overall tumor grade (ρ = 0.92, p = 0.009) and MCT1 expression (r = 0.89, p = 0.016), with similar results acquired from the multi-regional analysis. Conventional 1H-MRI parameters did not discriminate tumor grades. The correlation between MCT1 and ccRCC grade was confirmed within a TCGA dataset (p < 0.001), where MCT1 expression was a predictor of overall and disease-free survival. In conclusion, metabolic imaging using HP-13C-MRI differentiates tumor aggressiveness in ccRCC and correlates with the expression of MCT1, a predictor of survival. HP-13C-MRI may non-invasively characterize metabolic phenotypes within renal cancer. View Full-Text
Keywords: cancer metabolism; hyperpolarized 13C magnetic resonance imaging; monocarboxylate transporter; renal cell carcinoma cancer metabolism; hyperpolarized 13C magnetic resonance imaging; monocarboxylate transporter; renal cell carcinoma
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MDPI and ACS Style

Ursprung, S.; Woitek, R.; McLean, M.A.; Priest, A.N.; Crispin-Ortuzar, M.; Brodie, C.R.; Gill, A.B.; Gehrung, M.; Beer, L.; Riddick, A.C.P.; Field-Rayner, J.; Grist, J.T.; Deen, S.S.; Riemer, F.; Kaggie, J.D.; Zaccagna, F.; Duarte, J.A.G.; Locke, M.J.; Frary, A.; Aho, T.F.; Armitage, J.N.; Casey, R.; Mendichovszky, I.A.; Welsh, S.J.; Barrett, T.; Graves, M.J.; Eisen, T.; Mitchell, T.J.; Warren, A.Y.; Brindle, K.M.; Sala, E.; Stewart, G.D.; Gallagher, F.A. Hyperpolarized 13C-Pyruvate Metabolism as a Surrogate for Tumor Grade and Poor Outcome in Renal Cell Carcinoma—A Proof of Principle Study. Cancers 2022, 14, 335. https://doi.org/10.3390/cancers14020335

AMA Style

Ursprung S, Woitek R, McLean MA, Priest AN, Crispin-Ortuzar M, Brodie CR, Gill AB, Gehrung M, Beer L, Riddick ACP, Field-Rayner J, Grist JT, Deen SS, Riemer F, Kaggie JD, Zaccagna F, Duarte JAG, Locke MJ, Frary A, Aho TF, Armitage JN, Casey R, Mendichovszky IA, Welsh SJ, Barrett T, Graves MJ, Eisen T, Mitchell TJ, Warren AY, Brindle KM, Sala E, Stewart GD, Gallagher FA. Hyperpolarized 13C-Pyruvate Metabolism as a Surrogate for Tumor Grade and Poor Outcome in Renal Cell Carcinoma—A Proof of Principle Study. Cancers. 2022; 14(2):335. https://doi.org/10.3390/cancers14020335

Chicago/Turabian Style

Ursprung, Stephan, Ramona Woitek, Mary A. McLean, Andrew N. Priest, Mireia Crispin-Ortuzar, Cara R. Brodie, Andrew B. Gill, Marcel Gehrung, Lucian Beer, Antony C.P. Riddick, Johanna Field-Rayner, James T. Grist, Surrin S. Deen, Frank Riemer, Joshua D. Kaggie, Fulvio Zaccagna, Joao A.G. Duarte, Matthew J. Locke, Amy Frary, Tevita F. Aho, James N. Armitage, Ruth Casey, Iosif A. Mendichovszky, Sarah J. Welsh, Tristan Barrett, Martin J. Graves, Tim Eisen, Thomas J. Mitchell, Anne Y. Warren, Kevin M. Brindle, Evis Sala, Grant D. Stewart, and Ferdia A. Gallagher. 2022. "Hyperpolarized 13C-Pyruvate Metabolism as a Surrogate for Tumor Grade and Poor Outcome in Renal Cell Carcinoma—A Proof of Principle Study" Cancers 14, no. 2: 335. https://doi.org/10.3390/cancers14020335

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