Hyperpolarized 13C pyruvate magnetic resonance spectroscopy for in vivo metabolic phenotyping of rat HCC

Abstract The in vivo assessment of tissue metabolism represents a novel strategy for the evaluation of oncologic disease. Hepatocellular carcinoma (HCC) is a high-prevalence, high-mortality tumor entity often discovered at a late stage. Recent evidence indicates that survival differences depend on m...

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Autores principales:	Elisabeth Bliemsrieder, Georgios Kaissis, Martin Grashei, Geoffrey Topping, Jennifer Altomonte, Christian Hundshammer, Fabian Lohöfer, Irina Heid, Dominik Keim, Selamawit Gebrekidan, Marija Trajkovic-Arsic, Aline Winkelkotte, Katja Steiger, Roman Nawroth, Jens Siveke, Markus Schwaiger, Marcus Makowski, Franz Schilling, Rickmer Braren
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e0a491a41dc04952be5b8e9b40040ec7
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spelling	oai:doaj.org-article:e0a491a41dc04952be5b8e9b40040ec72021-12-02T14:12:41ZHyperpolarized 13C pyruvate magnetic resonance spectroscopy for in vivo metabolic phenotyping of rat HCC10.1038/s41598-020-80952-42045-2322https://doaj.org/article/e0a491a41dc04952be5b8e9b40040ec72021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80952-4https://doaj.org/toc/2045-2322Abstract The in vivo assessment of tissue metabolism represents a novel strategy for the evaluation of oncologic disease. Hepatocellular carcinoma (HCC) is a high-prevalence, high-mortality tumor entity often discovered at a late stage. Recent evidence indicates that survival differences depend on metabolic alterations in tumor tissue, with particular focus on glucose metabolism and lactate production. Here, we present an in vivo imaging technique for metabolic tumor phenotyping in rat models of HCC. Endogenous HCC was induced in Wistar rats by oral diethyl-nitrosamine administration. Peak lactate-to-alanine signal ratios (L/A) were assessed with hyperpolarized magnetic resonance spectroscopic imaging (HPMRSI) after [1-13C]pyruvate injection. Cell lines were derived from a subset of primary tumors, re-implanted in nude rats, and assessed in vivo with dynamic hyperpolarized magnetic resonance spectroscopy (HPMRS) after [1-13C]pyruvate injection and kinetic modelling of pyruvate metabolism, taking into account systemic lactate production and recirculation. For ex vivo validation, enzyme activity and metabolite concentrations were spectroscopically quantified in cell and tumor tissue extracts. Mean peak L/A was higher in endogenous HCC compared to non-tumorous tissue. Dynamic HPMRS revealed higher pyruvate-to-lactate conversion rates (k pl ) and lactate signal in subcutaneous tumors derived from high L/A tumor cells, consistent with ex vivo measurements of higher lactate dehydrogenase (LDH) levels in these cells. In conclusion, HPMRS and HPMRSI reveal distinct tumor phenotypes corresponding to differences in glycolytic metabolism in HCC tumor tissue.Elisabeth BliemsriederGeorgios KaissisMartin GrasheiGeoffrey ToppingJennifer AltomonteChristian HundshammerFabian LohöferIrina HeidDominik KeimSelamawit GebrekidanMarija Trajkovic-ArsicAline WinkelkotteKatja SteigerRoman NawrothJens SivekeMarkus SchwaigerMarcus MakowskiFranz SchillingRickmer BrarenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Elisabeth Bliemsrieder Georgios Kaissis Martin Grashei Geoffrey Topping Jennifer Altomonte Christian Hundshammer Fabian Lohöfer Irina Heid Dominik Keim Selamawit Gebrekidan Marija Trajkovic-Arsic Aline Winkelkotte Katja Steiger Roman Nawroth Jens Siveke Markus Schwaiger Marcus Makowski Franz Schilling Rickmer Braren Hyperpolarized 13C pyruvate magnetic resonance spectroscopy for in vivo metabolic phenotyping of rat HCC
description	Abstract The in vivo assessment of tissue metabolism represents a novel strategy for the evaluation of oncologic disease. Hepatocellular carcinoma (HCC) is a high-prevalence, high-mortality tumor entity often discovered at a late stage. Recent evidence indicates that survival differences depend on metabolic alterations in tumor tissue, with particular focus on glucose metabolism and lactate production. Here, we present an in vivo imaging technique for metabolic tumor phenotyping in rat models of HCC. Endogenous HCC was induced in Wistar rats by oral diethyl-nitrosamine administration. Peak lactate-to-alanine signal ratios (L/A) were assessed with hyperpolarized magnetic resonance spectroscopic imaging (HPMRSI) after [1-13C]pyruvate injection. Cell lines were derived from a subset of primary tumors, re-implanted in nude rats, and assessed in vivo with dynamic hyperpolarized magnetic resonance spectroscopy (HPMRS) after [1-13C]pyruvate injection and kinetic modelling of pyruvate metabolism, taking into account systemic lactate production and recirculation. For ex vivo validation, enzyme activity and metabolite concentrations were spectroscopically quantified in cell and tumor tissue extracts. Mean peak L/A was higher in endogenous HCC compared to non-tumorous tissue. Dynamic HPMRS revealed higher pyruvate-to-lactate conversion rates (k pl ) and lactate signal in subcutaneous tumors derived from high L/A tumor cells, consistent with ex vivo measurements of higher lactate dehydrogenase (LDH) levels in these cells. In conclusion, HPMRS and HPMRSI reveal distinct tumor phenotypes corresponding to differences in glycolytic metabolism in HCC tumor tissue.
format	article
author	Elisabeth Bliemsrieder Georgios Kaissis Martin Grashei Geoffrey Topping Jennifer Altomonte Christian Hundshammer Fabian Lohöfer Irina Heid Dominik Keim Selamawit Gebrekidan Marija Trajkovic-Arsic Aline Winkelkotte Katja Steiger Roman Nawroth Jens Siveke Markus Schwaiger Marcus Makowski Franz Schilling Rickmer Braren
author_facet	Elisabeth Bliemsrieder Georgios Kaissis Martin Grashei Geoffrey Topping Jennifer Altomonte Christian Hundshammer Fabian Lohöfer Irina Heid Dominik Keim Selamawit Gebrekidan Marija Trajkovic-Arsic Aline Winkelkotte Katja Steiger Roman Nawroth Jens Siveke Markus Schwaiger Marcus Makowski Franz Schilling Rickmer Braren
author_sort	Elisabeth Bliemsrieder
title	Hyperpolarized 13C pyruvate magnetic resonance spectroscopy for in vivo metabolic phenotyping of rat HCC
title_short	Hyperpolarized 13C pyruvate magnetic resonance spectroscopy for in vivo metabolic phenotyping of rat HCC
title_full	Hyperpolarized 13C pyruvate magnetic resonance spectroscopy for in vivo metabolic phenotyping of rat HCC
title_fullStr	Hyperpolarized 13C pyruvate magnetic resonance spectroscopy for in vivo metabolic phenotyping of rat HCC
title_full_unstemmed	Hyperpolarized 13C pyruvate magnetic resonance spectroscopy for in vivo metabolic phenotyping of rat HCC
title_sort	hyperpolarized 13c pyruvate magnetic resonance spectroscopy for in vivo metabolic phenotyping of rat hcc
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e0a491a41dc04952be5b8e9b40040ec7
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Hyperpolarized 13C pyruvate magnetic resonance spectroscopy for in vivo metabolic phenotyping of rat HCC

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