The spatial organization of proton and lactate transport in a rat brain tumor

Emmanuelle Grillon, Régine Farion, Katell Fablet, Michel de Waard, Chung Ming Tse, Mark Donowitz, Chantal Rémy, Jonathan A. Coles

Research output: Contribution to journalArticle

Abstract

Tumors create a heterogeneous acidic microenvironment which assists their growth and which must be taken into account in the design of drugs and their delivery. In addition, the acidic extracellular pH (pHe) is itself exploited in several experimental techniques for drug delivery. The way the acidity is created is not clear. We report here the spatial organization of key proton-handling proteins in C6 gliomas in rat brain. The mean profiles across the tumor rim of the Na+/H+ exchanger NHE1, and the lactate-H+ cotransporter MCT1, both showed peaks. NHE1, which is important for extension and migration of cells in vitro, showed a peak 1.55 times higher than in extratumoural tissue at 0.33 mm from the edge. MCT1 had a broader peak, further into the tumor (maximum 1.76 fold at 1.0 mm from the edge). In contrast, MCT4 and the carbonic anhydrase CAIX, which are associated with hypoxia, were not significantly upregulated in the rim. The spatial distribution of MCT4 was highly correlated with that of CAIX, suggesting that their expression is regulated by the same factors. Since protons extruded by NHE1 diffuse away through extracellular clefts, NHE1 requires a continuous source of intracellular protons. From the stoichiometries of metabolic pathways that produce or consume H+, and the greater availability of glucose compared to oxygen in most parts of a tumor, we support the classic view that most of the net proton efflux from C6 gliomas originates in glycolytic formation of lactate and H+ inside the tumor, but add that some lactate is taken up into cells in the rim on MCT1, and some lactate diffuses away, leaving its associated protons available to re-enter cells for extrusion on NHE1. Therapeutic inhibition of NHE1, MCT1 or CAIX is predicted to affect different parts of a tumor.

Original languageEnglish (US)
Article numbere17416
JournalPLoS One
Volume6
Issue number2
DOIs
StatePublished - 2011

Fingerprint

Brain Neoplasms
protons
lactates
Protons
Rats
Tumors
Lactic Acid
Brain
brain
neoplasms
rats
Neoplasms
Glioma
drugs
Sodium-Hydrogen Antiporter
Carbonic Anhydrases
Drug Design
carbonate dehydratase
stoichiometry
Metabolic Networks and Pathways

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

The spatial organization of proton and lactate transport in a rat brain tumor. / Grillon, Emmanuelle; Farion, Régine; Fablet, Katell; de Waard, Michel; Tse, Chung Ming; Donowitz, Mark; Rémy, Chantal; Coles, Jonathan A.

In: PLoS One, Vol. 6, No. 2, e17416, 2011.

Research output: Contribution to journalArticle

Grillon, E, Farion, R, Fablet, K, de Waard, M, Tse, CM, Donowitz, M, Rémy, C & Coles, JA 2011, 'The spatial organization of proton and lactate transport in a rat brain tumor', PLoS One, vol. 6, no. 2, e17416. https://doi.org/10.1371/journal.pone.0017416
Grillon, Emmanuelle ; Farion, Régine ; Fablet, Katell ; de Waard, Michel ; Tse, Chung Ming ; Donowitz, Mark ; Rémy, Chantal ; Coles, Jonathan A. / The spatial organization of proton and lactate transport in a rat brain tumor. In: PLoS One. 2011 ; Vol. 6, No. 2.
@article{ff9104bf20c84fb293587b1baf9157d9,
title = "The spatial organization of proton and lactate transport in a rat brain tumor",
abstract = "Tumors create a heterogeneous acidic microenvironment which assists their growth and which must be taken into account in the design of drugs and their delivery. In addition, the acidic extracellular pH (pHe) is itself exploited in several experimental techniques for drug delivery. The way the acidity is created is not clear. We report here the spatial organization of key proton-handling proteins in C6 gliomas in rat brain. The mean profiles across the tumor rim of the Na+/H+ exchanger NHE1, and the lactate-H+ cotransporter MCT1, both showed peaks. NHE1, which is important for extension and migration of cells in vitro, showed a peak 1.55 times higher than in extratumoural tissue at 0.33 mm from the edge. MCT1 had a broader peak, further into the tumor (maximum 1.76 fold at 1.0 mm from the edge). In contrast, MCT4 and the carbonic anhydrase CAIX, which are associated with hypoxia, were not significantly upregulated in the rim. The spatial distribution of MCT4 was highly correlated with that of CAIX, suggesting that their expression is regulated by the same factors. Since protons extruded by NHE1 diffuse away through extracellular clefts, NHE1 requires a continuous source of intracellular protons. From the stoichiometries of metabolic pathways that produce or consume H+, and the greater availability of glucose compared to oxygen in most parts of a tumor, we support the classic view that most of the net proton efflux from C6 gliomas originates in glycolytic formation of lactate and H+ inside the tumor, but add that some lactate is taken up into cells in the rim on MCT1, and some lactate diffuses away, leaving its associated protons available to re-enter cells for extrusion on NHE1. Therapeutic inhibition of NHE1, MCT1 or CAIX is predicted to affect different parts of a tumor.",
author = "Emmanuelle Grillon and R{\'e}gine Farion and Katell Fablet and {de Waard}, Michel and Tse, {Chung Ming} and Mark Donowitz and Chantal R{\'e}my and Coles, {Jonathan A.}",
year = "2011",
doi = "10.1371/journal.pone.0017416",
language = "English (US)",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "2",

}

TY - JOUR

T1 - The spatial organization of proton and lactate transport in a rat brain tumor

AU - Grillon, Emmanuelle

AU - Farion, Régine

AU - Fablet, Katell

AU - de Waard, Michel

AU - Tse, Chung Ming

AU - Donowitz, Mark

AU - Rémy, Chantal

AU - Coles, Jonathan A.

PY - 2011

Y1 - 2011

N2 - Tumors create a heterogeneous acidic microenvironment which assists their growth and which must be taken into account in the design of drugs and their delivery. In addition, the acidic extracellular pH (pHe) is itself exploited in several experimental techniques for drug delivery. The way the acidity is created is not clear. We report here the spatial organization of key proton-handling proteins in C6 gliomas in rat brain. The mean profiles across the tumor rim of the Na+/H+ exchanger NHE1, and the lactate-H+ cotransporter MCT1, both showed peaks. NHE1, which is important for extension and migration of cells in vitro, showed a peak 1.55 times higher than in extratumoural tissue at 0.33 mm from the edge. MCT1 had a broader peak, further into the tumor (maximum 1.76 fold at 1.0 mm from the edge). In contrast, MCT4 and the carbonic anhydrase CAIX, which are associated with hypoxia, were not significantly upregulated in the rim. The spatial distribution of MCT4 was highly correlated with that of CAIX, suggesting that their expression is regulated by the same factors. Since protons extruded by NHE1 diffuse away through extracellular clefts, NHE1 requires a continuous source of intracellular protons. From the stoichiometries of metabolic pathways that produce or consume H+, and the greater availability of glucose compared to oxygen in most parts of a tumor, we support the classic view that most of the net proton efflux from C6 gliomas originates in glycolytic formation of lactate and H+ inside the tumor, but add that some lactate is taken up into cells in the rim on MCT1, and some lactate diffuses away, leaving its associated protons available to re-enter cells for extrusion on NHE1. Therapeutic inhibition of NHE1, MCT1 or CAIX is predicted to affect different parts of a tumor.

AB - Tumors create a heterogeneous acidic microenvironment which assists their growth and which must be taken into account in the design of drugs and their delivery. In addition, the acidic extracellular pH (pHe) is itself exploited in several experimental techniques for drug delivery. The way the acidity is created is not clear. We report here the spatial organization of key proton-handling proteins in C6 gliomas in rat brain. The mean profiles across the tumor rim of the Na+/H+ exchanger NHE1, and the lactate-H+ cotransporter MCT1, both showed peaks. NHE1, which is important for extension and migration of cells in vitro, showed a peak 1.55 times higher than in extratumoural tissue at 0.33 mm from the edge. MCT1 had a broader peak, further into the tumor (maximum 1.76 fold at 1.0 mm from the edge). In contrast, MCT4 and the carbonic anhydrase CAIX, which are associated with hypoxia, were not significantly upregulated in the rim. The spatial distribution of MCT4 was highly correlated with that of CAIX, suggesting that their expression is regulated by the same factors. Since protons extruded by NHE1 diffuse away through extracellular clefts, NHE1 requires a continuous source of intracellular protons. From the stoichiometries of metabolic pathways that produce or consume H+, and the greater availability of glucose compared to oxygen in most parts of a tumor, we support the classic view that most of the net proton efflux from C6 gliomas originates in glycolytic formation of lactate and H+ inside the tumor, but add that some lactate is taken up into cells in the rim on MCT1, and some lactate diffuses away, leaving its associated protons available to re-enter cells for extrusion on NHE1. Therapeutic inhibition of NHE1, MCT1 or CAIX is predicted to affect different parts of a tumor.

UR - http://www.scopus.com/inward/record.url?scp=79952084540&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952084540&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0017416

DO - 10.1371/journal.pone.0017416

M3 - Article

C2 - 21390324

AN - SCOPUS:79952084540

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 2

M1 - e17416

ER -