Cited by 541Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerLymphatic System and Diseases

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Targeting the Lactate Transporter MCT1 in Endothelial Cells Inhibits Lactate-Induced HIF-1 Activation and Tumor Angiogenesis

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Sonveaux, Pierre, Copetti, Tamara, De Saedeleer, Christophe J., Végran, Frédérique, Verrax, Julien, Kennedy, Kelly M., Moon, Eui Jung, Dhup, Suveera, Danhier, Pierre, Frérart, Françoise, Gallez, Bernard, Ribeiro, Anthony, Michiels, Carine, Dewhirst, Mark W., Feron, Olivier·2012·PLoS ONE

DOI 10.1371/journal.pone.0033418PMC PMC3302812

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Abstract

Switching to a glycolytic metabolism is a rapid adaptation of tumor cells to hypoxia. Although this metabolic conversion may primarily represent a rescue pathway to meet the bioenergetic and biosynthetic demands of proliferating tumor cells, it also creates a gradient of lactate that mirrors the gradient of oxygen in tumors. More than a metabolic waste, the lactate anion is known to participate to cancer aggressiveness, in part through activation of the hypoxia-inducible factor-1 (HIF-1) pathway in tumor cells. Whether lactate may also directly favor HIF-1 activation in endothelial cells (ECs) thereby offering a new druggable option to block angiogenesis is however an unanswered question. In this study, we therefore focused on the role in ECs of monocarboxylate transporter 1 (MCT1) that we previously identified to be the main facilitator of lactate uptake in cancer cells. We found that blockade of lactate influx into ECs led to inhibition of HIF-1-dependent angiogenesis. Our demonstration is based on the unprecedented characterization of lactate-induced HIF-1 activation in normoxic ECs and the consecutive increase in vascular endothelial growth factor receptor 2 (VEGFR2) and basic fibroblast growth factor (bFGF) expression. Furthermore, using a variety of functional assays including endothelial cell migration and tubulogenesis together with in vivo imaging of tumor angiogenesis through intravital microscopy and immunohistochemistry, we documented that MCT1 blockers could act as bona fide HIF-1 inhibitors leading to anti-angiogenic effects. Together with the previous demonstration of MCT1 being a key regulator of lactate exchange between tumor cells, the current study identifies MCT1 inhibition as a therapeutic modality combining antimetabolic and anti-angiogenic activities.

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Background
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Authors: Sonveaux, P., Copetti, T., De Saedeleer, C. J., Végran, F., Verrax, J., Kennedy, K. M., Moon, E. J., Dhup, S., Danhier, P., Frérart, F., Gallez, B., Ribeiro, A., Michiels, C., Dewhirst, M. W., & Feron, O.
Affiliations: Duke Medical Center (US)
UCLouvain (BE)
Duke University (US)
University of Namur (BE)
Corresponding author: Sonveaux, Pierre
ORCID: Sonveaux, Pierre
Végran, Frédérique
Moon, Eui Jung
Dhup, Suveera
Danhier, Pierre
Gallez, Bernard
Michiels, Carine
Dewhirst, Mark W.
Venue: PLoS ONE
Publisher: Public Library of Science (PLoS)
Published: 2012-03-13
Volume: 7
Issue: 3
Pages: e33418
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0033418
PMC: PMC3302812
OpenAlex: W2003842905
Cited by: 536
References: 67
Citations by year: 2026: 34 · 2025: 38 · 2024: 25 · 2023: 50 · 2022: 58 · 2021: 46 · 2020: 62 · 2019: 34 · 2018: 36 · 2017: 36 · 2016: 30 · 2015: 32 · 2014: 26 · 2013: 22 · 2012: 6
FWCI: 9.21
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: PLoS ONE (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DIAL (Catholic University of Leuven) (submittedVersion, other-oa)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Figshare (submittedVersion, cc-by)
Repository of the University of Namur (submittedVersion, other-oa)
Funders: Belgian American Educational Foundation
Fonds De La Recherche Scientifique - FNRS
National Institutes of Health (FP7/2007-2013, 5p01ca042745-23)
National Cancer Institute (CA40355, R01CA040355, CA40355-24, P01-CA042745, CA40355-25)
FP7 Ideas: European Research Council (243188)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
Keywords: MCT1, MCT1 inhibition, lactate transport, endothelial cells, tumor angiogenesis, tumor hypoxia, glycolytic metabolism, VEGFR2, basic fibroblast growth factor, anti-angiogenic therapy, tumor microenvironment
MeSH terms: Monocarboxylate Transport Protein 1, Analysis of Variance, Animals, Cell Movement, Enzyme-Linked Immunosorbent Assay, Fibroblast Growth Factors, Humans, Immunohistochemistry, Luciferases, Neoplasms, Neovascularization, Pathologic, Blotting, Western, Polymerase Chain Reaction, Lactic Acid, Nuclear Magnetic Resonance, Biomolecular, Monocarboxylic Acid Transporters, Symporters, RNA Interference, RNA, Small Interfering, Vascular Endothelial Growth Factor Receptor-2, Endothelial Cells, Mice, Hypoxia-Inducible Factor 1

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Targeting the Lactate Transporter MCT1 in Endothelial Cells Inhibits Lactate-Induced HIF-1 Activation and Tumor Angiogenesis

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