PMID- 22428047
OWN - NLM
STAT- MEDLINE
DCOM- 20120820
LR  - 20220408
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 3
DP  - 2012
TI  - Targeting the lactate transporter MCT1 in endothelial cells inhibits 
      lactate-induced HIF-1 activation and tumor angiogenesis.
PG  - e33418
LID - 10.1371/journal.pone.0033418 [doi]
LID - e33418
AB  - 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.
FAU - Sonveaux, Pierre
AU  - Sonveaux P
AD  - Pole of Pharmacology, Institute of Experimental and Clinical Research, Universite 
      Catholique de Louvain, Brussels, Belgium. pierre.sonveaux@uclouvain.be
FAU - Copetti, Tamara
AU  - Copetti T
FAU - De Saedeleer, Christophe J
AU  - De Saedeleer CJ
FAU - Vegran, Frederique
AU  - Vegran F
FAU - Verrax, Julien
AU  - Verrax J
FAU - Kennedy, Kelly M
AU  - Kennedy KM
FAU - Moon, Eui Jung
AU  - Moon EJ
FAU - Dhup, Suveera
AU  - Dhup S
FAU - Danhier, Pierre
AU  - Danhier P
FAU - Frerart, Francoise
AU  - Frerart F
FAU - Gallez, Bernard
AU  - Gallez B
FAU - Ribeiro, Anthony
AU  - Ribeiro A
FAU - Michiels, Carine
AU  - Michiels C
FAU - Dewhirst, Mark W
AU  - Dewhirst MW
FAU - Feron, Olivier
AU  - Feron O
LA  - eng
GR  - P01 CA042745/CA/NCI NIH HHS/United States
GR  - CA40355-25/CA/NCI NIH HHS/United States
GR  - 243188/ERC_/European Research Council/International
GR  - CA40355-24/CA/NCI NIH HHS/United States
GR  - R01 CA040355/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120313
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Monocarboxylic Acid Transporters)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Symporters)
RN  - 0 (monocarboxylate transport protein 1)
RN  - 330E71H5Q4 (fibroblast growth factor 13)
RN  - 33X04XA5AT (Lactic Acid)
RN  - 62031-54-3 (Fibroblast Growth Factors)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
SB  - IM
MH  - Analysis of Variance
MH  - Animals
MH  - Blotting, Western
MH  - Cell Movement/physiology
MH  - Endothelial Cells/*metabolism/physiology
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Fibroblast Growth Factors/metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/*metabolism
MH  - Immunohistochemistry
MH  - Lactic Acid/*metabolism/pharmacology
MH  - Luciferases
MH  - Mice
MH  - Monocarboxylic Acid Transporters/*metabolism
MH  - Neoplasms/*blood supply
MH  - Neovascularization, Pathologic/*metabolism
MH  - Nuclear Magnetic Resonance, Biomolecular
MH  - Polymerase Chain Reaction
MH  - RNA Interference
MH  - RNA, Small Interfering/genetics
MH  - Symporters/*metabolism
MH  - Vascular Endothelial Growth Factor Receptor-2/metabolism
PMC - PMC3302812
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/03/20 06:00
MHDA- 2012/08/21 06:00
PMCR- 2012/03/13
CRDT- 2012/03/20 06:00
PHST- 2011/11/30 00:00 [received]
PHST- 2012/02/08 00:00 [accepted]
PHST- 2012/03/20 06:00 [entrez]
PHST- 2012/03/20 06:00 [pubmed]
PHST- 2012/08/21 06:00 [medline]
PHST- 2012/03/13 00:00 [pmc-release]
AID - PONE-D-11-24085 [pii]
AID - 10.1371/journal.pone.0033418 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(3):e33418. doi: 10.1371/journal.pone.0033418. Epub 2012 Mar 13.