title: Inhibition of tumor lactate oxidation: consequences for the tumor microenvironment.
abstract: OBJECTIVE
  Tumor cells are recognized as being highly glycolytic. However, recently it was suggested that lactate produced in hypoxic tumor areas may be taken up by the monocarboxylate transporter MCT1 and oxidized in well-oxygenated tumor parts. Furthermore, it was shown that inhibition of lactate oxidation using the MCT1 inhibitor α-cyano-hydroxycinnamate (CHC) can radio-sensitize tumors possibly by forcing a switch from lactate oxidization to glycolysis in oxygenated cells, which in turn improves tumor oxygenation and indirectly kills radio-resistant hypoxic tumor cells from glucose starvation.
  
  
  METHODS
  To provide direct evidence for the existence of a targetable energetic symbiosis, mice bearing SiHa or FaDu(dd) tumors were treated with CHC for different time periods. One hour prior to sacrifice, mice were administered with the glucose analog fluorodeoxyglucose (FDG) and the hypoxia-marker pimonidazole. Tumor cryosections were analyzed for regional glucose retention (FDG autoradiograms), hypoxia (pimonidazole retention) and glucose and lactate levels (bioluminescence imaging).
  
  
  RESULTS
  Treatment did not influence metabolite concentrations, necrosis or extent of hypoxia, but pixel-by-pixel analysis comparing FDG retention and hypoxia (a measure of the apparent in vivo Pasteur effect) showed that CHC treatment caused a transient reduction in the Pasteur effect in FaDu(dd) 1.5 h following CHC administration whereas a reduction was only observed in SiHa following repeated treatments.
  
  
  CONCLUSIONS
  In summary, our data show that CHC is able to influence the intratumoral distribution of glucose use between hypoxic and non-hypoxic tumor areas. That is in accordance with a functional tumor lactate-shuttle, but the absence of any detectable changes in hypoxic extent and tissue metabolites was unexpected and warrants further investigation.
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark. morten@oncology.dk
authors.forename: Morten
authors.initials: M
authors.lastname: Busk
authors.forename: Stefan
authors.initials: S
authors.lastname: Walenta
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mueller-Klieser
authors.forename: Torben
authors.initials: T
authors.lastname: Steiniche
authors.forename: Steen
authors.initials: S
authors.lastname: Jakobsen
authors.forename: Michael Robert
authors.initials: MR
authors.lastname: Horsman
authors.forename: Jens
authors.initials: J
authors.lastname: Overgaard
mesh_terms: D000818:Animals; D001345:Autoradiography; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects*; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000494:pharmacology*; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology; D006258:Head and Neck Neoplasms / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007773:Lactates / Q000378:metabolism*; D016014:Linear Models; D008163:Luminescent Measurements; D051379:Mice; D008819:Mice, Nude; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors; D009593:Nitroimidazoles / Q000494:pharmacology; D010084:Oxidation-Reduction; D027981:Symporters / Q000037:antagonists & inhibitors; D059016:Tumor Microenvironment; D002583:Uterine Cervical Neoplasms / Q000378:metabolism; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D002934:Cinnamates; D019788:Fluorodeoxyglucose F18; D005947:Glucose; D007773:Lactates; D027501:Monocarboxylic Acid Transporters; D009593:Nitroimidazoles; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C018253:alpha-cyanocinnamate; C033815:pimonidazole