title: In vivo pH in metabolic-defective Ras-transformed fibroblast tumors: key role of the monocarboxylate transporter, MCT4, for inducing an alkaline intracellular pH.
abstract: We present an investigation of tumor pH regulation, designed to support a new anticancer therapy concept that we had previously proposed. Our study uses a tumor model of ras-transformed hamster fibroblasts, CCL39, xenografted in the thighs of nude mice. We demonstrate, for the first time, that genetic modifications of specific mechanisms of proton production and/or proton transport result in distinct, reproducible changes in intracellular and extracellular tumor pH that can be detected and quantified noninvasively in vivo, simultaneously with determinations of tumor energetic status and necrosis in the same experiment. The CCL39 variants used were deficient in the sodium/proton exchanger, NHE-1, and/or in the monocarboxylate transporter, MCT4; further, variants were deficient in glycolysis or respiration. MCT4 expression markedly increased the gradient between intracellular and extracellular pH from 0.14 to 0.43 when compared to CCL39 wild-type tumors not expressing MCT4. The other genetic modifications studied produced smaller but significant increases in intracellular and decreases in extracellular pH. In general, increased pH gradients were paralleled by increased tumor growth performance and diminished necrotic regions, and 50% of the CCL39 variant expressing neither MCT4 nor NHE-1, but possessing full genetic capacity for glycolysis and oxidative phosphorylation, underwent regression before reaching a 1-cm diameter. Except for CCL39 wild-type tumors, no significant HIF-1α expression was detected. Our in vivo results support a multipronged approach to tumor treatment based on minimizing intracellular pH by targeting several proton production and proton transport processes, among which the very efficient MCT4 proton/lactate co-transport deserves particular attention.
authors.affiliation: Institute of Developmental Biology and Cancer, CNRS UMR 6543, Centre Antoine Lacassagne, Université de Nice, France.
authors.forename: Johanna
authors.initials: J
authors.lastname: Chiche
authors.forename: Yann
authors.initials: Y
authors.lastname: Le Fur
authors.forename: Christophe
authors.initials: C
authors.lastname: Vilmen
authors.forename: Frédéric
authors.initials: F
authors.lastname: Frassineti
authors.forename: Laurent
authors.initials: L
authors.lastname: Daniel
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Halestrap
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Cozzone
authors.forename: Jacques
authors.initials: J
authors.lastname: Pouysségur
authors.forename: Norbert W
authors.initials: NW
authors.lastname: Lutz
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D006224:Cricetinae; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D011905:Genes, ras; D006019:Glycolysis / Q000235:genetics / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007474:Ion Exchange; D017136:Ion Transport / Q000235:genetics / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009336:Necrosis / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010743:Phospholipids / Q000235:genetics / Q000378:metabolism; D011522:Protons; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D010743:Phospholipids; D011522:Protons; C498648:Slc16a4 protein, mouse; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1