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Cellular and Molecular Life Sciences

, Volume 73, Issue 7, pp 1333–1348 | Cite as

Metabolic changes associated with tumor metastasis, part 1: tumor pH, glycolysis and the pentose phosphate pathway

  • Valéry L. Payen
  • Paolo E. Porporato
  • Bjorn Baselet
  • Pierre Sonveaux
Review

Abstract

Metabolic adaptations are intimately associated with changes in cell behavior. Cancers are characterized by a high metabolic plasticity resulting from mutations and the selection of metabolic phenotypes conferring growth and invasive advantages. While metabolic plasticity allows cancer cells to cope with various microenvironmental situations that can be encountered in a primary tumor, there is increasing evidence that metabolism is also a major driver of cancer metastasis. Rather than a general switch promoting metastasis as a whole, a succession of metabolic adaptations is more likely needed to promote different steps of the metastatic process. This review addresses the contribution of pH, glycolysis and the pentose phosphate pathway, and a companion paper summarizes current knowledge regarding the contribution of mitochondria, lipids and amino acid metabolism. Extracellular acidification, intracellular alkalinization, the glycolytic enzyme phosphoglucose isomerase acting as an autocrine cytokine, lactate and the pentose phosphate pathway are emerging as important factors controlling cancer metastasis.

Keywords

Tumor metastasis Tumor pH Glycolysis Phosphoglucose isomerase (PGI) Lactate Pentose phosphate pathway (PPP) 

Abbreviations

6PGD

6-Phosphogluconate dehydrogenase

AE2

Anion exchanger 2

AMF

Autocrine motility factor = PGI

AP-1

Activator protein-1

CA

Carbonic anhydrase

CTC

Circulating tumor cell

ECM

Extracellular matrix

EMT

Epithelial-to-mesenchymal transition

ETC

Electron transport chain

HGF

Hepatocyte growth factor

HIF-1

Hypoxia-inducible factor-1

Hyal-2

Hyaluronidase 2

IL

Interleukin

LDH

Lactate dehydrogenase

MAPK

Mitogen-activated protein kinase

MCT

Monocarboxylate transporter

MIBG

Metaiodobenzylguanidine

MMP

Matrix metalloproteinase

MT1-MMP

Membrane-type 1 matrix metalloproteinase

NF-κB

Nuclear factor-κB

NHE

Sodium-proton exchanger

PGI

Phosphoglucose isomerase = AMF

PHD2

Prolyl-hydroxylase 2

pHe

Extracellular pH

pHi

Intracellular pH

PKM

Pyruvate kinase M

PPP

Pentose phosphate pathway

ROS

Reactive oxygen species

TKT

Transketolase

TKTL1

Transketolase-like 1

uPA

Urokinase

VEGF

Vascular endothelial growth factor

Notes

Acknowledgments

Work at the authors’ lab is supported by a Starting Grant from the European Research Council (ERC No. 243188 TUMETABO), Interuniversity Attraction Pole (IAP) grant #UP7-03 from the Belgian Science Policy Office (Belspo), an Action de Recherche Concertée from the Communauté Française de Belgique (ARC 14/19-058), the Belgian Fonds National de la Recherche Scientifique (F.R.S.-FNRS), the Télévie, the Belgian Fondation contre le Cancer (2012-186), the Belgian Federal Agency for Nuclear Control (FANC-AFCN), the Louvain Foundation and the UCL Fonds Spéciaux de la Recherche (FSR). Pierre Sonveaux is a F.R.S.-FNRS Research Associate, Paolo E. Porporato a F.R.S.-FNRS Postdoctoral Fellow and Valéry L. Payen a F.R.S.-FNRS PhD Fellow. Bjorn Baselet is a grantee of the Belgian Nuclear Research Center (SCK∙CEN).

References

  1. 1.
    Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell 127:679–695PubMedCrossRefGoogle Scholar
  2. 2.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70PubMedCrossRefGoogle Scholar
  3. 3.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674PubMedCrossRefGoogle Scholar
  4. 4.
    Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8:519–530PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Tennant DA, Duran RV, Gottlieb E (2010) Targeting metabolic transformation for cancer therapy. Nat Rev Cancer 10:267–277PubMedCrossRefGoogle Scholar
  6. 6.
    Porporato PE, Dhup S, Dadhich RK, Copetti T, Sonveaux P (2011) Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review. Front Pharmacol 2:49PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7:131–142PubMedCrossRefGoogle Scholar
  8. 8.
    Tiwari N, Gheldof A, Tatari M, Christofori G (2012) EMT as the ultimate survival mechanism of cancer cells. Semin Cancer Biol 22:194–207PubMedCrossRefGoogle Scholar
  9. 9.
    Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Frisch SM, Francis H (1994) Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 124:619–626PubMedCrossRefGoogle Scholar
  11. 11.
    Paoli P, Giannoni E, Chiarugi P (2013) Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta 1833:3481–3498PubMedCrossRefGoogle Scholar
  12. 12.
    Podsypanina K, Du YC, Jechlinger M, Beverly LJ, Hambardzumyan D, Varmus H (2008) Seeding and propagation of untransformed mouse mammary cells in the lung. Science 321:1841–1844PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Sieuwerts AM, Kraan J, Bolt J, van der Spoel P, Elstrodt F, Schutte M, Martens JW, Gratama JW, Sleijfer S, Foekens JA (2009) Anti-epithelial cell adhesion molecule antibodies and the detection of circulating normal-like breast tumor cells. J Natl Cancer Inst 101:61–66PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Lu J, Fan T, Zhao Q, Zeng W, Zaslavsky E, Chen JJ, Frohman MA, Golightly MG, Madajewicz S, Chen WT (2010) Isolation of circulating epithelial and tumor progenitor cells with an invasive phenotype from breast cancer patients. Int J Cancer 126:669–683PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Mimeault M, Batra SK (2014) Molecular biomarkers of cancer stem/progenitor cells associated with progression, metastases, and treatment resistance of aggressive cancers. Cancer Epidemiol Biomarkers Prev 23:234–254PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Nieto MA (2013) Epithelial plasticity: a common theme in embryonic and cancer cells. Science 342:1234850Google Scholar
  17. 17.
    Langley RR, Fidler IJ (2011) The seed and soil hypothesis revisited–the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer 128:2527–2535PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147:275–292PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Vanharanta S, Massague J (2013) Origins of metastatic traits. Cancer Cell 24:410–421PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49:6449–6465PubMedGoogle Scholar
  21. 21.
    Griffiths JR (1991) Are cancer cells acidic? Br J Cancer 64:425–427PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Gerweck LE, Seetharaman K (1996) Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. Cancer Res 56:1194–1198PubMedGoogle Scholar
  23. 23.
    Mookerjee SA, Goncalves RL, Gerencser AA, Nicholls DG, Brand MD (2015) The contributions of respiration and glycolysis to extracellular acid production. Biochim Biophys Acta 1847:171–181PubMedCrossRefGoogle Scholar
  24. 24.
    Dhup S, Dadhich RK, Porporato PE, Sonveaux P (2012) Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis. Curr Pharm Des 18:1319–1330PubMedCrossRefGoogle Scholar
  25. 25.
    Spugnini EP, Sonveaux P, Stock C, Perez-Sayans M, De MA, Avnet S, Garcia AG, Harguindey S, Fais S (2014) Proton channels and exchangers in cancer. Biochim Biophys Acta 1848:2715–2726PubMedCrossRefGoogle Scholar
  26. 26.
    Dimmer KS, Friedrich B, Lang F, Deitmer JW, Broer S (2000) The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem J 350(Pt 1):219–227PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Ullah MS, Davies AJ, Halestrap AP (2006) The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem 281:9030–9037PubMedCrossRefGoogle Scholar
  28. 28.
    Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, Feron O, Dewhirst MW (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118:3930–3942PubMedPubMedCentralGoogle Scholar
  29. 29.
    DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7:11–20PubMedCrossRefGoogle Scholar
  30. 30.
    Robergs RA, Ghiasvand F, Parker D (2004) Biochemistry of exercise-induced metabolic acidosis. Am J Physiol Regul Integr Comp Physiol 287:R502–R516PubMedCrossRefGoogle Scholar
  31. 31.
    Tomasetti C, Vogelstein B (2015) Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347:78–81PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Morita T, Nagaki T, Fukuda I, Okumura K (1992) Clastogenicity of low pH to various cultured mammalian cells. Mutat Res 268:297–305PubMedCrossRefGoogle Scholar
  33. 33.
    Yuan J, Glazer PM (1998) Mutagenesis induced by the tumor microenvironment. Mutat Res 400:439–446PubMedCrossRefGoogle Scholar
  34. 34.
    Yuan J, Narayanan L, Rockwell S, Glazer PM (2000) Diminished DNA repair and elevated mutagenesis in mammalian cells exposed to hypoxia and low pH. Cancer Res 60:4372–4376PubMedGoogle Scholar
  35. 35.
    Park HJ, Makepeace CM, Lyons JC, Song CW (1996) Effect of intracellular acidity and ionomycin on apoptosis in HL-60 cells. Eur J Cancer 32A:540–546PubMedCrossRefGoogle Scholar
  36. 36.
    Park HJ, Lyons JC, Ohtsubo T, Song CW (1999) Acidic environment causes apoptosis by increasing caspase activity. Br J Cancer 80:1892–1897PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Williams AC, Collard TJ, Paraskeva C (1999) An acidic environment leads to p53 dependent induction of apoptosis in human adenoma and carcinoma cell lines: implications for clonal selection during colorectal carcinogenesis. Oncogene 18:3199–3204PubMedCrossRefGoogle Scholar
  38. 38.
    Lardner A (2001) The effects of extracellular pH on immune function. J Leukoc Biol 69:522–530PubMedGoogle Scholar
  39. 39.
    Bosticardo M, Ariotti S, Losana G, Bernabei P, Forni G, Novelli F (2001) Biased activation of human T lymphocytes due to low extracellular pH is antagonized by B7/CD28 costimulation. Eur J Immunol 31:2829–2838PubMedCrossRefGoogle Scholar
  40. 40.
    Wojtkowiak JW, Verduzco D, Schramm KJ, Gillies RJ (2011) Drug resistance and cellular adaptation to tumor acidic pH microenvironment. Mol Pharm 8:2032–2038PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Chen KH, Tung PY, Wu JC, Chen Y, Chen PC, Huang SH, Wang SM (2008) An acidic extracellular pH induces Src kinase-dependent loss of beta-catenin from the adherens junction. Cancer Lett 267:37–48PubMedCrossRefGoogle Scholar
  42. 42.
    Donowitz M, Ming TC, Fuster D (2013) SLC9/NHE gene family, a plasma membrane and organellar family of Na(+)/H(+) exchangers. Mol Aspects Med 34:236–251PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Benej M, Pastorekova S, Pastorek J (2014) Carbonic anhydrase IX: regulation and role in cancer. Subcell Biochem 75:199–219PubMedCrossRefGoogle Scholar
  44. 44.
    Alper SL, Chernova MN, Stewart AK (2002) How pH regulates a pH regulator: a regulatory hot spot in the N-terminal cytoplasmic domain of the AE2 anion exchanger. Cell Biochem Biophys 36:123–136PubMedCrossRefGoogle Scholar
  45. 45.
    Klein M, Seeger P, Schuricht B, Alper SL, Schwab A (2000) Polarization of Na(+)/H(+) and Cl(-)/HCO (3)(-) exchangers in migrating renal epithelial cells. J Gen Physiol 115:599–608PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Lagana A, Vadnais J, Le PU, Nguyen TN, Laprade R, Nabi IR, Noel J (2000) Regulation of the formation of tumor cell pseudopodia by the Na(+)/H(+) exchanger NHE1. J Cell Sci 113(Pt 20):3649–3662PubMedGoogle Scholar
  47. 47.
    Svastova E, Witarski W, Csaderova L, Kosik I, Skvarkova L, Hulikova A, Zatovicova M, Barathova M, Kopacek J, Pastorek J, Pastorekova S (2012) Carbonic anhydrase IX interacts with bicarbonate transporters in lamellipodia and increases cell migration via its catalytic domain. J Biol Chem 287:3392–3402PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Denker SP, Barber DL (2002) Cell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1. J Cell Biol 159:1087–1096PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Stock C, Gassner B, Hauck CR, Arnold H, Mally S, Eble JA, Dieterich P, Schwab A (2005) Migration of human melanoma cells depends on extracellular pH and Na+/H+ exchange. J Physiol 567:225–238PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Riemann A, Schneider B, Gundel D, Stock C, Thews O, Gekle M (2014) Acidic priming enhances metastatic potential of cancer cells. Pflugers Arch 466:2127–2138PubMedCrossRefGoogle Scholar
  51. 51.
    Reshkin SJ, Bellizzi A, Albarani V, Guerra L, Tommasino M, Paradiso A, Casavola V (2000) Phosphoinositide 3-kinase is involved in the tumor-specific activation of human breast cancer cell Na(+)/H(+) exchange, motility, and invasion induced by serum deprivation. J Biol Chem 275:5361–5369PubMedCrossRefGoogle Scholar
  52. 52.
    Stuwe L, Muller M, Fabian A, Waning J, Mally S, Noel J, Schwab A, Stock C (2007) pH dependence of melanoma cell migration: protons extruded by NHE1 dominate protons of the bulk solution. J Physiol 585:351–360PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Shin HJ, Rho SB, Jung DC, Han IO, Oh ES, Kim JY (2011) Carbonic anhydrase IX (CA9) modulates tumor-associated cell migration and invasion. J Cell Sci 124:1077–1087PubMedCrossRefGoogle Scholar
  54. 54.
    Maciewicz RA, Wotton SF, Etherington DJ, Duance VC (1990) Susceptibility of the cartilage collagens types II, IX and XI to degradation by the cysteine proteinases, cathepsins B and L. FEBS Lett 269:189–193PubMedCrossRefGoogle Scholar
  55. 55.
    Buck MR, Karustis DG, Day NA, Honn KV, Sloane BF (1992) Degradation of extracellular-matrix proteins by human cathepsin B from normal and tumour tissues. Biochem J 282(Pt 1):273–278PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Ostad M, Weiss R, Droller M, Liu B (1992) Ha-ras oncogene induction of invasion and metastasis is associated with the activation and redistribution of protease(s) in rat-kidney cells. Int J Oncol 1:765–771PubMedGoogle Scholar
  57. 57.
    Kobayashi H, Moniwa N, Sugimura M, Shinohara H, Ohi H, Terao T (1993) Effects of membrane-associated cathepsin B on the activation of receptor-bound prourokinase and subsequent invasion of reconstituted basement membranes. Biochim Biophys Acta 1178:55–62PubMedCrossRefGoogle Scholar
  58. 58.
    Rozhin J, Sameni M, Ziegler G, Sloane BF (1994) Pericellular pH affects distribution and secretion of cathepsin B in malignant cells. Cancer Res 54:6517–6525PubMedGoogle Scholar
  59. 59.
    Bourguignon LY, Singleton PA, Diedrich F, Stern R, Gilad E (2004) CD44 interaction with Na + -H + exchanger (NHE1) creates acidic microenvironments leading to hyaluronidase-2 and cathepsin B activation and breast tumor cell invasion. J Biol Chem 279:26991–27007PubMedCrossRefGoogle Scholar
  60. 60.
    Rofstad EK, Mathiesen B, Kindem K, Galappathi K (2006) Acidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude mice. Cancer Res 66:6699–6707PubMedCrossRefGoogle Scholar
  61. 61.
    Glunde K, Guggino SE, Solaiyappan M, Pathak AP, Ichikawa Y, Bhujwalla ZM (2003) Extracellular acidification alters lysosomal trafficking in human breast cancer cells. Neoplasia 5:533–545PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Steffan JJ, Snider JL, Skalli O, Welbourne T, Cardelli JA (2009) Na+/H+ exchangers and RhoA regulate acidic extracellular pH-induced lysosome trafficking in prostate cancer cells. Traffic 10:737–753PubMedCrossRefGoogle Scholar
  63. 63.
    Steffan JJ, Williams BC, Welbourne T, Cardelli JA (2010) HGF-induced invasion by prostate tumor cells requires anterograde lysosome trafficking and activity of Na + -H + exchangers. J Cell Sci 123:1151–1159PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Busco G, Cardone RA, Greco MR, Bellizzi A, Colella M, Antelmi E, Mancini MT, Dell’Aquila ME, Casavola V, Paradiso A, Reshkin SJ (2010) NHE1 promotes invadopodial ECM proteolysis through acidification of the peri-invadopodial space. FASEB J 24:3903–3915PubMedCrossRefGoogle Scholar
  65. 65.
    Briozzo P, Morisset M, Capony F, Rougeot C, Rochefort H (1988) In vitro degradation of extracellular matrix with Mr 52,000 cathepsin D secreted by breast cancer cells. Cancer Res 48:3688–3692PubMedGoogle Scholar
  66. 66.
    Smith SM, Gottesman MM (1989) Activity and deletion analysis of recombinant human cathepsin L expressed in Escherichia coli. J Biol Chem 264:20487–20495PubMedGoogle Scholar
  67. 67.
    Rowan AD, Mason P, Mach L, Mort JS (1992) Rat procathepsin B. Proteolytic processing to the mature form in vitro. J Biol Chem 267:15993–15999PubMedGoogle Scholar
  68. 68.
    Kato Y, Ozono S, Shuin T, Miyazaki K (1996) Slow induction of gelatinase B mRNA by acidic culture conditions in mouse metastatic melanoma cells. Cell Biol Int 20:375–377PubMedCrossRefGoogle Scholar
  69. 69.
    Kato Y, Lambert CA, Colige AC, Mineur P, Noel A, Frankenne F, Foidart JM, Baba M, Hata R, Miyazaki K, Tsukuda M (2005) Acidic extracellular pH induces matrix metalloproteinase-9 expression in mouse metastatic melanoma cells through the phospholipase D-mitogen-activated protein kinase signaling. J Biol Chem 280:10938–10944PubMedCrossRefGoogle Scholar
  70. 70.
    Kato Y, Ozawa S, Tsukuda M, Kubota E, Miyazaki K, St Pierre Y, Hata R (2007) Acidic extracellular pH increases calcium influx-triggered phospholipase D activity along with acidic sphingomyelinase activation to induce matrix metalloproteinase-9 expression in mouse metastatic melanoma. FEBS J 274:3171–3183PubMedCrossRefGoogle Scholar
  71. 71.
    Martinez-Zaguilan R, Seftor EA, Seftor RE, Chu YW, Gillies RJ, Hendrix MJ (1996) Acidic pH enhances the invasive behavior of human melanoma cells. Clin Exp Metastasis 14:176–186PubMedCrossRefGoogle Scholar
  72. 72.
    Jang A, Hill RP (1997) An examination of the effects of hypoxia, acidosis, and glucose starvation on the expression of metastasis-associated genes in murine tumor cells. Clin Exp Metastasis 15:469–483PubMedCrossRefGoogle Scholar
  73. 73.
    Lin Y, Chang G, Wang J, Jin W, Wang L, Li H, Ma L, Li Q, Pang T (2011) NHE1 mediates MDA-MB-231 cells invasion through the regulation of MT1-MMP. Exp Cell Res 317:2031–2040PubMedCrossRefGoogle Scholar
  74. 74.
    Lin Y, Wang J, Jin W, Wang L, Li H, Ma L, Li Q, Pang T (2012) NHE1 mediates migration and invasion of HeLa cells via regulating the expression and localization of MT1-MMP. Cell Biochem Funct 30:41–46PubMedCrossRefGoogle Scholar
  75. 75.
    Nakajima M, Irimura T, Di FD, Di FN, Nicolson GL (1983) Heparan sulfate degradation: relation to tumor invasive and metastatic properties of mouse B16 melanoma sublines. Science 220:611–613PubMedCrossRefGoogle Scholar
  76. 76.
    Nakajima M, Irimura T, Di FN, Nicolson GL (1984) Metastatic melanoma cell heparanase. Characterization of heparan sulfate degradation fragments produced by B16 melanoma endoglucuronidase. J Biol Chem 259:2283–2290PubMedGoogle Scholar
  77. 77.
    Cuvier C, Jang A, Hill RP (1997) Exposure to hypoxia, glucose starvation and acidosis: effect on invasive capacity of murine tumor cells and correlation with cathepsin (L + B) secretion. Clin Exp Metastasis 15:19–25PubMedCrossRefGoogle Scholar
  78. 78.
    Parkkila S, Rajaniemi H, Parkkila AK, Kivela J, Waheed A, Pastorekova S, Pastorek J, Sly WS (2000) Carbonic anhydrase inhibitor suppresses invasion of renal cancer cells in vitro. Proc Natl Acad Sci U S A 97:2220–2224PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Schlappack OK, Zimmermann A, Hill RP (1991) Glucose starvation and acidosis: effect on experimental metastatic potential, DNA content and MTX resistance of murine tumour cells. Br J Cancer 64:663–670PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Moellering RE, Black KC, Krishnamurty C, Baggett BK, Stafford P, Rain M, Gatenby RA, Gillies RJ (2008) Acid treatment of melanoma cells selects for invasive phenotypes. Clin Exp Metastasis 25:411–425PubMedCrossRefGoogle Scholar
  81. 81.
    Kalliomaki T, Hill RP (2004) Effects of tumour acidification with glucose + MIBG on the spontaneous metastatic potential of two murine cell lines. Br J Cancer 90:1842–1849PubMedPubMedCentralGoogle Scholar
  82. 82.
    Porporato PE, Payen VL, Perez-Escuredo J, De Saedeleer CJ, Danhier P, Copetti T, Dhup S, Tardy M, Vazeille T, Bouzin C, Feron O, Michiels C, Gallez B, Sonveaux P (2014) A mitochondrial switch promotes tumor metastasis. Cell Rep 8:754–766PubMedCrossRefGoogle Scholar
  83. 83.
    Tan AS, Baty JW, Dong LF, Bezawork-Geleta A, Endaya B, Goodwin J, Bajzikova M, Kovarova J, Peterka M, Yan B, Pesdar EA, Sobol M, Filimonenko A, Stuart S, Vondrusova M, Kluckova K, Sachaphibulkij K, Rohlena J, Hozak P, Truksa J, Eccles D, Haupt LM, Griffiths LR, Neuzil J, Berridge MV (2015) Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metab 21:81–94PubMedCrossRefGoogle Scholar
  84. 84.
    Shi Q, Abbruzzese JL, Huang S, Fidler IJ, Xiong Q, Xie K (1999) Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic. Clin Cancer Res 5:3711–3721PubMedGoogle Scholar
  85. 85.
    Shi Q, Le X, Wang B, Xiong Q, Abbruzzese JL, Xie K (2000) Regulation of interleukin-8 expression by cellular pH in human pancreatic adenocarcinoma cells. J Interferon Cytokine Res 20:1023–1028PubMedCrossRefGoogle Scholar
  86. 86.
    Xu L, Fidler IJ (2000) Acidic pH-induced elevation in interleukin 8 expression by human ovarian carcinoma cells. Cancer Res 60:4610–4616PubMedGoogle Scholar
  87. 87.
    Shi Q, Le X, Wang B, Abbruzzese JL, Xiong Q, He Y, Xie K (2001) Regulation of vascular endothelial growth factor expression by acidosis in human cancer cells. Oncogene 20:3751–3756PubMedCrossRefGoogle Scholar
  88. 88.
    Fukumura D, Xu L, Chen Y, Gohongi T, Seed B, Jain RK (2001) Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res 61:6020–6024PubMedGoogle Scholar
  89. 89.
    Xu L, Fukumura D, Jain RK (2002) Acidic extracellular pH induces vascular endothelial growth factor (VEGF) in human glioblastoma cells via ERK1/2 MAPK signaling pathway: mechanism of low pH-induced VEGF. J Biol Chem 277:11368–11374PubMedCrossRefGoogle Scholar
  90. 90.
    Roberts WG, Palade GE (1995) Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 108(Pt 6):2369–2379PubMedGoogle Scholar
  91. 91.
    Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L (2006) VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol 7:359–371PubMedCrossRefGoogle Scholar
  92. 92.
    Unemori EN, Ferrara N, Bauer EA, Amento EP (1992) Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol 153:557–562PubMedCrossRefGoogle Scholar
  93. 93.
    Mandriota SJ, Seghezzi G, Vassalli JD, Ferrara N, Wasi S, Mazzieri R, Mignatti P, Pepper MS (1995) Vascular endothelial growth factor increases urokinase receptor expression in vascular endothelial cells. J Biol Chem 270:9709–9716PubMedCrossRefGoogle Scholar
  94. 94.
    Bar-Eli M (1999) Role of interleukin-8 in tumor growth and metastasis of human melanoma. Pathobiology 67:12–18PubMedCrossRefGoogle Scholar
  95. 95.
    Pacchiano F, Carta F, McDonald PC, Lou Y, Vullo D, Scozzafava A, Dedhar S, Supuran CT (2011) Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J Med Chem 54:1896–1902PubMedCrossRefGoogle Scholar
  96. 96.
    Lou Y, McDonald PC, Oloumi A, Chia S, Ostlund C, Ahmadi A, Kyle A, dem Auf KU, Leung S, Huntsman D, Clarke B, Sutherland BW, Waterhouse D, Bally M, Roskelley C, Overall CM, Minchinton A, Pacchiano F, Carta F, Scozzafava A, Touisni N, Winum JY, Supuran CT, Dedhar S (2011) Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res 71:3364–3376PubMedCrossRefGoogle Scholar
  97. 97.
    Robey IF, Baggett BK, Kirkpatrick ND, Roe DJ, Dosescu J, Sloane BF, Hashim AI, Morse DL, Raghunand N, Gatenby RA, Gillies RJ (2009) Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer Res 69:2260–2268PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Ibrahim HA, Cornnell HH, Coelho Ribeiro ML, Abrahams D, Cunningham J, Lloyd M, Martinez GV, Gatenby RA, Gillies RJ (2011) Reduction of metastasis using a non-volatile buffer. Clin Exp Metastasis 28:841–849CrossRefGoogle Scholar
  99. 99.
    Ibrahim-Hashim A, Wojtkowiak JW, de Lourdes Coelho RM, Estrella V, Bailey KM, Cornnell HH, Gatenby RA, Gillies RJ (2011) Free base lysine increases survival and reduces metastasis in prostate cancer model. J Cancer Sci Ther Suppl 1(4): JCST-S1-004Google Scholar
  100. 100.
    Bailey KM, Wojtkowiak JW, Cornnell HH, Ribeiro MC, Balagurunathan Y, Hashim AI, Gillies RJ (2014) Mechanisms of buffer therapy resistance. Neoplasia 16:354–364PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Liotta LA, Mandler R, Murano G, Katz DA, Gordon RK, Chiang PK, Schiffmann E (1986) Tumor cell autocrine motility factor. Proc Natl Acad Sci U S A 83:3302–3306PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Watanabe H, Carmi P, Hogan V, Raz T, Silletti S, Nabi IR, Raz A (1991) Purification of human tumor cell autocrine motility factor and molecular cloning of its receptor. J Biol Chem 266:13442–13448PubMedGoogle Scholar
  103. 103.
    Timar J, Trikha M, Szekeres K, Bazaz R, Tovari J, Silletti S, Raz A, Honn KV (1996) Autocrine motility factor signals integrin-mediated metastatic melanoma cell adhesion and invasion. Cancer Res 56:1902–1908PubMedGoogle Scholar
  104. 104.
    Torimura T, Ueno T, Kin M, Harada R, Nakamura T, Kawaguchi T, Harada M, Kumashiro R, Watanabe H, Avraham R, Sata M (2001) Autocrine motility factor enhances hepatoma cell invasion across the basement membrane through activation of beta1 integrins. Hepatology 34:62–71PubMedCrossRefGoogle Scholar
  105. 105.
    Niizeki H, Kobayashi M, Horiuchi I, Akakura N, Chen J, Wang J, Hamada JI, Seth P, Katoh H, Watanabe H, Raz A, Hosokawa M (2002) Hypoxia enhances the expression of autocrine motility factor and the motility of human pancreatic cancer cells. Br J Cancer 86:1914–1919PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Tsutsumi S, Yanagawa T, Shimura T, Kuwano H, Raz A (2004) Autocrine motility factor signaling enhances pancreatic cancer metastasis. Clin Cancer Res 10:7775–7784PubMedCrossRefGoogle Scholar
  107. 107.
    Yanagawa T, Watanabe H, Takeuchi T, Fujimoto S, Kurihara H, Takagishi K (2004) Overexpression of autocrine motility factor in metastatic tumor cells: possible association with augmented expression of KIF3A and GDI-beta. Lab Invest 84:513–522PubMedCrossRefGoogle Scholar
  108. 108.
    Funasaka T, Yanagawa T, Hogan V, Raz A (2005) Regulation of phosphoglucose isomerase/autocrine motility factor expression by hypoxia. FASEB J 19:1422–1430PubMedCrossRefGoogle Scholar
  109. 109.
    Tsutsumi S, Fukasawa T, Yamauchi H, Kato T, Kigure W, Morita H, Asao T, Kuwano H (2009) Phosphoglucose isomerase enhances colorectal cancer metastasis. Int J Oncol 35:1117–1121PubMedCrossRefGoogle Scholar
  110. 110.
    Tsutsumi S, Hogan V, Nabi IR, Raz A (2003) Overexpression of the autocrine motility factor/phosphoglucose isomerase induces transformation and survival of NIH-3T3 fibroblasts. Cancer Res 63:242–249PubMedGoogle Scholar
  111. 111.
    Kho DH, Zhang T, Balan V, Wang Y, Ha SW, Xie Y, Raz A (2014) Autocrine motility factor modulates EGF-mediated invasion signaling. Cancer Res 74:2229–2237PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Tsutsumi S, Gupta SK, Hogan V, Collard JG, Raz A (2002) Activation of small GTPase Rho is required for autocrine motility factor signaling. Cancer Res 62:4484–4490PubMedGoogle Scholar
  113. 113.
    Funasaka T, Hogan V, Raz A (2009) Phosphoglucose isomerase/autocrine motility factor mediates epithelial and mesenchymal phenotype conversions in breast cancer. Cancer Res 69:5349–5356PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Ahmad A, Aboukameel A, Kong D, Wang Z, Sethi S, Chen W, Sarkar FH, Raz A (2011) Phosphoglucose isomerase/autocrine motility factor mediates epithelial-mesenchymal transition regulated by miR-200 in breast cancer cells. Cancer Res 71:3400–3409PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Funasaka T, Haga A, Raz A, Nagase H (2001) Tumor autocrine motility factor is an angiogenic factor hat stimulates endothelial cell motility. Biochem Biophys Res Commun 284:1116–1125PubMedCrossRefGoogle Scholar
  116. 116.
    Funasaka T, Haga A, Raz A, Nagase H (2002) Autocrine motility factor secreted by tumor cells upregulates vascular endothelial growth factor receptor (Flt-1) expression in endothelial cells. Int J Cancer 101:217–223PubMedCrossRefGoogle Scholar
  117. 117.
    Funasaka T, Haga A, Raz A, Nagase H (2002) Tumor autocrine motility factor induces hyperpermeability of endothelial and mesothelial cells leading to accumulation of ascites fluid. Biochem Biophys Res Commun 293:192–200PubMedCrossRefGoogle Scholar
  118. 118.
    Filella X, Molina R, Jo J, Mas E, Ballesta AM (1991) Serum phosphohexose isomerase activities in patients with colorectal cancer. Tumour Biol 12:360–367PubMedCrossRefGoogle Scholar
  119. 119.
    Nakamori S, Watanabe H, Kameyama M, Imaoka S, Furukawa H, Ishikawa O, Sasaki Y, Kabuto T, Raz A (1994) Expression of autocrine motility factor receptor in colorectal cancer as a predictor for disease recurrence. Cancer 74:1855–1862PubMedCrossRefGoogle Scholar
  120. 120.
    Maruyama K, Watanabe H, Shiozaki H, Takayama T, Gofuku J, Yano H, Inoue M, Tamura S, Raz A, Monden M (1995) Expression of autocrine motility factor receptor in human esophageal squamous cell carcinoma. Int J Cancer 64:316–321PubMedCrossRefGoogle Scholar
  121. 121.
    Takanami I, Takeuchi K, Naruke M, Kodaira S, Tanaka F, Watanabe H, Raz A (1998) Autocrine motility factor in pulmonary adenocarcinomas: results of an immunohistochemical study. Tumour Biol 19:384–389PubMedCrossRefGoogle Scholar
  122. 122.
    Attanasio F, Caldieri G, Giacchetti G, van HR, Wieringa B, Buccione R (2011) Novel invadopodia components revealed by differential proteomic analysis. Eur J Cell Biol 90:115–127PubMedCrossRefGoogle Scholar
  123. 123.
    Beckner ME, Stracke ML, Liotta LA, Schiffmann E (1990) Glycolysis as primary energy source in tumor cell chemotaxis. J Natl Cancer Inst 82:1836–1840PubMedCrossRefGoogle Scholar
  124. 124.
    Schafer ZT, Grassian AR, Song L, Jiang Z, Gerhart-Hines Z, Irie HY, Gao S, Puigserver P, Brugge JS (2009) Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461:109–113PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Danhier P, Copetti T, De PG, Leveque P, Feron O, Jordan BF, Sonveaux P, Gallez B (2013) Influence of cell detachment on the respiration rate of tumor and endothelial cells. PLoS One 8:e53324PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Payen VL, Brisson L, Dewhirst MW, Sonveaux P (2015) Common responses of tumors and wounds to hypoxia. Cancer J 21:75–87PubMedCrossRefGoogle Scholar
  127. 127.
    Halestrap AP (2012) The monocarboxylate transporter family–Structure and functional characterization. IUBMB Life 64:1–9PubMedCrossRefGoogle Scholar
  128. 128.
    DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 104:19345–19350PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Walenta S, Schroeder T, Mueller-Klieser W (2004) Lactate in solid malignant tumors: potential basis of a metabolic classification in clinical oncology. Curr Med Chem 11:2195–2204PubMedCrossRefGoogle Scholar
  130. 130.
    Shime H, Yabu M, Akazawa T, Kodama K, Matsumoto M, Seya T, Inoue N (2008) Tumor-secreted lactic acid promotes IL-23/IL-17 proinflammatory pathway. J Immunol 180:7175–7183PubMedCrossRefGoogle Scholar
  131. 131.
    Yabu M, Shime H, Hara H, Saito T, Matsumoto M, Seya T, Akazawa T, Inoue N (2011) IL-23-dependent and -independent enhancement pathways of IL-17A production by lactic acid. Int Immunol 23:29–41PubMedCrossRefGoogle Scholar
  132. 132.
    Gottfried E, Kunz-Schughart LA, Ebner S, Mueller-Klieser W, Hoves S, Andreesen R, Mackensen A, Kreutz M (2006) Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 107:2013–2021PubMedCrossRefGoogle Scholar
  133. 133.
    Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwarz S, Rothe G, Hoves S, Renner K, Timischl B, Mackensen A, Kunz-Schughart L, Andreesen R, Krause SW, Kreutz M (2007) Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109:3812–3819PubMedCrossRefGoogle Scholar
  134. 134.
    Dietl K, Renner K, Dettmer K, Timischl B, Eberhart K, Dorn C, Hellerbrand C, Kastenberger M, Kunz-Schughart LA, Oefner PJ, Andreesen R, Gottfried E, Kreutz MP (2010) Lactic acid and acidification inhibit TNF secretion and glycolysis of human monocytes. J Immunol 184:1200–1209PubMedCrossRefGoogle Scholar
  135. 135.
    Goetze K, Walenta S, Ksiazkiewicz M, Kunz-Schughart LA, Mueller-Klieser W (2011) Lactate enhances motility of tumor cells and inhibits monocyte migration and cytokine release. Int J Oncol 39:453–463PubMedGoogle Scholar
  136. 136.
    Sattler UG, Hirschhaeusera F, Mueller-Klieser WF (2010) Manipulation of glycolysis in malignant tumors: fantasy or therapy? Curr Med Chem 17:96–108PubMedCrossRefGoogle Scholar
  137. 137.
    Walenta S, Salameh A, Lyng H, Evensen JF, Mitze M, Rofstad EK, Mueller-Klieser W (1997) Correlation of high lactate levels in head and neck tumors with incidence of metastasis. Am J Pathol 150:409–415PubMedPubMedCentralGoogle Scholar
  138. 138.
    Brizel DM, Schroeder T, Scher RL, Walenta S, Clough RW, Dewhirst MW, Mueller-Klieser W (2001) Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int J Radiat Oncol Biol Phys 51:349–353PubMedCrossRefGoogle Scholar
  139. 139.
    Walenta S, Chau TV, Schroeder T, Lehr HA, Kunz-Schughart LA, Fuerst A, Mueller-Klieser W (2003) Metabolic classification of human rectal adenocarcinomas: a novel guideline for clinical oncologists? J Cancer Res Clin Oncol 129:321–326PubMedCrossRefGoogle Scholar
  140. 140.
    Schwickert G, Walenta S, Sundfor K, Rofstad EK, Mueller-Klieser W (1995) Correlation of high lactate levels in human cervical cancer with incidence of metastasis. Cancer Res 55:4757–4759PubMedGoogle Scholar
  141. 141.
    Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfor K, Rofstad EK, Mueller-Klieser W (2000) High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res 60:916–921PubMedGoogle Scholar
  142. 142.
    Stern R, Shuster S, Neudecker BA, Formby B (2002) Lactate stimulates fibroblast expression of hyaluronan and CD44: the Warburg effect revisited. Exp Cell Res 276:24–31PubMedCrossRefGoogle Scholar
  143. 143.
    Baumann F, Leukel P, Doerfelt A, Beier CP, Dettmer K, Oefner PJ, Kastenberger M, Kreutz M, Nickl-Jockschat T, Bogdahn U, Bosserhoff AK, Hau P (2009) Lactate promotes glioma migration by TGF-beta2-dependent regulation of matrix metalloproteinase-2. Neuro Oncol 11:368–380PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Bonuccelli G, Tsirigos A, Whitaker-Menezes D, Pavlides S, Pestell RG, Chiavarina B, Frank PG, Flomenberg N, Howell A, Martinez-Outschoorn UE, Sotgia F, Lisanti MP (2010) Ketones and lactate “fuel” tumor growth and metastasis: evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell Cycle 9:3506–3514PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Martinez-Outschoorn UE, Prisco M, Ertel A, Tsirigos A, Lin Z, Pavlides S, Wang C, Flomenberg N, Knudsen ES, Howell A, Pestell RG, Sotgia F, Lisanti MP (2011) Ketones and lactate increase cancer cell “stemness,” driving recurrence, metastasis and poor clinical outcome in breast cancer: achieving personalized medicine via Metabolo-Genomics. Cell Cycle 10:1271–1286PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Lu H, Forbes RA, Verma A (2002) Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem 277:23111–23115PubMedCrossRefGoogle Scholar
  147. 147.
    Lu H, Dalgard CL, Mohyeldin A, McFate T, Tait AS, Verma A (2005) Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J Biol Chem 280:41928–41939PubMedCrossRefGoogle Scholar
  148. 148.
    Vegran F, Boidot R, Michiels C, Sonveaux P, Feron O (2011) Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesis. Cancer Res 71:2550–2560PubMedCrossRefGoogle Scholar
  149. 149.
    De Saedeleer CJ, Copetti T, Porporato PE, Verrax J, Feron O, Sonveaux P (2012) Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells. PLoS One 7:e46571PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Porporato PE, Payen VL, De Saedeleer CJ, Preat V, Thissen JP, Feron O, Sonveaux P (2012) Lactate stimulates angiogenesis and accelerates the healing of superficial and ischemic wounds in mice. Angiogenesis 15:581–592PubMedCrossRefGoogle Scholar
  151. 151.
    Sonveaux P, Copetti T, De Saedeleer CJ, Vegran F, Verrax J, Kennedy KM, Moon EJ, Dhup S, Danhier P, Frerart F, Gallez B, Ribeiro A, Michiels C, Dewhirst MW, Feron O (2012) Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS ONE 7:e33418PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Vegran F, Seront E, Sonveaux P, Feron O (2012) Lactate-induced IL-8 pathway in endothelial cells–response. Cancer Res 72:1903–1904CrossRefGoogle Scholar
  153. 153.
    Andela VB, Schwarz EM, Puzas JE, O’Keefe RJ, Rosier RN (2000) Tumor metastasis and the reciprocal regulation of prometastatic and antimetastatic factors by nuclear factor kappaB. Cancer Res 60:6557–6562PubMedGoogle Scholar
  154. 154.
    Lu X, Kang Y (2010) Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res 16:5928–5935PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Kennedy KM, Scarbrough PM, Ribeiro A, Richardson R, Yuan H, Sonveaux P, Landon CD, Chi JT, Pizzo S, Schroeder T, Dewhirst MW (2013) Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer. PLoS ONE 8:e75154PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Gallagher SM, Castorino JJ, Wang D, Philp NJ (2007) Monocarboxylate transporter 4 regulates maturation and trafficking of CD147 to the plasma membrane in the metastatic breast cancer cell line MDA-MB-231. Cancer Res 67:4182–4189PubMedCrossRefGoogle Scholar
  157. 157.
    Izumi H, Takahashi M, Uramoto H, Nakayama Y, Oyama T, Wang KY, Sasaguri Y, Nishizawa S, Kohno K (2011) Monocarboxylate transporters 1 and 4 are involved in the invasion activity of human lung cancer cells. Cancer Sci 102:1007–1013PubMedCrossRefGoogle Scholar
  158. 158.
    De Saedeleer CJ, Porporato PE, Copetti T, Perez-Escuredo J, Payen VL, Brisson L, Feron O, Sonveaux P (2014) Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration. Oncogene 33:4060–4068PubMedCrossRefGoogle Scholar
  159. 159.
    Zhao Z, Wu MS, Zou C, Tang Q, Lu J, Liu D, Wu Y, Yin J, Xie X, Shen J, Kang T, Wang J (2014) Downregulation of MCT1 inhibits tumor growth, metastasis and enhances chemotherapeutic efficacy in osteosarcoma through regulation of the NF-kappaB pathway. Cancer Lett 342:150–158PubMedCrossRefGoogle Scholar
  160. 160.
    Lee GH, Kim DS, Chung MJ, Chae SW, Kim HR, Chae HJ (2011) Lysyl oxidase-like-1 enhances lung metastasis when lactate accumulation and monocarboxylate transporter expression are involved. Oncol Lett 2:831–838PubMedPubMedCentralGoogle Scholar
  161. 161.
    Nakayama Y, Torigoe T, Inoue Y, Minagawa N, Izumi H, Kohno K, Yamaguchi K (2012) Prognostic significance of monocarboxylate transporter 4 expression in patients with colorectal cancer. Exp Ther Med 3:25–30PubMedPubMedCentralGoogle Scholar
  162. 162.
    Chen JL, Lucas JE, Schroeder T, Mori S, Wu J, Nevins J, Dewhirst M, West M, Chi JT (2008) The genomic analysis of lactic acidosis and acidosis response in human cancers. PLoS Genet 4:e1000293PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Kanekura T, Chen X, Kanzaki T (2002) Basigin (CD147) is expressed on melanoma cells and induces tumor cell invasion by stimulating production of matrix metalloproteinases by fibroblasts. Int J Cancer 99:520–528PubMedCrossRefGoogle Scholar
  164. 164.
    Pan Y, He B, Song G, Bao Q, Tang Z, Tian F, Wang S (2012) CD147 silencing via RNA interference reduces tumor cell invasion, metastasis and increases chemosensitivity in pancreatic cancer cells. Oncol Rep 27:2003–2009PubMedGoogle Scholar
  165. 165.
    Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Chen EI, Hewel J, Krueger JS, Tiraby C, Weber MR, Kralli A, Becker K, Yates JR III, Felding-Habermann B (2007) Adaptation of energy metabolism in breast cancer brain metastases. Cancer Res 67:1472–1486PubMedCrossRefGoogle Scholar
  167. 167.
    White NM, Newsted DW, Masui O, Romaschin AD, Siu KW, Yousef GM (2014) Identification and validation of dysregulated metabolic pathways in metastatic renal cell carcinoma. Tumour Biol 35:1833–1846PubMedCrossRefGoogle Scholar
  168. 168.
    Newell K, Franchi A, Pouyssegur J, Tannock I (1993) Studies with glycolysis-deficient cells suggest that production of lactic acid is not the only cause of tumor acidity. Proc Natl Acad Sci USA 90:1127–1131PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Yamagata M, Hasuda K, Stamato T, Tannock IF (1998) The contribution of lactic acid to acidification of tumours: studies of variant cells lacking lactate dehydrogenase. Br J Cancer 77:1726–1731PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Helmlinger G, Sckell A, Dellian M, Forbes NS, Jain RK (2002) Acid production in glycolysis-impaired tumors provides new insights into tumor metabolism. Clin Cancer Res 8:1284–1291PubMedGoogle Scholar
  171. 171.
    Sun W, Liu Y, Glazer CA, Shao C, Bhan S, Demokan S, Zhao M, Rudek MA, Ha PK, Califano JA (2010) TKTL1 is activated by promoter hypomethylation and contributes to head and neck squamous cell carcinoma carcinogenesis through increased aerobic glycolysis and HIF1alpha stabilization. Clin Cancer Res 16:857–866PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Pandolfi PP, Sonati F, Rivi R, Mason P, Grosveld F, Luzzatto L (1995) Targeted disruption of the housekeeping gene encoding glucose 6-phosphate dehydrogenase (G6PD): G6PD is dispensable for pentose synthesis but essential for defense against oxidative stress. EMBO J 14:5209–5215PubMedPubMedCentralGoogle Scholar
  173. 173.
    Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, Kalyanaraman B, Mutlu GM, Budinger GR, Chandel NS (2010) Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci U S A 107:8788–8793PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Ciou SC, Chou YT, Liu YL, Nieh YC, Lu JW, Huang SF, Chou YT, Cheng LH, Lo JF, Chen MJ, Yang MC, Yuh CH, Wang HD (2015) Ribose-5-phosphate isomerase A regulates hepatocarcinogenesis via PP2A and ERK signaling. Int J Cancer 137:104–115PubMedCrossRefGoogle Scholar
  175. 175.
    Mazurek S, Boschek CB, Hugo F, Eigenbrodt E (2005) Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin Cancer Biol 15:300–308PubMedCrossRefGoogle Scholar
  176. 176.
    Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC (2008) The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452:230–233PubMedCrossRefGoogle Scholar
  177. 177.
    David CJ, Chen M, Assanah M, Canoll P, Manley JL (2010) HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463:364–368PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Mazurek S (2011) Pyruvate kinase type M2: A key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol 43:969–980PubMedCrossRefGoogle Scholar
  179. 179.
    Anastasiou D, Poulogiannis G, Asara JM, Boxer MB, Jiang JK, Shen M, Bellinger G, Sasaki AT, Locasale JW, Auld DS, Thomas CJ, Vander Heiden MG, Cantley LC (2011) Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 334:1278–1283PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Peralta D, Bronowska AK, Morgan B, Doka E, Van LK, Nagy P, Grater F, Dick TP (2015) A proton relay enhances H2O2 sensitivity of GAPDH to facilitate metabolic adaptation. Nat Chem Biol 11:156–163PubMedCrossRefGoogle Scholar
  181. 181.
    Jiang P, Du W, Wang X, Mancuso A, Gao X, Wu M, Yang X (2011) p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol 13:310–316PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Wen D, Liu D, Tang J, Dong L, Liu Y, Tao Z, Wan J, Gao D, Wang L, Sun H, Fan J, Wu W (2015) Malic enzyme 1 induces epithelial-mesenchymal transition and indicates poor prognosis in hepatocellular carcinoma. Tumour Biol 36:6211–6221PubMedCrossRefGoogle Scholar
  183. 183.
    Fan J, Ye J, Kamphorst JJ, Shlomi T, Thompson CB, Rabinowitz JD (2014) Quantitative flux analysis reveals folate-dependent NADPH production. Nature 510:298–302PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Chan B, VanderLaan PA, Sukhatme VP (2013) 6-Phosphogluconate dehydrogenase regulates tumor cell migration in vitro by regulating receptor tyrosine kinase c-Met. Biochem Biophys Res Commun 439:247–251PubMedCrossRefGoogle Scholar
  185. 185.
    Ramos-Montoya A, Lee WN, Bassilian S, Lim S, Trebukhina RV, Kazhyna MV, Ciudad CJ, Noe V, Centelles JJ, Cascante M (2006) Pentose phosphate cycle oxidative and nonoxidative balance: a new vulnerable target for overcoming drug resistance in cancer. Int J Cancer 119:2733–2741PubMedCrossRefGoogle Scholar
  186. 186.
    Coy JF, Dressler D, Wilde J, Schubert P (2005) Mutations in the transketolase-like gene TKTL1: clinical implications for neurodegenerative diseases, diabetes and cancer. Clin Lab 51:257–273PubMedGoogle Scholar
  187. 187.
    Langbein S, Zerilli M, Zur HA, Staiger W, Rensch-Boschert K, Lukan N, Popa J, Ternullo MP, Steidler A, Weiss C, Grobholz R, Willeke F, Alken P, Stassi G, Schubert P, Coy JF (2006) Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted. Br J Cancer 94:578–585PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Hu LH, Yang JH, Zhang DT, Zhang S, Wang L, Cai PC, Zheng JF, Huang JS (2007) The TKTL1 gene influences total transketolase activity and cell proliferation in human colon cancer LoVo cells. Anticancer Drugs 18:427–433PubMedCrossRefGoogle Scholar
  189. 189.
    Zhang S, Yang JH, Guo CK, Cai PC (2007) Gene silencing of TKTL1 by RNAi inhibits cell proliferation in human hepatoma cells. Cancer Lett 253:108–114PubMedCrossRefGoogle Scholar
  190. 190.
    Langbein S, Frederiks WM, Zur HA, Popa J, Lehmann J, Weiss C, Alken P, Coy JF (2008) Metastasis is promoted by a bioenergetic switch: new targets for progressive renal cell cancer. Int J Cancer 122:2422–2428PubMedCrossRefGoogle Scholar
  191. 191.
    Krockenberger M, Honig A, Rieger L, Coy JF, Sutterlin M, Kapp M, Horn E, Dietl J, Kammerer U (2007) Transketolase-like 1 expression correlates with subtypes of ovarian cancer and the presence of distant metastases. Int J Gynecol Cancer 17:101–106PubMedCrossRefGoogle Scholar
  192. 192.
    Zerilli M, Amato MC, Martorana A, Cabibi D, Coy JF, Cappello F, Pompei G, Russo A, Giordano C, Rodolico V (2008) Increased expression of transketolase-like-1 in papillary thyroid carcinomas smaller than 1.5 cm in diameter is associated with lymph-node metastases. Cancer 113:936–944PubMedCrossRefGoogle Scholar
  193. 193.
    Diaz-Moralli S, Tarrado-Castellarnau M, Alenda C, Castells A, Cascante M (2011) Transketolase-like 1 expression is modulated during colorectal cancer progression and metastasis formation. PLoS One 6:e25323PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Mayer A, Von WA, Vaupel P (2010) Glucose metabolism of malignant cells is not regulated by transketolase-like (TKTL)-1. Int J Oncol 37:265–271PubMedCrossRefGoogle Scholar
  195. 195.
    Mayer A, Von WA, Vaupel P (2011) Evidence against a major role for TKTL-1 in hypoxic and normoxic cancer cells. Adv Exp Med Biol 701:123–128PubMedCrossRefGoogle Scholar
  196. 196.
    Murray CM, Hutchinson R, Bantick JR, Belfield GP, Benjamin AD, Brazma D, Bundick RV, Cook ID, Craggs RI, Edwards S, Evans LR, Harrison R, Holness E, Jackson AP, Jackson CG, Kingston LP, Perry MW, Ross AR, Rugman PA, Sidhu SS, Sullivan M, Taylor-Fishwick DA, Walker PC, Whitehead YM, Wilkinson DJ, Wright A, Donald DK (2005) Monocarboxylate transporter MCT1 is a target for immunosuppression. Nat Chem Biol 1:371–376PubMedCrossRefGoogle Scholar
  197. 197.
    Draoui N, Schicke O, Fernandes A, Drozak X, Nahra F, Dumont A, Douxfils J, Hermans E, Dogne JM, Corbau R, Marchand A, Chaltin P, Sonveaux P, Feron O, Riant O (2013) Synthesis and pharmacological evaluation of carboxycoumarins as a new antitumor treatment targeting lactate transport in cancer cells. Bioorg Med Chem 21:7107–7117PubMedCrossRefGoogle Scholar
  198. 198.
    Draoui N, Schicke O, Seront E, Bouzin C, Sonveaux P, Riant O, Feron O (2014) Antitumor activity of 7-aminocarboxycoumarin derivatives, a new class of potent inhibitors of lactate influx but not efflux. Mol Cancer Ther 13:1410–1418PubMedCrossRefGoogle Scholar
  199. 199.
    Lane AN, Fan TWM, Higashi RM (2009) Metabolic acidosis and the importance of balanced equations. Metabolomics 5:163–165CrossRefGoogle Scholar
  200. 200.
    Wichert M, Krall N (2015) Targeting carbonic anhydrase IX with small organic ligands. Curr Opin Chem Biol 26:48–54PubMedCrossRefGoogle Scholar
  201. 201.
    Liu J, Huang Y, Kumar A, Tan A, Jin S, Mozhi A, Liang XJ (2014) pH-sensitive nano-systems for drug delivery in cancer therapy. Biotechnol Adv 32:693–710PubMedCrossRefGoogle Scholar
  202. 202.
    Meng F, Zhong Y, Cheng R, Deng C, Zhong Z (2014) pH-sensitive polymeric nanoparticles for tumor-targeting doxorubicin delivery: concept and recent advances. Nanomedicine (Lond) 9:487–499CrossRefGoogle Scholar
  203. 203.
    Koivunen P, Hirsila M, Remes AM, Hassinen IE, Kivirikko KI, Myllyharju J (2007) Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J Biol Chem 282:4524–4532PubMedCrossRefGoogle Scholar
  204. 204.
    Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H, Liu L, Liu Y, Yang C, Xu Y, Zhao S, Ye D, Xiong Y, Guan KL (2012) Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev 26:1326–1338PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7:77–85PubMedCrossRefGoogle Scholar
  206. 206.
    Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Chung YL, Merino M, Trepel J, Zbar B, Toro J, Ratcliffe PJ, Linehan WM, Neckers L (2005) HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8:143–153PubMedCrossRefGoogle Scholar
  207. 207.
    Roland CL, Arumugam T, Deng D, Liu SH, Philip B, Gomez S, Burns WR, Ramachandran V, Wang H, Cruz-Monserrate Z, Logsdon CD (2014) Cell surface lactate receptor GPR81 is crucial for cancer cell survival. Cancer Res 74:5301–5310PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Giannoni E, Taddei ML, Morandi A, Comito G, Calvani M, Bianchini F, Richichi B, Raugei G, Wong N, Tang D, Chiarugi P (2015) Targeting stromal-induced pyruvate kinase M2 nuclear translocation impairs oxphos and prostate cancer metastatic spread. Oncotarget 6:24061–24074PubMedPubMedCentralCrossRefGoogle Scholar
  209. 209.
    Lincet H, Icard P (2015) How do glycolytic enzymes favour cancer cell proliferation by nonmetabolic functions? Oncogene 34:3751–3759PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing 2015

Authors and Affiliations

  • Valéry L. Payen
    • 1
  • Paolo E. Porporato
    • 1
  • Bjorn Baselet
    • 1
    • 2
  • Pierre Sonveaux
    • 1
  1. 1.Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC)Université catholique de Louvain (UCL)BrusselsBelgium
  2. 2.Radiobiology Unit, Belgian Nuclear Research Centre, SCK∙CENMolBelgium

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