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

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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.

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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

References

  1. Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell 127:679–695

    Article  CAS  PubMed  Google Scholar 

  2. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  CAS  PubMed  Google Scholar 

  3. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  4. Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8:519–530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tennant DA, Duran RV, Gottlieb E (2010) Targeting metabolic transformation for cancer therapy. Nat Rev Cancer 10:267–277

    Article  CAS  PubMed  Google Scholar 

  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 2:49

    Article  PubMed  PubMed Central  Google Scholar 

  7. Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7:131–142

    Article  CAS  PubMed  Google Scholar 

  8. Tiwari N, Gheldof A, Tatari M, Christofori G (2012) EMT as the ultimate survival mechanism of cancer cells. Semin Cancer Biol 22:194–207

    Article  CAS  PubMed  Google Scholar 

  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 133:704–715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Frisch SM, Francis H (1994) Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 124:619–626

    Article  CAS  PubMed  Google Scholar 

  11. Paoli P, Giannoni E, Chiarugi P (2013) Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta 1833:3481–3498

    Article  CAS  PubMed  Google Scholar 

  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 321:1841–1844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 101:61–66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 126:669–683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 23:234–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nieto MA (2013) Epithelial plasticity: a common theme in embryonic and cancer cells. Science 342:1234850

  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 128:2527–2535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147:275–292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Vanharanta S, Massague J (2013) Origins of metastatic traits. Cancer Cell 24:410–421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49:6449–6465

    CAS  PubMed  Google Scholar 

  21. Griffiths JR (1991) Are cancer cells acidic? Br J Cancer 64:425–427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gerweck LE, Seetharaman K (1996) Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. Cancer Res 56:1194–1198

    CAS  PubMed  Google Scholar 

  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 1847:171–181

    Article  CAS  PubMed  Google Scholar 

  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 18:1319–1330

    Article  CAS  PubMed  Google Scholar 

  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 1848:2715–2726

    Article  PubMed  CAS  Google Scholar 

  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):219–227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 281:9030–9037

    Article  CAS  PubMed  Google Scholar 

  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 118:3930–3942

    CAS  PubMed  PubMed Central  Google Scholar 

  29. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7:11–20

    Article  CAS  PubMed  Google Scholar 

  30. Robergs RA, Ghiasvand F, Parker D (2004) Biochemistry of exercise-induced metabolic acidosis. Am J Physiol Regul Integr Comp Physiol 287:R502–R516

    Article  CAS  PubMed  Google Scholar 

  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 347:78–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Morita T, Nagaki T, Fukuda I, Okumura K (1992) Clastogenicity of low pH to various cultured mammalian cells. Mutat Res 268:297–305

    Article  CAS  PubMed  Google Scholar 

  33. Yuan J, Glazer PM (1998) Mutagenesis induced by the tumor microenvironment. Mutat Res 400:439–446

    Article  CAS  PubMed  Google Scholar 

  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 60:4372–4376

    CAS  PubMed  Google Scholar 

  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:540–546

    Article  CAS  PubMed  Google Scholar 

  36. Park HJ, Lyons JC, Ohtsubo T, Song CW (1999) Acidic environment causes apoptosis by increasing caspase activity. Br J Cancer 80:1892–1897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 18:3199–3204

    Article  CAS  PubMed  Google Scholar 

  38. Lardner A (2001) The effects of extracellular pH on immune function. J Leukoc Biol 69:522–530

    CAS  PubMed  Google Scholar 

  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 31:2829–2838

    Article  CAS  PubMed  Google Scholar 

  40. Wojtkowiak JW, Verduzco D, Schramm KJ, Gillies RJ (2011) Drug resistance and cellular adaptation to tumor acidic pH microenvironment. Mol Pharm 8:2032–2038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 267:37–48

    Article  CAS  PubMed  Google Scholar 

  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 34:236–251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Benej M, Pastorekova S, Pastorek J (2014) Carbonic anhydrase IX: regulation and role in cancer. Subcell Biochem 75:199–219

    Article  CAS  PubMed  Google Scholar 

  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 36:123–136

    Article  CAS  PubMed  Google Scholar 

  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 115:599–608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):3649–3662

    CAS  PubMed  Google Scholar 

  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 287:3392–3402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Denker SP, Barber DL (2002) Cell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1. J Cell Biol 159:1087–1096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 567:225–238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Riemann A, Schneider B, Gundel D, Stock C, Thews O, Gekle M (2014) Acidic priming enhances metastatic potential of cancer cells. Pflugers Arch 466:2127–2138

    Article  CAS  PubMed  Google Scholar 

  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 275:5361–5369

    Article  CAS  PubMed  Google Scholar 

  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 585:351–360

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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 124:1077–1087

    Article  CAS  PubMed  Google Scholar 

  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 269:189–193

    Article  CAS  PubMed  Google Scholar 

  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):273–278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 1:765–771

    CAS  PubMed  Google Scholar 

  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 1178:55–62

    Article  CAS  PubMed  Google Scholar 

  58. Rozhin J, Sameni M, Ziegler G, Sloane BF (1994) Pericellular pH affects distribution and secretion of cathepsin B in malignant cells. Cancer Res 54:6517–6525

    CAS  PubMed  Google Scholar 

  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 279:26991–27007

    Article  CAS  PubMed  Google Scholar 

  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 66:6699–6707

    Article  CAS  PubMed  Google Scholar 

  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 5:533–545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 10:737–753

    Article  CAS  PubMed  Google Scholar 

  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 123:1151–1159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 24:3903–3915

    Article  CAS  PubMed  Google Scholar 

  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 48:3688–3692

    CAS  PubMed  Google Scholar 

  66. Smith SM, Gottesman MM (1989) Activity and deletion analysis of recombinant human cathepsin L expressed in Escherichia coli. J Biol Chem 264:20487–20495

    CAS  PubMed  Google Scholar 

  67. Rowan AD, Mason P, Mach L, Mort JS (1992) Rat procathepsin B. Proteolytic processing to the mature form in vitro. J Biol Chem 267:15993–15999

    CAS  PubMed  Google Scholar 

  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 20:375–377

    Article  CAS  PubMed  Google Scholar 

  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 280:10938–10944

    Article  CAS  PubMed  Google Scholar 

  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 274:3171–3183

    Article  CAS  PubMed  Google Scholar 

  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 14:176–186

    Article  CAS  PubMed  Google Scholar 

  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 15:469–483

    Article  CAS  PubMed  Google Scholar 

  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 317:2031–2040

    Article  CAS  PubMed  Google Scholar 

  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 30:41–46

    Article  CAS  PubMed  Google Scholar 

  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 220:611–613

    Article  CAS  PubMed  Google Scholar 

  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 259:2283–2290

    CAS  PubMed  Google Scholar 

  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 15:19–25

    Article  CAS  PubMed  Google Scholar 

  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 97:2220–2224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 64:663–670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 25:411–425

    Article  CAS  PubMed  Google Scholar 

  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 90:1842–1849

    CAS  PubMed  PubMed Central  Google Scholar 

  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 8:754–766

    Article  CAS  PubMed  Google Scholar 

  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 21:81–94

    Article  CAS  PubMed  Google Scholar 

  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 5:3711–3721

    CAS  PubMed  Google Scholar 

  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 20:1023–1028

    Article  CAS  PubMed  Google Scholar 

  86. Xu L, Fidler IJ (2000) Acidic pH-induced elevation in interleukin 8 expression by human ovarian carcinoma cells. Cancer Res 60:4610–4616

    CAS  PubMed  Google Scholar 

  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 20:3751–3756

    Article  CAS  PubMed  Google Scholar 

  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 61:6020–6024

    CAS  PubMed  Google Scholar 

  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 277:11368–11374

    Article  CAS  PubMed  Google Scholar 

  90. Roberts WG, Palade GE (1995) Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 108(Pt 6):2369–2379

    CAS  PubMed  Google Scholar 

  91. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L (2006) VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol 7:359–371

    Article  CAS  PubMed  Google Scholar 

  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 153:557–562

    Article  CAS  PubMed  Google Scholar 

  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 270:9709–9716

    Article  CAS  PubMed  Google Scholar 

  94. Bar-Eli M (1999) Role of interleukin-8 in tumor growth and metastasis of human melanoma. Pathobiology 67:12–18

    Article  CAS  PubMed  Google Scholar 

  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 54:1896–1902

    Article  CAS  PubMed  Google Scholar 

  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 71:3364–3376

    Article  CAS  PubMed  Google Scholar 

  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 69:2260–2268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 28:841–849

    Article  CAS  Google Scholar 

  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-S1-004

  100. Bailey KM, Wojtkowiak JW, Cornnell HH, Ribeiro MC, Balagurunathan Y, Hashim AI, Gillies RJ (2014) Mechanisms of buffer therapy resistance. Neoplasia 16:354–364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 83:3302–3306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 266:13442–13448

    CAS  PubMed  Google Scholar 

  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 56:1902–1908

    CAS  PubMed  Google Scholar 

  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 34:62–71

    Article  CAS  PubMed  Google Scholar 

  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 86:1914–1919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Tsutsumi S, Yanagawa T, Shimura T, Kuwano H, Raz A (2004) Autocrine motility factor signaling enhances pancreatic cancer metastasis. Clin Cancer Res 10:7775–7784

    Article  CAS  PubMed  Google Scholar 

  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 84:513–522

    Article  CAS  PubMed  Google Scholar 

  108. Funasaka T, Yanagawa T, Hogan V, Raz A (2005) Regulation of phosphoglucose isomerase/autocrine motility factor expression by hypoxia. FASEB J 19:1422–1430

    Article  CAS  PubMed  Google Scholar 

  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 35:1117–1121

    Article  CAS  PubMed  Google Scholar 

  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 63:242–249

    CAS  PubMed  Google Scholar 

  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 74:2229–2237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 62:4484–4490

    CAS  PubMed  Google Scholar 

  113. Funasaka T, Hogan V, Raz A (2009) Phosphoglucose isomerase/autocrine motility factor mediates epithelial and mesenchymal phenotype conversions in breast cancer. Cancer Res 69:5349–5356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 71:3400–3409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 284:1116–1125

    Article  CAS  PubMed  Google Scholar 

  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 101:217–223

    Article  CAS  PubMed  Google Scholar 

  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 293:192–200

    Article  CAS  PubMed  Google Scholar 

  118. Filella X, Molina R, Jo J, Mas E, Ballesta AM (1991) Serum phosphohexose isomerase activities in patients with colorectal cancer. Tumour Biol 12:360–367

    Article  CAS  PubMed  Google Scholar 

  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 74:1855–1862

    Article  CAS  PubMed  Google Scholar 

  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 64:316–321

    Article  CAS  PubMed  Google Scholar 

  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 19:384–389

    Article  CAS  PubMed  Google Scholar 

  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 90:115–127

    Article  CAS  PubMed  Google Scholar 

  123. Beckner ME, Stracke ML, Liotta LA, Schiffmann E (1990) Glycolysis as primary energy source in tumor cell chemotaxis. J Natl Cancer Inst 82:1836–1840

    Article  CAS  PubMed  Google Scholar 

  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 461:109–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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:e53324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Payen VL, Brisson L, Dewhirst MW, Sonveaux P (2015) Common responses of tumors and wounds to hypoxia. Cancer J 21:75–87

    Article  CAS  PubMed  Google Scholar 

  127. Halestrap AP (2012) The monocarboxylate transporter family–Structure and functional characterization. IUBMB Life 64:1–9

    Article  CAS  PubMed  Google Scholar 

  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 104:19345–19350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 11:2195–2204

    Article  CAS  PubMed  Google Scholar 

  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 180:7175–7183

    Article  CAS  PubMed  Google Scholar 

  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 23:29–41

    Article  CAS  PubMed  Google Scholar 

  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 107:2013–2021

    Article  CAS  PubMed  Google Scholar 

  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 109:3812–3819

    Article  CAS  PubMed  Google Scholar 

  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 184:1200–1209

    Article  CAS  PubMed  Google Scholar 

  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 39:453–463

    CAS  PubMed  Google Scholar 

  136. Sattler UG, Hirschhaeusera F, Mueller-Klieser WF (2010) Manipulation of glycolysis in malignant tumors: fantasy or therapy? Curr Med Chem 17:96–108

    Article  CAS  PubMed  Google Scholar 

  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 150:409–415

    CAS  PubMed  PubMed Central  Google Scholar 

  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 51:349–353

    Article  CAS  PubMed  Google Scholar 

  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 129:321–326

    Article  PubMed  Google Scholar 

  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 55:4757–4759

    CAS  PubMed  Google Scholar 

  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 60:916–921

    CAS  PubMed  Google Scholar 

  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 276:24–31

    Article  CAS  PubMed  Google Scholar 

  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 11:368–380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 9:3506–3514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 10:1271–1286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 277:23111–23115

    Article  CAS  PubMed  Google Scholar 

  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 280:41928–41939

    Article  CAS  PubMed  Google Scholar 

  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 71:2550–2560

    Article  CAS  PubMed  Google Scholar 

  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:e46571

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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 15:581–592

    Article  CAS  PubMed  Google Scholar 

  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:e33418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Vegran F, Seront E, Sonveaux P, Feron O (2012) Lactate-induced IL-8 pathway in endothelial cells–response. Cancer Res 72:1903–1904

    Article  CAS  Google Scholar 

  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 60:6557–6562

    CAS  PubMed  Google Scholar 

  154. Lu X, Kang Y (2010) Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res 16:5928–5935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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:e75154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 67:4182–4189

    Article  CAS  PubMed  Google Scholar 

  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 102:1007–1013

    Article  CAS  PubMed  Google Scholar 

  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 33:4060–4068

    Article  PubMed  CAS  Google Scholar 

  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 342:150–158

    Article  CAS  PubMed  Google Scholar 

  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 2:831–838

    CAS  PubMed  PubMed Central  Google Scholar 

  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 3:25–30

    PubMed  PubMed Central  Google Scholar 

  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:e1000293

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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 99:520–528

    Article  CAS  PubMed  Google Scholar 

  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 27:2003–2009

    CAS  PubMed  Google Scholar 

  165. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 67:1472–1486

    Article  CAS  PubMed  Google Scholar 

  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 35:1833–1846

    Article  CAS  PubMed  Google Scholar 

  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 90:1127–1131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 77:1726–1731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 8:1284–1291

    CAS  PubMed  Google Scholar 

  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 16:857–866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 14:5209–5215

    CAS  PubMed  PubMed Central  Google Scholar 

  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 107:8788–8793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 137:104–115

    Article  CAS  PubMed  Google Scholar 

  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 15:300–308

    Article  CAS  PubMed  Google Scholar 

  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 452:230–233

    Article  CAS  PubMed  Google Scholar 

  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 463:364–368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Mazurek S (2011) Pyruvate kinase type M2: A key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol 43:969–980

    Article  CAS  PubMed  Google Scholar 

  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 334:1278–1283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 11:156–163

    Article  CAS  PubMed  Google Scholar 

  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 13:310–316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 36:6211–6221

    Article  CAS  PubMed  Google Scholar 

  183. Fan J, Ye J, Kamphorst JJ, Shlomi T, Thompson CB, Rabinowitz JD (2014) Quantitative flux analysis reveals folate-dependent NADPH production. Nature 510:298–302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 439:247–251

    Article  CAS  PubMed  Google Scholar 

  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 119:2733–2741

    Article  CAS  PubMed  Google Scholar 

  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 51:257–273

    CAS  PubMed  Google Scholar 

  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 94:578–585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 18:427–433

    Article  CAS  PubMed  Google Scholar 

  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 253:108–114

    Article  CAS  PubMed  Google Scholar 

  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 122:2422–2428

    Article  CAS  PubMed  Google Scholar 

  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 17:101–106

    Article  CAS  PubMed  Google Scholar 

  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 113:936–944

    Article  PubMed  Google Scholar 

  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:e25323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Mayer A, Von WA, Vaupel P (2010) Glucose metabolism of malignant cells is not regulated by transketolase-like (TKTL)-1. Int J Oncol 37:265–271

    Article  CAS  PubMed  Google Scholar 

  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 701:123–128

    Article  CAS  PubMed  Google Scholar 

  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 1:371–376

    Article  CAS  PubMed  Google Scholar 

  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 21:7107–7117

    Article  CAS  PubMed  Google Scholar 

  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 13:1410–1418

    Article  CAS  PubMed  Google Scholar 

  199. Lane AN, Fan TWM, Higashi RM (2009) Metabolic acidosis and the importance of balanced equations. Metabolomics 5:163–165

    Article  CAS  Google Scholar 

  200. Wichert M, Krall N (2015) Targeting carbonic anhydrase IX with small organic ligands. Curr Opin Chem Biol 26:48–54

    Article  CAS  PubMed  Google Scholar 

  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 32:693–710

    Article  CAS  PubMed  Google Scholar 

  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) 9:487–499

    Article  CAS  Google Scholar 

  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 282:4524–4532

    Article  CAS  PubMed  Google Scholar 

  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 26:1326–1338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 7:77–85

    Article  CAS  PubMed  Google Scholar 

  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 8:143–153

    Article  CAS  PubMed  Google Scholar 

  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 74:5301–5310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 6:24061–24074

    Article  PubMed  PubMed Central  Google Scholar 

  209. Lincet H, Icard P (2015) How do glycolytic enzymes favour cancer cell proliferation by nonmetabolic functions? Oncogene 34:3751–3759

    Article  CAS  PubMed  Google Scholar 

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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).

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    Authors and Affiliations

    1. Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Avenue Emmanuel Mounier 52, box B1.53.09, 1200, Brussels, Belgium

      Valéry L. Payen, Paolo E. Porporato, Bjorn Baselet & Pierre Sonveaux

    2. Radiobiology Unit, Belgian Nuclear Research Centre, SCK∙CEN, 2400, Mol, Belgium

      Bjorn Baselet

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    1. Valéry L. Payen
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    2. Paolo E. Porporato
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    3. Bjorn Baselet
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    4. Pierre Sonveaux
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    Correspondence to Pierre Sonveaux.

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    V. L. Payen and P. E. Porporato equally contributed to this manuscript.

    Submitted as a companion paper to “Porporato PE, Payen VL, Baselet B, Sonveaux P. Metabolic changes associated with tumor metastasis, part 2: mitochondria, lipid and amino acid metabolism.”

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    Payen, V.L., Porporato, P.E., Baselet, B. et al. Metabolic changes associated with tumor metastasis, part 1: tumor pH, glycolysis and the pentose phosphate pathway. Cell. Mol. Life Sci. 73, 1333–1348 (2016). https://doi.org/10.1007/s00018-015-2098-5

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    • DOI: https://doi.org/10.1007/s00018-015-2098-5

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