Common responses of tumors and wounds to hypoxia

Cancer Journal (United States)

Volumn 21, Issue 2, 2015, Pages 75-87

  Payen, Valéry L ^a   Brisson, Lucie ^a   Dewhirst, Mark W ^b   Sonveaux, Pierre ^a  

^a UNIVERSITY OF LOUVAIN MEDICAL SCHOOL   (Belgium)

^b DUKE UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

angiogenic switch; Cancer; glycolytic switch; hypoxia; hypoxia inducible factor 1 (HIF 1); lactate; monocarboxylate transporters (MCTs); Pasteur effect; tumor metabolism; Warburg effect; wound healing

Indexed keywords

HYPOXIA INDUCIBLE FACTOR 1; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LACTIC ACID; TRANSACTIVATOR PROTEIN; TRANSCRIPTION FACTOR;

ADAPTATION; ANGIOGENESIS; CANCER CELL; CANCER RESISTANCE; CELL SURVIVAL; CHEMOTHERAPY; CITRIC ACID CYCLE; FERMENTATION; GENE TARGETING; GLYCOLYSIS; HUMAN; HYPOXIA; HYPOXIC CELL; METABOLISM; NEOPLASM; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; RADIOTHERAPY; REVIEW; TUMOR MICROENVIRONMENT; WOUND; ANIMAL; ANOXIA; DRUG RESISTANCE; GENE EXPRESSION REGULATION; GENETICS; INJURY; NEOPLASMS; NEOVASCULARIZATION (PATHOLOGY); RADIATION DOSE;

ADAPTATION, BIOLOGICAL; ANIMALS; ANOXIA; CELL SURVIVAL; DRUG RESISTANCE, NEOPLASM; GENE EXPRESSION REGULATION, NEOPLASTIC; GLYCOLYSIS; HUMANS; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; RADIATION TOLERANCE; WOUNDS AND INJURIES;

EID: 84926646150     PISSN: 15289117     EISSN: 1540336X     Source Type: Journal    
DOI: 10.1097/PPO.0000000000000098     Document Type: Review

References (178)

1. Stock D, LeslieAG,Walker JE.Molecular architecture of the rotarymotor in ATP synthase. Science. 1999;286:1700-1705.
2. Hinkle PC. P/O ratios of mitochondrial oxidative phosphorylation. Biochim Biophys Acta. 2005;1706:1-11.
3. Wu R, Racker E. Regulatory mechanisms in carbohydrate metabolism. IV. Pasteur effect and Crabtree effect in ascites tumor cells. J Biol Chem. 1959;234:1036-1041.
4. Mazurek S. Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol. 2011; 43:969-980.
5. Kim JW, Tchernyshyov I, Semenza GL, et al. HIF-1-mediated expression of pyruvate dehydrogenase kinase: ametabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3:177-185.
6. Papandreou I, Cairns RA, Fontana L, et al. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006;3:187-197.
7. Mullen AR, Wheaton WW, Jin ES, et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature. 2012; 481:385-388.
8. Hensley CT,Wasti AT, DeBerardinis RJ. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J Clin Invest. 2013;123: 3678-3684.
9. Hanahan D,Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674.
10. Warburg O. On the origin of cancer cells. Science. 1956;123:309-314.
11. Moreno-Sanchez R, Rodriguez-Enriquez S, Marin-Hernandez A, et al. Energy metabolism in tumor cells. FEBS J. 2007;274:1393-1418.
12. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986;315: 1650-1659.
13. Braun RD, Lanzen JL, Snyder SA, et al. Comparison of tumor and normal tissue oxygen tension measurements using OxyLite or microelectrodes in rodents. Am J Physiol Heart Circ Physiol. 2001;280:H2533-H2544.
14. Tsai AG, Johnson PC, Intaglietta M. Oxygen gradients in the microcirculation. Physiol Rev. 2003;83:933-963.
15. Zhong Z, Arteel GE, Connor HD, et al. Cyclosporin A increases hypoxia and free radical production in rat kidneys: prevention by dietary glycine. Am J Physiol. 1998;275:F595-F604.
16. Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004;10:858-864.
17. Arteel GE, Thurman RG, Yates JM, et al. Evidence that hypoxia markers detect oxygen gradients in liver: pimonidazole and retrograde perfusion of rat liver. Br J Cancer. 1995;72:889-895.
18. Kobayashi H, Takizawa N. Oxygen saturation and pH changes in cremaster microvessels of the rat. Am J Physiol. 1996;270:H1453-H1461.
19. DewhirstMW, Cao Y,Moeller B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer. 2008;8: 425-437.
20. Dewhirst MW. Relationships between cycling hypoxia, HIF-1, angiogenesis and oxidative stress. Radiat Res. 2009;172:653-665.
21. James PE, Grinberg OY, SwartzHM. Superoxide production by phagocytosing macrophages in relation to the intracellular distribution of oxygen. J Leukoc Biol. 1998;64:78-84.
22. Clifford DP, Repine JE. Hydrogen peroxide mediated killing of bacteria. Mol Cell Biochem. 1982;49:143-149.
23. Johnston RB Jr, Kitagawa S, Edwards CK III, et al. The respiratory burst in activated macrophages: studies of its molecular basis and evidence for downregulation in chronic infection. Adv Exp Med Biol. 1988;23963-72.
24. BaggioliniM, Boulay F, Badwey JA, et al. Activation of neutrophil leukocytes: chemoattractant receptors and respiratory burst. FASEB J. 1993;7: 1004-1010.
25. Allen DB, Maguire JJ, Mahdavian M, et al. Wound hypoxia and acidosis limit neutrophil bacterial killing mechanisms. Arch Surg. 1997;132: 991-996.
26. Cho M, Hunt TK, Hussain MZ. Hydrogen peroxide stimulates macrophage vascular endothelial growth factor release. Am J Physiol Heart Circ Physiol. 2001;280:H2357-H2363.
27. Sen CK, Khanna S, Babior BM, et al. Oxidant-induced vascular endothelial growth factor expression in human keratinocytes and cutaneous wound healing. J Biol Chem. 2002;277:33284-33290.
28. Roy S, Khanna S, Nallu K, et al. Dermalwound healing is subject to redox control. Mol Ther. 2006;13:211-220.
29. Haroon ZA, Raleigh JA, Greenberg CS, et al. Early wound healing exhibits cytokine surge without evidence of hypoxia. Ann Surg. 2000;231: 137-147.
30. Gray LH, Conger AD, Ebert M, et al. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol. 1953;26:638-648.
31. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer. 2004;4:437-447.
32. Graven KK, Zimmerman LH, Dickson EW, et al. Endothelial cell hypoxia associated proteins are cell and stress specific. J Cell Physiol. 1993;157: 544-554.
33. Millar TM, Phan V, Tibbles LA. ROS generation in endothelial hypoxia and reoxygenation stimulates MAP kinase signaling and kinasedependent neutrophil recruitment. Free Radic Biol Med. 2007;42: 1165-1177.
34. Semenza GL. Molecular mechanisms mediating metastasis of hypoxic breast cancer cells. Trends Mol Med. 2012;18:534-543.
35. Epstein AC, Gleadle JM,McNeill LA, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001;107:43-54.
36. Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292:468-472.
37. Masson N,Willam C,Maxwell PH, et al. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J. 2001;20:5197-5206.
38. Yu F,White SB, ZhaoQ, et al. HIF-1alpha binding toVHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci U S A. 2001; 98:9630-9635.
39. Berra E, Benizri E, Ginouves A, et al. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J. 2003;22:4082-4090.
40. Berra E, Roux D, Richard DE, et al. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) escapes O(2)-driven proteasomal degradation irrespective of its subcellular localization: nucleus or cytoplasm. EMBO Rep. 2001; 2:615-620.
41. Kallio PJ, Wilson WJ, O'Brien S, et al. Regulation of the hypoxiainducible transcription factor 1alpha by the ubiquitin-proteasome pathway. J Biol Chem. 1999;274:6519-6525.
42. Hirsila M, Koivunen P, Gunzler V, et al. Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J Biol Chem. 2003;278:30772-30780.
43. Jiang BH, Semenza GL, Bauer C, et al. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol. 1996;271:C1172-C1180
44. Metzen E, Berchner-Pfannschmidt U, Stengel P, et al. Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing. J Cell Sci. 2003;116:1319-1326.
45. Stiehl DP, Wirthner R, Koditz J, et al. Increased prolyl 4-hydroxylase domain proteins compensate for decreased oxygen levels. Evidence for an autoregulatory oxygen-sensing system. J Biol Chem. 2006;281: 23482-23491.
46. Guzy RD, Hoyos B, Robin E, et al.Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab. 2005;1:401-408.
47. Wellen KE, Thompson CB. Cellular metabolic stress: considering how cells respond to nutrient excess. Mol Cell. 2010;40:323-332.
48. Chandel NS, Maltepe E, Goldwasser E, et al. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci U S A. 1998;95:11715-11720.
49. Chandel NS, McClintock DS, Feliciano CE, et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem. 2000;275:25130-25138.
50. Brunelle JK, Bell EL, Quesada NM, et al. Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. Cell Metab. 2005;1:409-414.
51. Mansfield KD, Guzy RD, Pan Y, et al. Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. Cell Metab. 2005;1:393-399.
52. Sun W, Zhou S, Chang SS, et al. Mitochondrial mutations contribute to HIF1alpha accumulation via increased reactive oxygen species and upregulated pyruvate dehydrogenase kinase 2 in head and neck squamous cell carcinoma. Clin Cancer Res. 2009;15:476-484.
53. Lu H, Forbes RA, Verma A. Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem. 2002;277:23111-23115.
54. Lu H, Dalgard CL, Mohyeldin A, et al. Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J Biol Chem. 2005;280:41928-41939.
55. Hewitson KS, Lienard BM, McDonoughMA, et al. Structural and mechanistic studies on the inhibition of the hypoxia-inducible transcription factor hydroxylases by tricarboxylic acid cycle intermediates. J Biol Chem. 2007;282:3293-3301.
56. de Saedeleer CJ, Copetti T, Porporato PE, et al. Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells. PLoS One. 2012;7:e46571.
57. Sonveaux P, Copetti T, de Saedeleer CJ, et al. Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS One. 2012;7:e33418.
58. Hewitson KS, McNeill LA, Riordan MV, et al. Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J Biol Chem. 2002;277: 26351-26355.
59. Lando D, Peet DJ, Gorman JJ, et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 2002;16:1466-1471.
60. Bento CF, Pereira P. Regulation of hypoxia-inducible factor 1 and the loss of the cellular response to hypoxia in diabetes. Diabetologia. 2011;54: 1946-1956.
61. Greer SN, Metcalf JL, Wang Y, et al. The updated biology of hypoxiainducible factor. EMBO J. 2012;31:2448-2460.
62. Kuschel A, Simon P, Tug S. Functional regulation of HIF-1alpha under normoxia-is there more than post-translational regulation? J Cell Physiol. 2012;227:514-524.
63. Yang Y, Sun M, Wang L, et al. HIFs, angiogenesis, and cancer. J Cell Biochem. 2013;114:967-974.
64. Gu YZ, Moran SM, Hogenesch JB, et al. Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha. Gene Expr. 1998;7:205-213.
65. Maxwell PH,WiesenerMS, Chang GW, et al. The tumour suppressor proteinVHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399:271-275.
66. Maynard MA, Qi H, Chung J, et al.Multiple splice variants of the human HIF-3 alpha locus are targets of the vonHippel-Lindau E3 ubiquitin ligase complex. J Biol Chem. 2003;278:11032-11040.
67. HeikkilaM, Pasanen A, Kivirikko KI, et al. Roles of the human hypoxiainducible factor (HIF)-3alpha variants in the hypoxia response. Cell Mol Life Sci. 2011;68:3885-3901.
68. Kunz M, Ibrahim SM. Molecular responses to hypoxia in tumor cells. Mol Cancer. 2003;223.
69. Gloire G, Legrand-Poels S, Piette J. NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol. 2006;72:1493-1505.
70. Cummins EP, Berra E, Comerford KM, et al. Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci U S A. 2006;103:18154-18159.
71. Yoshida T, Hashimura M, Mastumoto T, et al. Transcriptional upregulation of HIF-1alpha by NF-kappaB/p65 and its associations with betacatenin/ p300 complexes in endometrial carcinoma cells. Lab Invest. 2013;93:1184-1193.
72. Vegran F, Boidot R,Michiels C, et al. Lactate influx through the endothelial cell monocarboxylate transporterMCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 2011;71: 2550-2560.
73. Ausserer WA, Bourrat-Floeck B, Green CJ, et al. Regulation of c-jun expression during hypoxic and low-glucose stress. Mol Cell Biol. 1994;14: 5032-5042.
74. Yao KS, Xanthoudakis S, Curran T, et al. Activation of AP-1 and of a nuclear redox factor, Ref-1, in the response of HT29 colon cancer cells to hypoxia. Mol Cell Biol. 1994;14:5997-6003.
75. Bandyopadhyay RS, PhelanM, Faller DV. Hypoxia induces AP-1-regulated genes and AP-1 transcription factor binding in human endothelial and other cell types. Biochim Biophys Acta. 1995;1264:72-78.
76. Muller JM, Krauss B, Kaltschmidt C, et al. Hypoxia induces c-fos transcription via a mitogen-activated protein kinase-dependent pathway. J Biol Chem. 1997;272:23435-23439.
77. PremkumarDR,Mishra RR, Overholt JL, et al. L-type Ca(2+) channel activation regulates induction of c-fos transcription by hypoxia. JApplPhysiol. 2000;88:1898-1906.
78. Minet E, Michel G, Mottet D, et al. c-JUN gene induction and AP-1 activity is regulated by a JNK-dependent pathway in hypoxic HepG2 cells. Exp Cell Res. 2001;265:114-124.
79. Laderoute KR, Calaoagan JM, Gustafson-Brown C, et al. The response of c-jun/AP-1 to chronic hypoxia is hypoxia-inducible factor 1 alpha dependent. Mol Cell Biol. 2002;22:2515-2523.
80. Alfranca A, GutierrezMD, Vara A, et al. c-Jun and hypoxia-inducible factor 1 functionally cooperate in hypoxia-induced gene transcription. Mol Cell Biol. 2002;22:12-22.
81. Minet E, Ernest I, Michel G, et al. HIF1A gene transcription is dependent on a core promoter sequence encompassing activating and inhibiting sequences located upstream from the transcription initiation site and cis elements located within the 5 UTR. Biochem Biophys Res Commun. 1999;261:534-540.
82. Stein B, Baldwin AS Jr, Ballard DW, et al. Cross-coupling of the NFkappa B p65 and Fos/Jun transcription factors produces potentiated biological function. EMBO J. 1993;12:3879-3891.
83. Mathupala SP, Rempel A, Pedersen PL. Glucose catabolism in cancer cells: identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions. J Biol Chem. 2001;276:43407-43412.
84. Nakashima RA, Mangan PS, Colombini M, et al. Hexokinase receptor complex in hepatoma mitochondria: evidence from N,N-dicyclohexylcarbodiimide-labeling studies for the involvement of the pore-forming protein VDAC. Biochemistry. 1986;25: 1015-1021.
85. Pastorino JG, Shulga N, Hoek JB. Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis. J Biol Chem. 2002;277:7610-7618.
86. Minchenko A, Leshchinsky I, Opentanova I, et al. Hypoxia-inducible factor-1-mediated expression of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) gene. Its possible role in theWarburg effect. J Biol Chem. 2002;277:6183-6187.
87. Semenza GL, Roth PH, Fang HM, et al. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem. 1994;269:23757-23763.
88. Luo W, Hu H, Chang R, et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011;145:732-744.
89. Dang CV. The interplay between MYC and HIF in the Warburg effect. Ernst Schering Found Symp Proc. 2007;4:35-53.
90. Kluza J, Corazao-Rozas P, Touil Y, et al. Inactivation of the HIF-1alpha/ PDK3 signaling axis drives melanoma toward mitochondrial oxidative metabolism and potentiates the therapeutic activity of pro-oxidants. Cancer Res. 2012;72:5035-5047.
91. ThangarajuM, Carswell KN, Prasad PD, et al. Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/ HDAC3. Biochem J. 2009;417:379-389.
92. Dimmer KS, Friedrich B, Lang F, et al. The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem J. 2000;350:219-227.
93. Ullah MS, Davies AJ, Halestrap AP. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem. 2006;281:9030-9037.
94. Wykoff CC, Beasley NJ,Watson PH, et al. Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res. 2000;60:7075-7083.
95. Chiche J, Ilc K, Laferriere J, Trottier E, et al. Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res. 2009;69: 358-368.
96. Shimoda LA, Fallon M, Pisarcik S, et al. HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol. 2006;291: L941-L949.
97. Mo XG, Chen QW, Li XS, et al. Suppression of NHE1 by small interfering RNA inhibits HIF-1alpha-induced angiogenesis in vitro via modulation of calpain activity. Microvasc Res. 2011;81:160-168.
98. Kuwata F, Suzuki N, Otsuka K, et al. Enzymatic regulation of glycolysis and gluconeogenesis in rabbit periodontal ligament under various physiological pH conditions. J Nihon Univ Sch Dent. 1991;33:81-90.
99. PeakM, al-Habori M, Agius L. Regulation of glycogen synthesis and glycolysis by insulin, pH and cell volume. Interactions between swelling and alkalinization in mediating the effects of insulin. Biochem J. 1992;282: 797-805.
100. Matsuyama S, Llopis J, Deveraux QL, et al. Changes in intramitochondrial and cytosolic pH: early events that modulate caspase activation during apoptosis. Nat Cell Biol. 2000;2:318-325.
101. PrescottDM, Charles HC, Poulson JM, et al. The relationship between intracellular and extracellular pH in spontaneous canine tumors. Clin Cancer Res. 2000;6:2501-2505.
102. Lagadic-Gossmann D, Huc L, Lecureur V. Alterations of intracellular pH homeostasis in apoptosis: origins and roles. Cell DeathDiffer. 2004;11:953-961.
103. SjostrandM, Holmang A, Strindberg L, et al. Estimations of muscle interstitial insulin, glucose, and lactate in type 2 diabetic subjects. Am J Physiol Endocrinol Metab. 2000;279:E1097-E1103.
104. Hunt TK, Conolly WB, Aronson SB, et al. Anaerobic metabolism and wound healing: an hypothesis for the initiation and cessation of collagen synthesis in wounds. Am J Surg. 1978;135:328-332.
105. Jensen JA,Hunt TK, Scheuenstuhl H, et al. Effect of lactate, pyruvate, and pH on secretion of angiogenesis and mitogenesis factors by macrophages. Lab Invest. 1986;54:574-578.
106. Hunt TK, Aslam RS, Beckert S, et al. Aerobically derived lactate stimulates revascularization and tissue repair via redox mechanisms. Antioxid Redox Signal. 2007;9:1115-1124.
107. Walenta S, Salameh A, Lyng H, et al. Correlation of high lactate levels in head and neck tumors with incidence of metastasis. Am J Pathol. 1997; 150:409-415.
108. Walenta S, Snyder S, Haroon ZA, et al. Tissue gradients of energy metabolites mirror oxygen tension gradients in a rat mammary carcinoma model. Int J Radiat Oncol Biol Phys. 2001;51:840-848.
109. Walenta S, Schroeder T, Mueller-KlieserW. Lactate in solid malignant tumors: potential basis of a metabolic classification in clinical oncology. Curr Med Chem. 2004;11:2195-2204.
110. DeBerardinis RJ,Mancuso A, Daikhin E, et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A. 2007;104:19345-19350.
111. Sonveaux P, Vegran F, Schroeder T, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008;118: 3930-3942.
112. Halestrap AP, Meredith D. The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch. 2004;447:619-628.
113. Kennedy KM, Scarbrough PM, Ribeiro A, et al. Catabolismof exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer. PLoS One. 2013;8:e75154.
114. Tanaka M, Nakamura F, Mizokawa S, et al. Role of lactate in the brain energy metabolism: revealed by bioradiography. Neurosci Res. 2004; 48:13-20.
115. Leite TC, Coelho RG, Da SD, et al. Lactate downregulates the glycolytic enzymes hexokinase and phosphofructokinase in diverse tissues from mice. FEBS Lett. 2011;585:92-98.
116. PatelMS, Jomain-BaumM, Ballard FJ, et al. Pathway of carbon flow during fatty acid synthesis from lactate and pyruvate in rat adipose tissue. J Lipid Res. 1971;12:179-191.
117. Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J. 1999;343: 281-299.
118. Gladden LB. Lactate metabolism: a new paradigm for the third millennium. J Physiol. 2004;558:5-30.
119. Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, et al. Evidence for a stromal-epithelial "lactate shuttle" in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle. 2011;10:1772-1783.
120. Fiaschi T, Marini A, Giannoni E, et al. Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumorstroma interplay. Cancer Res. 2012;72:5130-5140.
121. Chiavarina B, Martinez-Outschoorn UE, Whitaker-Menezes D, et al.Metabolic reprogramming and two-compartment tumor metabolism: opposing role(s) of HIF1alpha and HIF2alpha in tumor-associated fibroblasts and human breast cancer cells. Cell Cycle. 2012;11:3280-3289.
122. Magistretti PJ, Pellerin L. Astrocytes couple synaptic activity to glucose utilization in the brain. News Physiol Sci. 1999;14:177-182.
123. Gerhardt H, Golding M, Fruttiger M, et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol. 2003;161: 1163-1177.
124. Coulon C, Georgiadou M, Roncal C, et al. From vessel sprouting to normalization: role of the prolyl hydroxylase domain protein/hypoxiainducible factor oxygen-sensing machinery. Arterioscler Thromb Vasc Biol. 2010;30:2331-2336.
125. Gupta GP, Massague J. Cancer metastasis: building a framework. Cell. 2006;127:679-695.
126. Pries AR, Hopfner M, le Noble F, et al. The shunt problem: control of functional shunting in normal and tumour vasculature. Nat Rev Cancer. 2010;10:587-593.
127. Secomb TW, Alberding JP, Hsu R, et al. Angiogenesis: an adaptive dynamic biological patterning problem. PLoS Comput Biol. 2013;9: e1002983.
128. Pries AR, Cornelissen AJ, Sloot AA, et al. Structural adaptation and heterogeneity of normal and tumor microvascular networks. PLoS Comput Biol. 2009;5:e1000394.
129. Olsson AK, Dimberg A, Kreuger J, et al. VEGF receptor signaling-in control of vascular function. Nat Rev Mol Cell Biol. 2006;7:359-371.
130. Forsythe JA, Jiang BH, Iyer NV, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996;16:4604-4613.
131. Nilsson I, Shibuya M, Wennstrom S. Differential activation of vascular genes by hypoxia in primary endothelial cells. Exp Cell Res. 2004;299: 476-485.
132. Calvani M, Rapisarda A, Uranchimeg B, et al. Hypoxic induction of an HIF-1alpha-dependent bFGFautocrine loop drives angiogenesis in human endothelial cells. Blood. 2006;107:2705-2712.
133. Shi YH, Bingle L, Gong LH, et al. Basic FGF augments hypoxia induced HIF-1-alpha expression and VEGF release in T47D breast cancer cells. Pathology. 2007;39:396-400.
134. Storti P, Bolzoni M, Donofrio G, et al. Hypoxia-inducible factor (HIF)-1alpha suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction. Leukemia. 2013;27: 1697-1706.
135. Himelstein BP, Koch CJ. Studies of type IVcollagenase regulation by hypoxia. Cancer Lett. 1998;124:127-133.
136. Ahn GO, Brown JM. Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. Cancer Cell. 2008;13:193-205.
137. Du R, Lu KV, Petritsch C, et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell. 2008;13:206-220.
138. Coulet F, Nadaud S, AgrapartM, et al. Identification of hypoxia-response element in the human endothelial nitric-oxide synthase gene promoter. J Biol Chem. 2003;278:46230-46240.
139. Milovanova TN, Bhopale VM, Sorokina EM, et al. Lactate stimulates vasculogenic stem cells via the thioredoxin system and engages an autocrine activation loop involving hypoxia-inducible factor 1. Mol Cell Biol. 2008;28:6248-6261.
140. Wu YY, Chen YL, Jao YC, et al. miR-320 regulates tumor angiogenesis driven by vascular endothelial cells in oral cancer by silencing neuropilin 1. Angiogenesis. 2014;17:247-260.
141. Damert A, Ikeda E, Risau W. Activator-protein-1 binding potentiates the hypoxia-induciblefactor-1-mediated hypoxia-induced transcriptional activation of vascular-endothelial growth factor expression in C6 glioma cells. Biochem J. 1997;327:419-423.
142. Strieter RM, Kunkel SL, Elner VM, et al. Interleukin-8. A corneal factor that induces neovascularization. Am J Pathol. 1992;141:1279-1284.
143. Kunz M, Hartmann A, Flory E, et al. Anoxia-induced up-regulation of interleukin-8 in human malignant melanoma. A potential mechanism for high tumor aggressiveness. Am J Pathol. 1999;155:753-763.
144. Shi Q, Le X, Abbruzzese JL, et al. Cooperation between transcription factor AP-1 and NF-kappaB in the induction of interleukin-8 in human pancreatic adenocarcinoma cells by hypoxia. J Interferon Cytokine Res. 1999; 19:1363-1371.
145. Waugh DJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res. 2008;14:6735-6741.
146. Constant JS, Feng JJ, Zabel DD, et al. Lactate elicits vascular endothelial growth factor frommacrophages: a possible alternative to hypoxia. Wound Repair Regen. 2000;8:353-360.
147. Burns PA, Wilson DJ. Angiogenesis mediated by metabolites is dependent on vascular endothelial growth factor (VEGF). Angiogenesis. 2003;6:73-77.
148. Beckert S, Farrahi F, Aslam RS, et al. Lactate stimulates endothelial cell migration. Wound Repair Regen. 2006;14:321-324.
149. Kumar VB, Viji RI, Kiran MS, et al. Endothelial cell response to lactate: implication of PAR modification of VEGF. J Cell Physiol. 2007;211:477-485.
150. Porporato PE, Payen VL, de Saedeleer CJ, et al. Lactate stimulates angiogenesis and accelerates the healing of superficial and ischemic wounds in mice. Angiogenesis. 2012;15:581-592.
151. Zabel DD, Feng JJ, Scheuenstuhl H, et al. Lactate stimulation of macrophage-derived angiogenic activity is associated with inhibition of poly(ADP-ribose) synthesis. Lab Invest. 1996;74:644-649.
152. Ghani QP, Wagner S, Becker HD, et al. Regulatory role of lactate in wound repair. Methods Enzymol. 2004;381:565-575.
153. Wagner S, Hussain MZ, Beckert S, et al. Lactate down-regulates cellular poly(ADP-ribose) formation in cultured human skin fibroblasts. Eur J Clin Invest. 2007;37:134-139.
154. Martin-Oliva D, Aguilar-Quesada R, O'valle F, et al. Inhibition of poly (ADP-ribose) polymerase modulates tumor-related gene expression, including hypoxia-inducible factor-1 activation, during skin carcinogenesis. Cancer Res. 2006;66:5744-5756.
155. Xiong M, Elson G, Legarda D, et al. Production of vascular endothelial growth factor by murine macrophages: regulation by hypoxia, lactate, and the inducible nitric oxide synthase pathway. Am J Pathol. 1998;153:587-598.
156. Comstock JP, Udenfriend S. Effect of lactate on collagen proline hydroxylase activity in cultured L-929 fibroblasts. Proc Natl Acad Sci U S A. 1970;66:552-557.
157. Hussain MZ, Ghani QP, Hunt TK. Inhibition of prolyl hydroxylase by poly(ADP-ribose) and phosphoribosyl-AMP. Possible role of ADPribosylation in intracellular prolyl hydroxylase regulation. J Biol Chem. 1989;264:7850-7855.
158. Murray B, Wilson DJ. A study of metabolites as intermediate effectors in angiogenesis. Angiogenesis. 2001;4:71-77.
159. Chereddy KK, Coco R, Memvanga PB, et al. Combined effect of PLGA and curcumin on wound healing activity. J Control Release. 2013;171: 208-215.
160. Aslan E, Adem S. In vitro effects of some flavones on human pyruvate kinase isoenzyme M2. J BiochemMol Toxicol. 2014;29:109-113.
161. Draoui N, Schicke O, Fernandes A, et al. Synthesis and pharmacological evaluation of carboxycoumarins as a new antitumor treatment targeting lactate transport in cancer cells. Bioorg Med Chem. 2013;21:7107-7117.
162. Draoui N, Schicke O, Seront E, et al. Antitumor activity of 7-aminocarboxycoumarin derivatives, a new class of potent inhibitors of lactate influx but not efflux. Mol Cancer Ther. 2014;13:1410-1418.
163. Polanski R, Hodgkinson CL, Fusi A, et al. Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clin Cancer Res. 2014;20:926-937.
164. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8:592-603.
165. Chereddy KK, Her CH, Comune M, et al. PLGA nanoparticles loaded with host defense peptide LL37 promote wound healing. J Control Release. 2014;194:C138-C147.
166. Chen C, Pore N, Behrooz A, et al. Regulation of glut1mRNA by hypoxiainducible factor-1. Interaction between H-ras and hypoxia. J Biol Chem. 2001;276:9519-9525.
167. Maxwell PH, Dachs GU, Gleadle JM, et al. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci U S A. 1997;94:8104-8109.
168. Luo F, Liu X, Yan N, et al. Hypoxia-inducible transcription factor-1alpha promotes hypoxia-induced A549 apoptosis via a mechanism that involves the glycolysis pathway. BMC Cancer. 2006;6:26.
169. Jean JC, Rich CB, Joyce-Brady M. Hypoxia results in an HIF-1-dependent induction of brain-specific aldolase C in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2006;291:L950-L956.
170. Gess B, Hofbauer KH, Deutzmann R, et al. Hypoxia up-regulates triosephosphate isomerase expression via a HIF-dependent pathway. Pflugers Arch. 2004;448:175-180.
171. Graven KK, Bellur D, Klahn BD, et al. HIF-2alpha regulates glyceraldehyde-3-phosphate dehydrogenase expression in endothelial cells. Biochim Biophys Acta. 2003;1626:10-18.
172. Pelletier J, Bellot G, Gounon P, et al. Glycogen synthesis is induced in hypoxia by the hypoxia-inducible factor and promotes cancer cell survival. Front Oncol. 2012;2:18.
173. Ma X,Wang X, Cao J, et al. Effect of proline analogues on activity of human prolyl hydroxylase and the regulation of HIF signal transduction pathway. PLoS One. 2014;9:e95692.
174. Firth JD, Ebert BL, Ratcliffe PJ. Hypoxic regulation of lactate dehydrogenase A. Interaction between hypoxia-inducible factor 1 and cAMP response elements. J Biol Chem. 1995;270:21021-21027.
175. Lu CW, Lin SC, Chen KF, et al. Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance. J Biol Chem. 2008;283:28106-28114.
176. Gerber HP, Condorelli F, Park J, et al. Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J Biol Chem. 1997;272: 23659-23667.
177. Camenisch G, Stroka DM, Gassmann M, et al. Attenuation of HIF-1 DNA-binding activity limits hypoxia-inducible endothelin-1 expression. Pflugers Arch. 2001;443:240-249.
178. Han ZB, Ren H, Zhao H, et al. Hypoxia-inducible factor (HIF)-1 alpha directly enhances the transcriptional activity of stem cell factor (SCF) in response to hypoxia and epidermal growth factor (EGF). Carcinogenesis. 2008;29:1853-1861.