Microenvironmental and cellular consequences of altered blood flow in tumours

British Journal of Radiology

Volumn 76, Issue SPEC. ISS. 1, 2003, Pages

  Raghunand, N ^a   Gatenby, R A ^a   Gillies, R J ^a  

^a UNIVERSITY OF ARIZONA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; AUTOCRINE MOTILITY FACTOR; DOXORUBICIN; FLUORODEOXYGLUCOSE F 18; FLUOROURACIL; GADOLINIUM TEXAPHYRIN; GLUCOSE; GLUCOSE TRANSPORTER 1; HYPOXIA INDUCIBLE FACTOR 1ALPHA; INTERLEUKIN 8; LACTIC ACID; MELPHALAN; MITOXANTRONE; OXYGEN; PRODRUG; PROTEINASE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE (PHOSPHATE) DEHYDROGENASE (QUINONE); TIRAPAZAMINE; UROKINASE; VASCULOTROPIN;

ACIDITY; ACIDOSIS; ANTINEOPLASTIC ACTIVITY; CANCER INVASION; CANCER SURVIVAL; CARCINOGENESIS; CELL PROLIFERATION; CELL SURVIVAL; CORRELATION ANALYSIS; DRUG EFFICACY; DRUG MECHANISM; EMPIRICISM; ENZYME ACTIVATION; EVIDENCE BASED MEDICINE; EXTRACELLULAR MATRIX; GLUCOSE BLOOD LEVEL; GLUCOSE TRANSPORT; GLYCOLYSIS; HUMAN; HYPOXEMIA; IMAGING SYSTEM; METASTASIS; MICROENVIRONMENT; MICROVASCULATURE; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; OXYGEN TENSION; PH; PHENOTYPE; POSITRON EMISSION TOMOGRAPHY; REVIEW; SIGNAL TRANSDUCTION; SOLID TUMOR; TISSUE PERFUSION; TUMOR BLOOD FLOW; TUMOR CELL; TUMOR VASCULARIZATION;

CELL HYPOXIA; DNA-BINDING PROTEINS; GLYCOLYSIS; HUMANS; HYDROGEN-ION CONCENTRATION; HYPOXIA-INDUCIBLE FACTOR 1; HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT; MICROCIRCULATION; NEOPLASM METASTASIS; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; NUCLEAR PROTEINS; TRANSCRIPTION FACTORS; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 8844224030     PISSN: 00071285     EISSN: None     Source Type: Journal    
DOI: 10.1259/bjr/12913493     Document Type: Review

References (163)

1. Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific growth factors and blood vessel formation. Nature 2000;407:242-8.
2. Augustin HG. Translating angiogenesis research into the clinic: the challenges ahead. Br J Radiol 2003;76:S3-S10.
3. Tozer G. Antiangiogenesis and antivascular targets. Br J Radiol 2003;76:S23-S35.
4. Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin Oncol 2002;29:10-4.
5. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86:353-64.
6. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407:249-57.
7. Goldberg-Cohen I, Furneauxb H, Levy AP. A 40-bp RNA element that mediates stabilization of vascular endothelial growth factor mRNA by HuR. J Biol Chem 2002;277: 13635-40.
8. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, et al. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 2001;292:464-8.
9. Jaakkola P, Mole DR, Tian Y-M, Wilson MI, Gielbert J, Gaskell SJ, et al. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001;292:468-72.
10. Semenza GL. Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr Opin Genet Dev 1998;8:588-94.
11. Vaux EC, Wood SM, Cockman ME, Nicholls LG, Yeates KM, Pugh CW, et al. Selection of mutant CHO cells with constitutive activation of the HIF system and inactivation of the von Hippel-Lindau tumor suppressor. J Biol Chem 2001;276:44323-30.
12. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, et al. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 1999;59:5830-5.
13. Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, et al. The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 2000;157:411-21.
14. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 2001;21:3995-4004.
15. Fukuda R, Hirota K, Fan F, Jung YD, Ellis LM, Semenza GL. Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J Biol Chem 2002;277:38205-311.
16. Fukuda R, Kelly B, Semenza GL. Vascular endothelial growth factor gene expression in colon cancer cells exposed to prostaglandin E2 is mediated by hypoxia-inducible factor 1. Cancer Res 2003;63:2330-4.
17. Dewhirst MW. Concepts of oxygen transport at the microcirculatory level. Semin Radiat Oncol 1998;8: 143-50.
18. Dafni H, Israely T, Bhujwalla ZM, Benjamin LE, Neeman M. Overexpression of vascular endothelial growth factor 165 drives peritumor interstitial convection and induces lymphatic drain: magnetic resonance imaging, confocal microscopy, and histological tracking of triple-labeled albumin. Cancer Res 2002;62:6731-9.
19. Li CY, Shan S, Cao Y, Dewhirst MW. Role of incipient angiogenesis in cancer metastasis. Cancer Metastasis Rev 2000;19:7-11.
20. Jain RK. Delivery of molecular and cellular medicine to solid tumors. Adv Drug Delivery Rev 2001;46:149-68.
21. Jain RK. Transport of molecules in the tumor interstitium: a review. Cancer Res 1987;47:3039-51.
22. el-Kareh AW, Secomb TW. Theoretical models for drug delivery to solid tumors. Crit Rev Biomed Engin 1997; 25:503-71.
23. Milosevic M, Fyles A, Hedley D, Pintilie M, Levin W, Manchul L, et al. Interstitial fluid pressure predicts survival in patients with cervix cancer independent of clinical prognostic factors and tumor oxygen measurements. Cancer Res 2001;61:6400-5.
24. Rofstad EK, Tunheim SH, Mathiesen B, Graff BA, Halsør EF, Nilsen K, et al. Pulmonary and lymph node metastasis is associated with primary tumor interstitial fluid pressure in human melanoma xenografts. Cancer Res 2002;62:661-4.
25. Acker JC, Dewhirst MW, Honore GM, Samulski TV, Tucker JA, Oleson JR. Blood perfusion measurements in human tumors, evaluation of laser Doppler methods. Int J Hypertherm 1990;6:287-304.
26. Vaupel P. Tumor blood flow. In: Molls M, Vaupel P, editors. Blood perfusion and microenvironment of human tumors: implications for clinical radio-oncology. Berlin: Springer-Verlag, 1998:41-6.
27. Kimura H, Braun RD, Ong ET, Hsu R, Secomb TW, Papahadjopoulos D, et al. Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res 1996; 56:5522-8.
28. Cooper RA, Carrington BM, Loncaster JA, Todd SM, Davidson SE, Logue JP, et al. Tumour oxygenation levels correlate with dynamic contrast-enhanced magnetic resonance imaging parameters in carcinoma of the cervix. Radiother Oncol 2000;57:53-9.
29. Krogh A. The number and distribution of capillaries in muscles with calculations of the oxygen pressure head necessary for supplying the tissue. J Physiol 1919;52: 409-15.
30. Secomb TW, Hsu R, Dewhirst MW, Klitzman B, Gross JF. Analysis of oxygen transport to tumor tissue by microvascular networks. Int J Radiat Oncol Biol Phys 1993;25:481-9.
31. Helmlinger G, Yuan F, Dellian M, Jain RK. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nature Med 1997;3:177-82.
32. Thomlinson RH, Gray LH. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 1955;9:539-49.
33. Turner KJ, Crew JP, Wykoff CC, Watson PH, Poulsom R, Pastorek J, et al. The hypoxia-inducible genes VEGF and CA9 are differentially regulated in superficial vs invasive bladder cancer. Br J Cancer 2002;86:1276-82.
34. Wike-Hooley JL, Haveman J, Reinhold HS. The relevance of tumour pH to the treatment of malignant disease. Radiother Oncol 1984;2:343-66.
35. Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 1989;49: 6449-65.
36. Hockel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic and molecular aspects. J Natl Cancer Inst 2001;93:266-76.
37. Giaccia AJ, Koumenis C, Denko N. The influence of tumor hypoxia on tumor progression. In: Vaupel P, Kelleher DK, editors. Tumor hypoxia: pathophysiology, clinical significance and therapeutic perspectives. Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH, 1999: 115-24.
38. Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumors. Nature 1996;379:88-91.
39. Dameron KM, Volpert OV, Tainsky MA, Bouck N. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 1994;265:1582-4.
40. Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor-1a. Genes Dev 2000;14:34-44.
41. Zhang L, Yu D, Hu M, Xiong S, Lang A, Ellis LM, et al. Wild-type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression. Cancer Res 2000;60:3655-61.
42. Sherif ZA, Nakai S, Pirollo KF, Rait A, Chang EH. Downmodulation of bFGF-binding protein expression following restoration of p53 function. Cancer Gene Ther 2001;8:771-82.
43. Carmeliet P, Dor Y, Herbert J-M, Fukumura D, Brusselmans K, Dewerchin M, et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 1998;394:485-90.
44. Rofstad EK. Microenvironment-induced cancer metastasis. Int J Radiat Biol 2000;76:589-605.
45. Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 1996;56:4509-15.
46. Brizel DM, Scully SP, Harrelson JM, Layfield LJ, Bean JM, Prosnitz LR, et al. Tumor oxygenation predicts the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 1996;56:941-3.
47. Cairns RA, Kalliomaki T, Hill RP. Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors. Cancer Res 2001;61:8903-8.
48. Andreasen PA, Kjoller L, Christensen L, Duffy MJ. The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 1997;72:1-22.
49. Graham CH, Forsdike J, Fitzgerald CJ, Macdonald-Goodfellow S. Hypoxia-mediated stimulation of carcinoma cell invasiveness via upregulation of urokinase receptor expression. Int J Cancer 1999;80:617-23.
50. Kroon ME, Koolwijk P, van der Vecht B, van Hinsbergh VW. Urokinase receptor expression on human microvascutal endothelial cells is increased by hypoxia: implications for capillary-like tube formation in a fibrin matrix. Blood 2000;96:2775-83.
51. Rofstad EK, Rasmussen H, Galappathi K, Mathiesen B, Nilsen K, Graff BA. Hypoxia promotes lymph node metastasis in human melanoma xenografts by up-regulating the urokinase-type plasminogen activator receptor. Cancer Res 2002;62:1847-53.
52. Krishnamachary B, Berg-Dixon S, Kelly B, Agani F, Feldser D, Ferreira G, et al. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res 2003; 63:1138-43.
53. Shi Q, Abbruzzese JL, Huang S, Fidler IJ, Xiong Q, Xie K. Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic. Clin Cancer Res 1999;5:3711-21.
54. Rofstad EK, Halsor EF. Hypoxia-associated spontaneous pulmonary metastasis in human melanoma xenografts: involvement of microvascular hot spots induced in hypoxic foci by interleukin 8. Br J Cancer 2002;86:301-8.
55. Niizeki H, Kobayashi M, Horiuchi I, Akakura N, Chen J, Wang J, et al. Hypoxia enhances the expression of autocrine motility factor and the motility of human pancreatic cancer cells. Br J Cancer 2002;86:1914-9.
56. Watanabe H, Takehana K, Date M, Shinozaki T, Raz A. Tumor cell autocrine motility factor is the neuroleukin/phosphohexose isomerase polypeptide. Cancer Res 1996; 56:2960-3.
57. Gatenby RA, Kessler HB, Rosenblum JS, Coia LR, Moldofsky PJ, Hartz WH, et al. Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int J Radiat Oncol Biol Phys 1988;14:831-8.
58. Secomb TW, Hsu R, Ong ET, Gross JF, Dewhirst MW. Analysis of the effects of oxygen supply and demand on hypoxic fraction in tumors. Acta Oncol 1995;34:313-6.
59. Snyder SA, Lanzen JL, Braun RD, Rosner G, Secomb TW, Biaglow J, et al. Simultaneous administration of glucose and hyperoxic gas achieves greater improvement in tumor oxygenation than hyperoxic gas alone. Int J Radiat Oncol Biol Phys 2001;51:494-506.
60. Koch CJ. Unusual oxygen concentration dependence of toxicity of SR-4233, a hypoxic cell toxin. Cancer Res 1993;53:3992-7.
61. Brown JM, Lemmon MJ. Potentiation by the hypoxic cytotoxin SR4233 of cell killing produced by fractionated irradiation of mouse tumors. Cancer Res 1990;50: 7745-9.
62. Young SW, Qing F, Harriman A, Sessler JL, Dow WC, Mody TD, et al. Gadolinium(III) texaphyrin: a tumor selective radiation sensitizer that is detectable by MRI. Proc Natl Acad Sci USA 1996;93:6610-5.
63. Jaffar M, Williams KJ, Stratford IJ. Bioreductive and gene therapy approaches to hypoxic diseases. Adv Drug Delivery Rev 2001;53:217-28.
64. Gillies RJ, Martinez-Zaguilan R, Martinez GM, Serrano R, Perona R. Tumorigenic 3T3 cells maintain an alkaline intracellular pH under physiological conditions. Proc Natl Acad Sci USA 1990;87:7414-8.
65. Stubbs M, Rodrigues LM, Howe FA, Wang J, Keong KS, Veech RL, et al. The metabolic consequences of a reversed pH gradient in rat tumors. Cancer Res 1994;54:4011-6.
66. Stubbs M, McSheehy PMJ, Griffiths JR. Causes and consequences of acidic pH in tumors: a magnetic resonance study. Advan Enzyme Regul 1999;39:13-30.
67. Schornack PA, Gillies RJ. Contributions of cell metabolism and H+ diffusion to the acidic pH of tumors. Neoplasia 2003;5:135-45.
68. Shi Q, Le X, Wang B, Abbruzzese JL, Xiong Q, He Y, et al. Regulation of vascular endothelial growth factor by acidosis in human cancer cells. Oncogene 2001;20: 3751-6.
69. Fukumura D, Xu L, Chen Y, Gohongi T, Seed B, Jain RK. Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res 2001;61:6020-4.
70. Williams AC, Collard TJ, Paraskeva C. 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 1999;18:3199-204.
71. Turner GA. Increased release of tumor cells by collagenase at acid pH: a possible mechanism for metastasis. Experientia 1979;35:1657-8.
72. Schlappack OK, Zimmermann A, Hill RP. Glucose starvation and acidosis: effect on experimental metastatic potential, DNA content and MTX resistance of murine tumour cells. Br J Cancer 1991;64:663-70.
73. Dong JM, Prence EM, Sahagian GG. Mechanism for selective secretion of a lysosomal protease by transformed mouse fibroblasts. J Biol Chem 1989;264:7377-83.
74. Sloane BF, Moin K, Krepela E, Rozhin J. Cathepsin B and its endogenous inhibitors: the role in tumor malignancy. Cancer Metastasis Rev 1990;9:333-52.
75. Rochefort H. Biological and clinical significance of cathepsin D in breast cancer. Semin Cancer Biol 1990;1:153-60.
76. Kane SE, Gottesman MM. The role of cathepsin L in malignant transformation. Semin Cancer Biol 1990;1: 127-36.
77. Rozhin J, Sameni M, Zeigler G, Sloane BF. Pericellular pH affects distribution and secretion of cathepsin B in malignant cells. Cancer Res 1994;54:6517-25.
78. Webb SD, Sherratt JA,, Fish RG. Alterations in proteolytic activity at low pH and its association with invasion: a theoretical model. Clin Exp Metas 1999;17:397-407.
79. Duffy MJ, Macguire TM, McDermott EW, O'Higgins N. Urokinase plasminogen activator: a prognostic marker in multiple types of cancer. J Surg Oncol 1999;71:130-5.
80. Goretzki L, Schmitt M, Mann K, Calvete J, Chucholowski N, Kramer M, et al. Effective activation of the proenzyme form of the urokinase-type plasminogen activator (pro-uPA) by the cysteine protease cathepsin L. FEBS Lett 1992;297:112-8.
81. Morikawa W, Yamamoto K, Ishikawa S, Takemoto S, Ono M, Fukushi J, et al. Angiostatin generation by cathepsin D secreted by human prostate carcinoma cells. J Biol Chem 2000;275:38912-20.
82. Felbor U, Dreier L, Bryant RAR, Ploegh HL, Olsen BR, Mothes W. Secreted cathepsin L generates endostatin from collagen XVIII. EMBO Journal 2000;19:1187-94.
83. Martinez-Zaguilan R, Seftor EA, Seftor RE, Chu YW, Gillies RJ, Hendrix MJ. Acidic pH enhances the invasive behavior of human melanoma cells. Clin Exp Metas 1996;14:176-86.
84. Kato Y, Nakayama Y, Umeda M, Miyazaki K. Induction of a 103-kDa gelatinase/type IV collagenase by acidic culture conditions in mouse metastatic melanoma cell lines. J Biol Chem 1992;267:11424-30.
85. Murdoch AD, Dodge GR, Cohen I, Tuan RS, Iozzo RV. Primary structure of the human heparan sulfate proteoglycan from basement membrane (HSPG2/Perlecan). J Biol Chem 1992;267:8544-57.
86. Nakajima M, Irimura T, Di Ferrante D, Di Ferrante N, Nicolson GL. Heparan sulfate degradation: relation to tumor invasive and metastatic properties of mouse B16 melanoma sublines. Science 1983;220:611-3.
87. Gilat D, Hershkoviz R, Goldkorn I, Cahalon L, Korner G, Vlodavsky I, et al. Molecular behavior adapts to context: heparanase functions as an extracellular matrix-degrading enzyme or as a T cell adhesion molecule, depending on the local pH. J Exp Med 1995;181:1929-34.
88. Toyoshima M, Nakajima M. Human heparanase: purification, characterization, cloning, and expression. J Biol Chem 1999;274:24153-60.
89. Trowell OA. The effect of environmental factors on the radiosensitivity of lymph nodes cultured in vitro. Br J Radiol 1953;306:302-9.
90. Haveman J. The influence of pH on the survival after X-irradiation of cultured malignant cells. Effects of carbonylcyanide-3-chlorophenylhydrazone. Int J Radiat Biol 1980;37:201-5.
91. Rottinger EM, Mendonca M. Radioresistance secondary to low pH in human glial cells and Chinese hamster ovary cells. Int J Radiat Oncol Biol Phys 1982;8:1309-14.
92. Holahan EV, Stuart PK, Dewey WC. Enhancement of survival of CHO cells by acidic pH after X-irradiation. Radiat Res 1982;89:433-5.
93. Freeman ML, Sierra E. An acidic extracellular environment reduces the fixation of radiation damage. Radiat Resist 1984;97:154-61.
94. Raghunand N, He X, Van Sluis R, Mahoney B, Baggett B, Taylor CW, et al. Enhancement of chemotherapy by manipulation of tumour pH. Br J Cancer 1999;80: 1005-11.
95. Raghunand N, Mahoney B, Van Sluis R, Baggett B, Gillies RJ. Acute metabolic alkalosis enhances response of C3H mouse mammary tumors to the weak base mitoxantrone. Neoplasia 2001;3:227-35.
96. Mahoney BP, Raghunand N, Baggett B, Gillies RJ. Tumor acidity, ion trapping and chemotherapeutics I. Acid pH affects the distribution of chemotherapeutic agents in vitro. Biochem Pharmacol 2003;66:1207-18.
97. Raghunand N, Mahoney BP, Gillies RJ. Tumor acidity, ion trapping and chemotherapeutics II. pH-Dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents. Biochem Pharmacol 2003;66:1219-29.
98. Raghunand N, Martinez-Zaguilan R, Wright SH, Gillies RJ. pH and drug resistance II: turnover of acidic vesicles and resistance to weakly basic chemotherapeutic drugs. Biochem Pharmacol 1999;57:1047-58.
99. McSheehy PM, Robinson SP, Ojugo AS, Aboagye EO, Cannell MB, Leach MO, et al. Carbogen breathing increases 5-fluorouracil uptake and cytotoxicity in hypoxic murine RIF-1 tumors: a magnetic resonance study in vivo. Cancer Res 1998;58:1185-94.
100. Kozin SV, Shkarin P, Gerweck LE. The cell membrane pH gradient in tumors enhances cytotoxicity of specific weak acid chemotherapeutics. Cancer Res 2001;61:4740-3.
101. Skarsgard LD, Skwarchuk MW, Vinczan A, Kristl J, Chaplin DJ. The cytotoxicity of melphalan and its relationship to pH, hypoxia and drug uptake. Anticancer Res 1995;15:219-23.
102. Kelley ST, Menon C, Buerk DG, Bauer TW, Fraker DL. Acidosis plus melphalan induces nitric oxide-mediated tumor regression in an isolated limb perfusion human melanoma xenograft model. Surgery 2002;132:252-8.
103. Raghunand N, Gillies RJ. pH and drug resistance in tumors. Drug Resistance Updates 2000;3:39-47.
104. Airley R, Loncaster J, Davidson S, Bromley M, Roberts S, Patterson A, et al. Glucose transporter Glut-1 expression correlates with tumor hypoxia and predicts metastasis-free survival in advanced carcinoma of the cervix. Clin Cancer Res 2001;7:928-34.
105. Brizel DM, Schroeder T, Scher RL, Walenta S, Clough RW, Dewhirst MW, et al. Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001;51:349-53.
106. Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfor K, Rofstad EK, et al. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res 2000; 60:916-21.
107. Sundfor K, Lyng H, Rofstad EK. Tumor hypoxia and vascular density as predictors of metastasis in squamous cell carcinoma of the uterine cervix. Br J Cancer 1998;78: 822-7.
108. Garcia-Martin ML, Herigault G, Remy C, Farion R, Ballesteros P, Coles JA, et al. Mapping extracellular pH in rat brain gliomas in vivo by 1H magnetic resonance spectroscopic imaging: comparison with maps of metabolites. Cancer Res 2001;61:6524-31.
109. Terpstra M, Gruetter R, High WB, Mescher M, DelaBarre L, Merkle H, et al. Lactate turnover in rat glioma measured by in vivo nuclear magnetic resonance spectroscopy. Cancer Res 1998;58:5083-8.
110. Stryer L. Biochemistry (3rd edn). New York: Feeman and Company, 1988:420-1.
111. Pfeiffer T, Schuster S, Bonhoeffer S. Cooperation and competition in the evolution of ATP-producing pathways. Science 2001;292:504-7.
112. Warburg O. The metabolism of tumors. London: Constable Press, 1930.
113. Burk D, Woods M, Hunter J. On the significance of glycolysis for cancer growth, with special reference to Morris rat hepatomas. J Natl Cancer Inst 1967;38:839-63.
114. Medina RA, Owen GI. Glucose transporter: expression, regulation and cancer. Biol Res 2002;35:9-26.
115. Brown RS, Wahl RL. Overexpression of Glut-1 glucose transporter in human breast cancer. Cancer 1993;72: 2979-85.
116. Nagase Y, Takata K, Moriyama N, Aso Y, Murakami T, Hirano H. Immunohistochemical localization of glucose transporters in human renal cell carcinoma. J Urol 1995;153:798-801.
117. Younes M, Brown RW, Stephenson M. Overexpression of Glut 1 and Glut 3 in stage 1 non-small cell lung carcinoma is associated with poor survival. Cancer 1997;80:1046-51.
118. Schonberger J, Ruschoff J, Grimm D, Marienhagen J, Rummele P, Meyringer R, et al. Glucose transporter 1 gene expression is related to thyroid neoplasms with an unfavorable prognosis: an immunohistochemical study. Thyroid 2002;12:747-54.
119. Kunkel M, Reichert TE, Benz P, Lehr HA, Jeong JH, Wieand S, et al. Overexpression of Glut-1 and increased glucose metabolism in tumors are associated with a poor prognosis in patients with oral squamous cell carcinoma. Cancer 2003;97:1015-24.
120. Mineta H, Miura K, Takebayashi S, Misawa K, Araki K, Misawa Y, et al. Prognostic value of glucose transporter 1 expression in patients with hypopharyngeal carcinoma. Anticancer Res 2002;22:3489-94.
121. Kato H, Takita J, Miyazaki T, Nakajima M, Fukai Y, Masuda N, et al. Glut-1 glucose transporter expression in esophageal squamous cell carcinoma is associated with tumor aggressiveness. Anticancer Res 2002;22:2635-9.
122. Kim YW, Park YK, Yoon TY, Lee SM. Expression of the GLUT1 glucose transporter in gallbladder carcinomas. Hepato-Gastroenterology 2002;49:907-11.
123. Kawamura T, Kusakabe T, Sugino T, Watanabe K, Fukuda T, Nashimoto A, et al. Expression of glucose transporter-1 in human gastric carcinoma: association with tumor aggressiveness, metastasis, and patient survival. Cancer 2001;92:634-41.
124. Younes M, Juarez D, Lechago LV, Lerner SP. Glut 1 expression in transitional cell carcinoma of the urinary bladder is associated with poor patient survival. Anticancer Res 2001;21:575-8.
125. Mendez LE, Manci N, Cantuaria G, Gomez-Marin O, Penalver M, Braunschweiger P, et al. Expression of glucose transporter-1 in cervical cancer and its precursors. Gynecol Oncol 2002;86:138-43.
126. Kalir T, Wang BY, Goldfischer M, Haber RS, Reder I, Demopoulos R, et al. Immunohistochemical staining of GLUT1 in benign, borderline, and malignant ovarian epithelia. Cancer 2002;94:1078-82.
127. Lambert DW, Wood IS, Ellis A, Shirazi-Beechey SP. Molecular changes in the expression of human colonic nutrient transporters during the transition from normality to malignancy. Br J Cancer 2002;86:1261-9.
128. Minchenko A, Leshchinsky I, Opentanova I, Sang N, Srinivas V, Caro J. Hypoxia-inducible factor-1 (HIF-1) mediated expression of the 6-phosphofructo-2-kinases/fructose-2-6-bisphosphatase-3 (PFKBF3) gene: its possible role in the Warburg effect. J Biol Chem 2002;277: 6183-7.
129. Semenza GL, Artemov D, Bedi A, Bhujwalla Z, Chiles K, Feldser D, et al. 'The metabolism of tumours': 70 years later. Novartis Foundation Symposium 2001;240:251-60; discussion 260-4.
130. Baer S, Casaubon L, Schwartz MR, Marcogliese A, Younes M. Glut3 expression in biopsy specimens of laryngeal carcinoma is associated with poor survival. Laryngoscope 2002;112:393-6.
131. Di Chiro G, Hatazawa J, Katz DA, Rizzoli HV, De Michele DJ. Glucose utilization by intracranial meningiomas as an index of tumor aggressivity and probability of recurrence: a PET study. Radiology 1987;64:521-6.
132. Haberkorn U, Strauss LG, Reisser C, Haag D, Dimitrakopoulou A, Ziegler S, et al. Glucose uptake, perfusion, and cell proliferation in head and neck tumors: relation of positron emission tomography to flow cytometry. J Nucl Med 1991;32:1548-55.
133. Hawkins RA, Hoh C, Glaspy J, Choi Y, Dahlbom M, Rege S, et al. The role of positron emission tomography in oncology and other whole-body applications. Semin Nucl Med 1992;22:268-84.
134. Patz EF Jr, Lowe VJ, Hoffman JM, Paine SS, Harris LK, Goodman PC. Persistent or recurrent bronchogenic carcinoma: detection with PET and 2-[F-18]-2-deoxy-D-glucose. Radiology 1994;191:379-82.
135. Yonekura Y, Benua RS, Brill AB, Som P, Yeh SD, Kemeny NE, et al. Increased accumulation of 2-deoxy-2[18F]fluoro-D-glucose in liver metastasis from colon cancer. J Nucl Med 1982;23:1133-7.
136. Bos R, van Der Hoeven JJ, van Der Wall E, van Der Groep P, van Diest PJ, Comans EF, et al. Biologic correlates of (18)fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography. J Clin Oncol 2002;20:379-87.
137. Brown RS, Goodman TM, Zasadny KR, Greenson JK, Wahl RL. Expression of hexokinase II and Glut-1 in untreated human breast cancer. Nucl Med Biol 2002;29: 443-53.
138. Rivenzon-Segal D, Margalit R, Degani H. Glycolysis as a metabolic marker in orthotopic breast cancer, monitored by in vivo (13)C MRS. Am J Physiol Endocrinol Metab 2002;283:E626-E630.
139. Oyama M, Kim J, Jones LA, Mercer NM, Engelbach JA, Sharp TL, et al. MicroPET assessment of androgenic control of glucose and acetate uptake in the rat prostate and a prostate cancer tumor model. Nucl Med Biol 2002;29: 783-90.
140. Mamede M, Saga T, Ishimori T, Nakamoto Y, Sato N, Higashi T, et al. Differential uptake of 18F-fluorodeoxyglucose by experimental tumors xenografted into immunocompetent and immunodeficient mice and the effect of immunomodificationtion. Neoplasia 2003;5:179-83.
141. Griffiths JR. Are cancer cells acidic? Br J Cancer 1991;64:425-7.
142. Raghunand N, Altbach MI, Van Sluis R, Baggett B, Taylor CW, Bhujwalla ZM, et al. Plasmalemmal pH gradients in drug-sensitive and drug-resistant MCF-7 human breast carcinoma xenografts measured by 31P MR spectroscopy. Biochem Pharmacol 1999;57:309-12.
143. Grinstein S, Rotin D, Mason MJ. Na+/H+ exchange and growth factor-induced cytosolic pH changes. Role in cellular proliferation. Biochim Biophys Acta 1989;988:73-97.
144. Martinez-Zaguilan R, Raghunand N, Lynch RM, Bellamy W, Martinez GM, Rojas B, et al. pH and drug resistance I: Plasmalemmal V-type H+-ATPase is functionally expressed in drug resistant human breast carcinoma cell lines. Biochem Pharmacol 1999;57:1037-46.
145. Wong P, Kleemann HW, Tannock IF. Cytostatic potential of novel agents that inhibit the regulation of intracellular pH. Br J Cancer 2002;87:238-45.
146. Reshkin SJ, Bellizzi A, Caldeira S, Albarani V, Malanchi I, Poignee M, et al. Na+/H+ exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes. FASEB Journal 2000;14:2185-97.
147. Younes M, Ertan A, Lechago LV, Somoana J, Lechago J. Human erythrocyte glucose transporter (Glut 1) is immunohistochemically detected as a late event during malignant progression in Barrett's metaplasia. Cancer Epidemiol Biomarkers Prev 1997;6:303-5.
148. Younes M, Lechago LV, Lechago J. Overexpression of the human erythrocyte glucose transporter occurs as a late event in human colorectal carcinogenesis and is associated with an increased incidence of lymph node metastases. Clin Cancer Res 1996;2:1151-4.
149. Yasuda S, Fujii H, Nakahara Y, Nishiumi M, Takahashi W, Ide M, et al. 18F-FDG PET detection of colonic adenomas. J Nucl Med 2001;42:254-9.
150. Manchester K. The quest of three giants of science for an understanding of cancer. Endeavour 1997;21:72-6.
151. Racker E. Bioenergetics and the problem of tumor growth. American Scientist 1972;60:56-63.
152. Bissell MJ, Radinsky D. Putting tumours in context. Nature Essays 2001;1:46-54.
153. Gray JW, Collins C. Genome changes and gene expression in human solid tumors. Carcinogenesis 2000;21:443-52.
154. Yashiro M, Carethers JM, Laghi L, Saito K, Slezak P, Jaramillo E, et al. Genetic pathways in the evolution of morphologically distinct colorectal neoplasms. Cancer Res 2001;61:2676-83.
155. Nunney L. Lineage selection and the evolution of multistage carcinogenesis. Proc R Soc London B Biol Sci 1999;266: 493-8.
156. Michelson S, Miller BE, Glicksman AS, Leith JT. Tumor micro-ecology and competitive interactions. J Theor Biol 1987;128:233-46.
157. Tomlinson IP. Game-theory models of interaction between tumour cells. Eur J Cancer 1997;33:1495-500.
158. Gatenby RA, Gawlinski ET. A reaction-diffusion model of cancer invasion. Cancer Res 1996;56:5745-53.
159. Gatenby RA, Gawlinski E. Mathematical models of tumor invasion mediated by transformation-induced alteration of microenvironmental pH. Novartis Foundation Symposium 2001;240:85-99.
160. Patel AA, Gawlinski ET, Lemieux SK, Gateriby RA. A cellular automaton model of early tumor growth and invasion. J Theor Biol 2001;213:315-31.
161. Park HJ, Lyons JC, Ohtsubo T, Song CW. Acidic environment causes apoptosis by increasing caspase activity. Br J Cancer 1999;80:1892-7.
162. Lardner A. The effects of extracellular pH on immune function. J Leukoc Biol 2001;69:522-30.
163. Gatenby RA, Gawlinski ET, Tangen C, Flanigan RC. The possible role of postoperative azotemia in enhanced survival of patients with metastatic renal cancer following cytoreductive nephrectomy. Cancer Res 2002;62:5218-22.