Microenvironmental and cellular consequences of altered blood flow in tumours.

Tumour angiogenesis is triggered by various signals characteristic of the tumour microenvironment, including low oxygen tension, low extracellular pH and low glucose concentration. Tumour microvasculature is chaotic, producing perfusion heterogeneities which can be visualized by MRI and other modalities. Inefficient perfusion in tumours produces regions of transient and chronic hypoxia. Tumour hypoxia is associated with adverse clinical outcomes and reduced patient survival. Hypoxia may be a factor in activation of extracellular matrix-degrading proteases, and some studies have correlated primary tumour hypoxia with likelihood of tumour cell dissemination. Exposure to hypoxia either induces or selects for cells that are hyperglycolytic, and this in turn produces local acidosis which is also a common feature of solid tumours. Increased glucose uptake in hyperglycolyzing tumour cells is the basis of lesion-visualization in positron emission tomography using 18F-fluorodeoxyglucose. Tumour acidity can reduce the effectiveness of weak-base drugs, but can be exploited to increase the anti-tumour activity of weak-acid chemotherapeutics. Evidence linking tumour acidity with increased activity of several extracellular matrix-degrading enzyme systems is examined. High levels of lactate, another end-product of glycolysis, in primary lesions have been correlated with increased likelihood of metastasis. In the numerous studies correlating hypoxia, acidity and lactate with metastasis, the direction of the causality has not been adequately established. We hypothesize that adoption of a hyperglycolytic phenotype is a necessary feature of carcinogenesis itself, and confers a survival and proliferative advantage to tumour cells over surrounding normal cells. Empirical evidence supporting this "acid-mediated tumour invasion" model is discussed.

[1]  E. T. Gawlinski,et al.  Mathematical models of tumour invasion mediated by transformation-induced alteration of microenvironmental pH. , 2001, Novartis Foundation symposium.

[2]  L. Skarsgard,et al.  The cytotoxicity of melphalan and its relationship to pH, hypoxia and drug uptake. , 1995, Anticancer research.

[3]  Peter Bartenstein,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 , 2003, Cancer.

[4]  P. Carmeliet,et al.  Angiogenesis in cancer and other diseases , 2000, Nature.

[5]  R. Gillies,et al.  Tumor acidity, ion trapping and chemotherapeutics. II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents. , 2003, Biochemical pharmacology.

[6]  J. Griffiths,et al.  Causes and consequences of acidic pH in tumors: a magnetic resonance study. , 1999, Advances in enzyme regulation.

[7]  Michael I. Wilson,et al.  Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation , 2001, Science.

[8]  M. Lemmon,et al.  Potentiation by the hypoxic cytotoxin SR 4233 of cell killing produced by fractionated irradiation of mouse tumors. , 1990, Cancer research.

[9]  J. Sherratt,et al.  Alterations in proteolytic activity at low pH and its association with invasion: A theoretical model , 1999, Clinical & Experimental Metastasis.

[10]  T. Sugino,et al.  Expression of glucose transporter‐1 in human gastric carcinoma , 2001, Cancer.

[11]  R. Gillies,et al.  pH and drug resistance. II. Turnover of acidic vesicles and resistance to weakly basic chemotherapeutic drugs. , 1999, Biochemical pharmacology.

[12]  I. Fidler,et al.  Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[13]  G. Tozer Measuring tumour vascular response to antivascular and antiangiogenic drugs. , 2003, The British journal of radiology.

[14]  R K Jain,et al.  Transport of molecules in the tumor interstitium: a review. , 1987, Cancer research.

[15]  D. Hedley,et al.  Interstitial fluid pressure predicts survival in patients with cervix cancer independent of clinical prognostic factors and tumor oxygen measurements. , 2001, Cancer research.

[16]  H. Rochefort,et al.  Biological and clinical significance of cathepsin D in breast cancer. , 1992, Acta oncologica.

[17]  T. Ohtsubo,et al.  Acidic environment causes apoptosis by increasing caspase activity , 1999, British Journal of Cancer.

[18]  R. Wahl,et al.  Expression of hexokinase II and Glut-1 in untreated human breast cancer. , 2002, Nuclear medicine and biology.

[19]  P. Okunieff,et al.  Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. , 1989, Cancer research.

[20]  M. Ivan,et al.  HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing , 2001, Science.

[21]  P. Carmeliet,et al.  Role of HIF-1 alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis (vol 394, pg 485, 1998) , 1998 .

[22]  A. Harris,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. , 2000, The American journal of pathology.

[23]  G. Semenza,et al.  Vascular endothelial growth factor gene expression in colon cancer cells exposed to prostaglandin E2 is mediated by hypoxia-inducible factor 1. , 2003, Cancer research.

[24]  S Cerdán,et al.  Mapping extracellular pH in rat brain gliomas in vivo by 1H magnetic resonance spectroscopic imaging: comparison with maps of metabolites. , 2001, Cancer research.

[25]  F. Young Biochemistry , 1955, The Indian Medical Gazette.

[26]  K. Manchester The quest by three giants of science for an understanding of cancer. , 1997, Endeavour.

[27]  E. T. Gawlinski,et al.  A reaction-diffusion model of cancer invasion. , 1996, Cancer research.

[28]  G. Owen,et al.  Glucose transporters: expression, regulation and cancer. , 2002, Biological research.

[29]  S. Ishikawa,et al.  Angiostatin Generation by Cathepsin D Secreted by Human Prostate Carcinoma Cells* , 2000, The Journal of Biological Chemistry.

[30]  P. Carmeliet,et al.  Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis , 1998, Nature.

[31]  R. Hill,et al.  Glucose starvation and acidosis: effect on experimental metastatic potential, DNA content and MTX resistance of murine tumour cells. , 1991, British Journal of Cancer.

[32]  Robert J. Gillies,et al.  Acidic pH enhances the invasive behavior of human melanoma cells , 1996, Clinical & Experimental Metastasis.

[33]  E. Rofstad Microenvironment-induced cancer metastasis , 2000, International journal of radiation biology.

[34]  J. Takita,et al.  Glut-1 glucose transporter expression in esophageal squamous cell carcinoma is associated with tumor aggressiveness. , 2002, Anticancer research.

[35]  G. Semenza,et al.  'The metabolism of tumours': 70 years later. , 2001, Novartis Foundation symposium.

[36]  Brenda Baggett,et al.  Tumor acidity, ion trapping and chemotherapeutics. I. Acid pH affects the distribution of chemotherapeutic agents in vitro. , 2003, Biochemical pharmacology.

[37]  G. Rosner,et al.  Simultaneous administration of glucose and hyperoxic gas achieves greater improvement in tumor oxygenation than hyperoxic gas alone. , 2001, International journal of radiation oncology, biology, physics.

[38]  E. Racker Bioenergetics and the problem of tumor growth. , 1972, American scientist.

[39]  E. Rofstad,et al.  Hypoxia promotes lymph node metastasis in human melanoma xenografts by up-regulating the urokinase-type plasminogen activator receptor. , 2002, Cancer research.

[40]  H. Augustin Translating angiogenesis research into the clinic: the challenges ahead. , 2003, The British journal of radiology.

[41]  H. Ploegh,et al.  Secreted cathepsin L generates endostatin from collagen XVIII , 2000, The EMBO journal.

[42]  R. Gillies,et al.  Plasmalemmal pH-gradients in drug-sensitive and drug-resistant MCF-7 human breast carcinoma xenografts measured by 31P magnetic resonance spectroscopy. , 1999, Biochemical pharmacology.

[43]  Stanley J. Wiegand,et al.  Vascular-specific growth factors and blood vessel formation , 2000, Nature.

[44]  S. Shirazi-Beechey,et al.  Molecular changes in the expression of human colonic nutrient transporters during the transition from normality to malignancy , 2002, British Journal of Cancer.

[45]  R. Gillies,et al.  pH and drug resistance. I. Functional expression of plasmalemmal V-type H+-ATPase in drug-resistant human breast carcinoma cell lines. , 1999, Biochemical pharmacology.

[46]  M. Neeman,et al.  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. , 2002, Cancer research.

[47]  R. Jain Delivery of molecular and cellular medicine to solid tumors. , 2001, Advanced drug delivery reviews.

[48]  E. Rofstad,et al.  Pulmonary and lymph node metastasis is associated with primary tumor interstitial fluid pressure in human melanoma xenografts. , 2002, Cancer research.

[49]  R. Airley,et al.  Glucose transporter glut-1 expression correlates with tumor hypoxia and predicts metastasis-free survival in advanced carcinoma of the cervix. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[50]  E. Rofstad,et al.  Hypoxia-associated spontaneous pulmonary metastasis in human melanoma xenografts: involvement of microvascular hot spots induced in hypoxic foci by interleukin 8 , 2002, British Journal of Cancer.

[51]  E. T. Gawlinski,et al.  A cellular automaton model of early tumor growth and invasion. , 2001, Journal of theoretical biology.

[52]  M. Dewhirst,et al.  Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. , 1996, Cancer research.

[53]  J R Oleson,et al.  Blood perfusion measurements in human tumours: evaluation of laser Doppler methods. , 1990, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[54]  Hisataka Kobayashi,et al.  Differential uptake of (18)F-fluorodeoxyglucose by experimental tumors xenografted into immunocompetent and immunodeficient mice and the effect of immunomodification. , 2003, Neoplasia.

[55]  D A Hilton,et al.  Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. , 1999, Cancer research.

[56]  G. Semenza,et al.  Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. , 2000, Genes & development.

[57]  S. Macdonald-Goodfellow,et al.  Hypoxia‐mediated stimulation of carcinoma cell invasiveness via upregulation of urokinase receptor expression , 1999, International journal of cancer.

[58]  J. Abbruzzese,et al.  Regulation of vascular endothelial growth factor expression by acidosis in human cancer cells , 2001, Oncogene.

[59]  M. Dewhirst,et al.  Role of Incipient Angiogenesis in Cancer Metastasis , 2004, Cancer and Metastasis Reviews.

[60]  Bonnie F. Sloane,et al.  Cathepsin B and its endogenous inhibitors: the role in tumor malignancy , 1990, Cancer and Metastasis Reviews.

[61]  C. Koch Unusual oxygen concentration dependence of toxicity of SR-4233, a hypoxic cell toxin. , 1993, Cancer research.

[62]  R. Edlich,et al.  Tumor Blood Flow , 1969, Angiology.

[63]  R L Wahl,et al.  An Immunohistochemical Study , 2006 .

[64]  Kane Se,et al.  The role of cathepsin L in malignant transformation. , 1990 .

[65]  L. Ellis,et al.  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* , 2002, The Journal of Biological Chemistry.

[66]  M. Duffy,et al.  The urokinase‐type plasminogen activator system in cancer metastasis: A review , 1997, International journal of cancer.

[67]  R. Hill,et al.  Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors. , 2001, Cancer research.

[68]  P. Vaupel,et al.  Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. , 2001, Journal of the National Cancer Institute.

[69]  M. Duffy,et al.  Urokinase plasminogen activator: A prognostic marker in multiple types of cancer , 1999, Journal of surgical oncology.

[70]  C. Paraskeva,et al.  An acidic environment leads to p53 dependent induction of apoptosis in human adenoma and carcinoma cell lines: implications for clonal selection during colorectal carcinogenesis , 1999, Oncogene.

[71]  H. Lyng,et al.  Tumour hypoxia and vascular density as predictors of metastasis in squamous cell carcinoma of the uterine cervix. , 1998, British Journal of Cancer.

[72]  David E. Housman,et al.  Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours , 1996, Nature.

[73]  E. T. Gawlinski,et al.  The possible role of postoperative azotemia in enhanced survival of patients with metastatic renal cancer after cytoreductive nephrectomy. , 2002, Cancer research.

[74]  M. Dewhirst,et al.  Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. , 1996, Cancer research.

[75]  L. Gerweck,et al.  The cell transmembrane pH gradient in tumors enhances cytotoxicity of specific weak acid chemotherapeutics. , 2001, Cancer research.

[76]  M. Younes,et al.  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. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[77]  R. Gillies,et al.  Tumorigenic 3T3 cells maintain an alkaline intracellular pH under physiological conditions. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[78]  M. Dewhirst,et al.  Concepts of oxygen transport at the microcirculatory level. , 1998, Seminars in radiation oncology.

[79]  Mark A. Stephenson,et al.  Overexpression of glut1 and glut3 in stage I nonsmall cell lung carcinoma is Associated with poor survival , 1997, Cancer.

[80]  O. A. Trowell [The effect of environmental factors on the radiosensitivity of lymph nodes cultured in vitro]. , 1953, The British journal of radiology.

[81]  S. Baer,et al.  Glut3 Expression in Biopsy Specimens of Laryngeal Carcinoma Is Associated With Poor Survival , 2002, The Laryngoscope.

[82]  J. Hamada,et al.  Hypoxia enhances the expression of autocrine motility factor and the motility of human pancreatic cancer cells , 2002, British Journal of Cancer.

[83]  K. Dameron,et al.  Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. , 1994, Science.

[84]  J. Rüschoff,et al.  Glucose transporter 1 gene expression is related to thyroid neoplasms with an unfavorable prognosis: an immunohistochemical study. , 2002, Thyroid : official journal of the American Thyroid Association.

[85]  L. H. Gray,et al.  The Histological Structure of Some Human Lung Cancers and the Possible Implications for Radiotherapy , 1955, British Journal of Cancer.

[86]  Rakesh K. Jain,et al.  Interstitial pH and pO2 gradients in solid tumors in vivo: High-resolution measurements reveal a lack of correlation , 1997, Nature Medicine.

[87]  R. Gillies,et al.  Acute metabolic alkalosis enhances response of C3H mouse mammary tumors to the weak base mitoxantrone. , 2001, Neoplasia.

[88]  I. Stratford,et al.  Bioreductive and gene therapy approaches to hypoxic diseases. , 2001, Advanced drug delivery reviews.

[89]  J. Leith,et al.  Tumor micro-ecology and competitive interactions. , 1987, Journal of theoretical biology.

[90]  G. di Chiro,et al.  Glucose utilization by intracranial meningiomas as an index of tumor aggressivity and probability of recurrence: a PET study. , 1987, Radiology.

[91]  I. Tomlinson,et al.  Game-theory models of interactions between tumour cells. , 1997, European journal of cancer.

[92]  J. Gray,et al.  Genome changes and gene expression in human solid tumors. , 2000, Carcinogenesis.

[93]  R. Gillies,et al.  pH and drug resistance in tumors. , 2000, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[94]  S Grinstein,et al.  Na+/H+ exchange and growth factor-induced cytosolic pH changes. Role in cellular proliferation. , 1989, Biochimica et biophysica acta.

[95]  N. Nishiumi,et al.  18F-FDG PET detection of colonic adenomas. , 2001, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[96]  A. Levy,et al.  A 40-bp RNA Element That Mediates Stabilization of Vascular Endothelial Growth Factor mRNA by HuR* , 2002, The Journal of Biological Chemistry.

[97]  Mina J. Bissell,et al.  Putting tumours in context , 2001, Nature Reviews Cancer.

[98]  M. Dewhirst,et al.  Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. , 2001, International journal of radiation oncology, biology, physics.

[99]  J. Griffiths Are cancer cells acidic? , 1991, British Journal of Cancer.

[100]  E. Chang,et al.  Downmodulation of bFGF-binding protein expression following restoration of p53 function , 2001, Cancer Gene Therapy.

[101]  J. Griffiths,et al.  Carbogen breathing increases 5-fluorouracil uptake and cytotoxicity in hypoxic murine RIF-1 tumors: a magnetic resonance study in vivo. , 1998, Cancer research.

[102]  T. Secomb,et al.  Theoretical models for drug delivery to solid tumors. , 1997, Critical reviews in biomedical engineering.

[103]  M. Freeman,et al.  An acidic extracellular environment reduces the fixation of radiation damage. , 1984, Radiation research.

[104]  R. Jain,et al.  Delivery of molecular and cellular medicine to solid tumors. , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[105]  J. Haveman The influence of pH on the survival after X-irradiation of cultured malignant cells. Effects of carbonylcyanide-3-chlorophenylhydrazone. , 1980, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[106]  J S Fowler,et al.  Increased accumulation of 2-deoxy-2-[18F]Fluoro-D-glucose in liver metastases from colon carcinoma. , 1982, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[107]  E. T. Gawlinski,et al.  A Cellular Automaton Model of Early Tumor Growth and Invasion: The Effects of Native Tissue Vascularity and Increased Anaerobic Tumor Metabolism , 2001 .

[108]  S. Caldeira,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 , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[109]  A Krogh,et al.  The number and distribution of capillaries in muscles with calculations of the oxygen pressure head necessary for supplying the tissue , 1919, The Journal of physiology.

[110]  A. Lardner The effects of extracellular pH on immune function , 2001, Journal of leukocyte biology.

[111]  M. Nadji,et al.  Expression of glucose transporter-1 in cervical cancer and its precursors. , 2002, Gynecologic oncology.

[112]  G. Turner Increased release of tumour cells by collagenase at acid pH: A possible mechanism for metastasis , 2005, Experientia.

[113]  Y. Kato,et al.  Induction of 103-kDa gelatinase/type IV collagenase by acidic culture conditions in mouse metastatic melanoma cell lines. , 1992, The Journal of biological chemistry.

[114]  W. Dewey,et al.  Enhancement of survival of CHO cells by acidic pH after x irradiation. , 1982, Radiation research.

[115]  K. Miura,et al.  Prognostic value of glucose transporter 1 expression in patients with hypopharyngeal carcinoma. , 2002, Anticancer research.

[116]  K. Takata,et al.  Immunohistochemical localization of glucose transporters in human renal cell carcinoma. , 1995, The Journal of urology.

[117]  R. Hershkoviz,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 , 1995, The Journal of experimental medicine.

[118]  Bonnie F. Sloane,et al.  Pericellular pH affects distribution and secretion of cathepsin B in malignant cells. , 1994, Cancer research.

[119]  I. Tannock,et al.  Cytostatic potential of novel agents that inhibit the regulation of intracellular pH , 2002, British Journal of Cancer.

[120]  G. R. Dodge,et al.  Primary structure of the human heparan sulfate proteoglycan from basement membrane (HSPG2/perlecan). A chimeric molecule with multiple domains homologous to the low density lipoprotein receptor, laminin, neural cell adhesion molecules, and epidermal growth factor. , 1992, The Journal of biological chemistry.

[121]  R. Gillies,et al.  ©1999 Cancer Research Campaign Article no. bjoc.1998.0455 Enhancement of chemotherapy by manipulation of tumour pH , 2022 .

[122]  P. V. van Diest,et al.  Biologic correlates of (18)fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[123]  J. Calvete,et al.  Effective activation of the proenzyme form of the urokinase‐type plasminogen activator (pro‐uPA) by the cysteine protease cathepsin L , 1992, FEBS letters.

[124]  L. Ellis,et al.  Wild-type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression. , 2000, Cancer research.

[125]  Robert J Gillies,et al.  Contributions of cell metabolism and H+ diffusion to the acidic pH of tumors. , 2003, Neoplasia.

[126]  V. Lowe,et al.  Persistent or recurrent bronchogenic carcinoma: detection with PET and 2-[F-18]-2-deoxy-D-glucose. , 1994, Radiology.

[127]  P. Ratcliffe,et al.  Selection of Mutant CHO Cells with Constitutive Activation of the HIF System and Inactivation of the von Hippel-Lindau Tumor Suppressor* , 2001, The Journal of Biological Chemistry.

[128]  G. Semenza,et al.  Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. , 2003, Cancer research.

[129]  D. Fraker,et al.  Acidosis plus melphalan induces nitric oxide-mediated tumor regression in an isolated limb perfusion human melanoma xenograft model. , 2002, Surgery.

[130]  T Shinozaki,et al.  Tumor cell autocrine motility factor is the neuroleukin/phosphohexose isomerase polypeptide. , 1996, Cancer research.

[131]  D. Burstein,et al.  Immunohistochemical staining of GLUT1 in benign, borderline, and malignant ovarian epithelia , 2002, Cancer.

[132]  L. Nunney,et al.  Lineage selection and the evolution of multistage carcinogenesis , 1999, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[133]  S. Lerner,et al.  Glut 1 expression in transitional cell carcinoma of the urinary bladder is associated with poor patient survival. , 2001, Anticancer research.

[134]  C. Boland,et al.  Genetic pathways in the evolution of morphologically distinct colorectal neoplasms. , 2001, Cancer research.

[135]  E. Röttinger,et al.  Radioresistance secondary to low pH in human glial cells and Chinese hamster ovary cells. , 1982, International journal of radiation oncology, biology, physics.

[136]  Joonyoung Kim,et al.  MicroPET assessment of androgenic control of glucose and acetate uptake in the rat prostate and a prostate cancer tumor model. , 2002, Nuclear medicine and biology.

[137]  D. Burk,et al.  On the significance of glucolysis for cancer growth, with special reference to Morris rat hepatomas. , 1967, Journal of the National Cancer Institute.

[138]  R. Gatenby,et al.  Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. , 1988, International journal of radiation oncology, biology, physics.

[139]  J F Gross,et al.  Analysis of oxygen transport to tumor tissue by microvascular networks. , 1993, International journal of radiation oncology, biology, physics.

[140]  M. Gottesman,et al.  The role of cathepsin L in malignant transformation. , 1990, Seminars in cancer biology.

[141]  G. Semenza Hypoxia-inducible factor 1: master regulator of O2 homeostasis. , 1998, Current opinion in genetics & development.

[142]  Otto Warburn,et al.  THE METABOLISM OF TUMORS , 1931 .

[143]  J P Logue,et al.  Tumour oxygenation levels correlate with dynamic contrast-enhanced magnetic resonance imaging parameters in carcinoma of the cervix. , 2000, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[144]  E. Hoffman,et al.  The role of positron emission tomography in oncology and other whole-body applications. , 1992, Seminars in nuclear medicine.

[145]  K. Takata,et al.  Investigative Urology: Immunohistochemical Localization of Glucose Transporters in Human Renal Cell Carcinoma , 1995 .

[146]  G van Kaick,et al.  Glucose uptake, perfusion, and cell proliferation in head and neck tumors: relation of positron emission tomography to flow cytometry. , 1991, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[147]  V. V. van Hinsbergh,et al.  Urokinase receptor expression on human microvascular endothelial cells is increased by hypoxia: implications for capillary-like tube formation in a fibrin matrix. , 2000, Blood.

[148]  J. Sessler,et al.  Gadolinium(III) texaphyrin: a tumor selective radiation sensitizer that is detectable by MRI. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[149]  T. Irimura,et al.  Heparan sulfate degradation: relation to tumor invasive and metastatic properties of mouse B16 melanoma sublines. , 1983, Science.

[150]  A. Harris,et al.  The hypoxia-inducible genes VEGF and CA9 are differentially regulated in superficial vs invasive bladder cancer , 2002, British Journal of Cancer.

[151]  S. Bonhoeffer,et al.  Cooperation and Competition in the Evolution of ATP-Producing Pathways , 2001, Science.

[152]  Youn Wha Kim,et al.  Expression of the GLUT1 glucose transporter in gallbladder carcinomas. , 2002, Hepato-gastroenterology.

[153]  G. Sahagian,et al.  Mechanism for selective secretion of a lysosomal protease by transformed mouse fibroblasts. , 1989, The Journal of biological chemistry.

[154]  A. Harris,et al.  The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages , 2000 .

[155]  J. Haveman,et al.  The relevance of tumour pH to the treatment of malignant disease. , 1984, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[156]  G. Semenza,et al.  HER2 (neu) Signaling Increases the Rate of Hypoxia-Inducible Factor 1α (HIF-1α) Synthesis: Novel Mechanism for HIF-1-Mediated Vascular Endothelial Growth Factor Expression , 2001, Molecular and Cellular Biology.

[157]  Keith R.F. Elliott,et al.  Biochemistry, 3rd edn , 1990 .

[158]  R Gruetter,et al.  Lactate turnover in rat glioma measured by in vivo nuclear magnetic resonance spectroscopy. , 1998, Cancer research.

[159]  P Vaupel,et al.  Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. , 1996, Cancer research.

[160]  M. Younes,et al.  Human erythrocyte glucose transporter (Glut1) is immunohistochemically detected as a late event during malignant progression in Barrett's metaplasia. , 1997, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[161]  H. Degani,et al.  Glycolysis as a metabolic marker in orthotopic breast cancer, monitored by in vivo (13)C MRS. , 2002, American journal of physiology. Endocrinology and metabolism.

[162]  J F Gross,et al.  Analysis of the effects of oxygen supply and demand on hypoxic fraction in tumors. , 1995, Acta oncologica.

[163]  E. Rofstad,et al.  High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. , 2000, Cancer research.

[164]  R K Jain,et al.  Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. , 2001, Cancer research.

[165]  D. Hanahan,et al.  Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis , 1996, Cell.

[166]  Napoleone Ferrara,et al.  Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. , 2002, Seminars in oncology.

[167]  K. Jeong,et al.  Metabolic consequences of a reversed pH gradient in rat tumors. , 1994, Cancer research.

[168]  Paul J. van Diest,et al.  Biologic correlates of 18fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography , 2002 .

[169]  N. Sang,et al.  Hypoxia-inducible Factor-1-mediated Expression of the 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) Gene , 2002, The Journal of Biological Chemistry.

[170]  Turner Ga Increased release of tumour cells by collagenase at acid pH: A possible mechanism for metastasis , 1979 .