Contributions of cell metabolism and H+ diffusion to the acidic pH of tumors.

The tumor microenvironment is hypoxic and acidic. These conditions have a significant impact on tumor progression and response to therapies. There is strong evidence that tumor hypoxia results from inefficient perfusion due to a chaotic vasculature. Consequently, some tumor regions are well oxygenated and others are hypoxic. It is commonly believed that hypoxic regions are acidic due to a stimulation of glycolysis through hypoxia, yet this is not yet demonstrated. The current study investigates the causes of tumor acidity by determining acid production rates and the mechanism of diffusion for H(+) equivalents through model systems. Two breast cancer cell lines were investigated with divergent metabolic profiles: nonmetastatic MCF-7/s and highly metastatic MDA-mb-435 cells. Glycolysis and acid production are inhibited by oxygen in MCF-7/s cells, but not in MDA-mb-435 cells. Tumors of MDA-mb-435 cells are significantly more acidic than are tumors of MCF-7/s cells, suggesting that tumor acidity is primarily caused by endogenous metabolism, and not the lack of oxygen. Metabolically produced protons are shown to diffuse in association with mobile buffers, in concordance with previous studies. The metabolic and diffusion data were analyzed using a reaction-diffusion model to demonstrate that the consequent pH profiles conform well to measured pH values for tumors of these two cell lines.

[1]  S S Gambhir,et al.  A tabulated summary of the FDG PET literature. , 2001, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[2]  R. Gillies,et al.  Nm23‐transfected MDA‐mB‐435 human breast carcinoma cells form tumors with altered phospholipid metabolism and pH: A 31P nuclear magnetic resonance study in vivo and in vitro , 1999, Magnetic resonance in medicine.

[3]  P. Thibault,et al.  Transcription Factor HIF-1 Is a Necessary Mediator of the Pasteur Effect in Mammalian Cells , 2001, Molecular and Cellular Biology.

[4]  K. Svoboda,et al.  Time-dependent diffusion of water in a biological model system. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[5]  D. Carling,et al.  Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia , 2000, Current Biology.

[6]  F. Howe,et al.  Why are cancers acidic? A carrier-mediated diffusion model for H+ transport in the interstitial fluid. , 2001, Novartis Foundation symposium.

[7]  S. McLaughlin,et al.  The role of fixed and mobile buffers in the kinetics of proton movement. , 1987, Biochimica et biophysica acta.

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

[9]  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.

[10]  R. Nuccitelli,et al.  Current pulses involving chloride and potassium efflux relieve excess pressure in Pelvetia embryos , 2004, Planta.

[11]  P. Glazer,et al.  Mutagenesis induced by the tumor microenvironment. , 1998, Mutation research.

[12]  D. Hardie.  Metabolic control: A new solution to an old problem , 2000, Current Biology.

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

[14]  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.

[15]  P. Okunieff,et al.  Angiogenesis determines blood flow, metabolism, growth rate, and ATPase kinetics of tumors growing in an irradiated bed: 31P and 2H nuclear magnetic resonance studies. , 1991, Cancer research.

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

[17]  N. Agmon,et al.  The Grotthuss mechanism , 1995 .

[18]  M. Brand,et al.  Top-down control analysis of ATP turnover, glycolysis and oxidative phosphorylation in rat hepatocytes. , 1999, European journal of biochemistry.

[19]  J F Gross,et al.  Theoretical simulation of oxygen transport to tumors by three-dimensional networks of microvessels. , 1998, Advances in experimental medicine and biology.

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

[21]  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.

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

[23]  D Artemov,et al.  Combined vascular and extracellular pH imaging of solid tumors , 2002, NMR in biomedicine.

[24]  Marc Dellian,et al.  Acid production in glycolysis-impaired tumors provides new insights into tumor metabolism. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[25]  C. Horváth,et al.  Buffer-facilitated proton transport. pH profile of bound enzymes. , 1974, Biochimica et biophysica acta.

[26]  P. Glazer,et al.  Diminished DNA repair and elevated mutagenesis in mammalian cells exposed to hypoxia and low pH. , 2000, Cancer research.

[27]  B. Dale,et al.  Optimum fiber spacing in a hollow fiber bioreactor , 1988, Biotechnology and bioengineering.

[28]  I. Tannock,et al.  The contribution of lactic acid to acidification of tumours: studies of variant cells lacking lactate dehydrogenase. , 1998, British Journal of Cancer.

[29]  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.

[30]  M. Aardema,et al.  Multistage neoplastic transformation of Syrian hamster embryo cells cultured at pH 6.70. , 1990, Cancer research.

[31]  M. Dewhirst,et al.  Microvascular studies on the origins of perfusion-limited hypoxia. , 1996, The British journal of cancer. Supplement.

[32]  O. Warburg.  [Origin of cancer cells]. , 1956, Oncologia.

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

[34]  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.

[35]  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.

[36]  R. Sutherland,et al.  Oxygen diffusion distance and development of necrosis in multicell spheroids. , 1979, Radiation research.

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

[38]  R. Gillies,et al.  Causes and effects of heterogeneous perfusion in tumors. , 1999, Neoplasia.

[39]  M. Spector,et al.  Warburg effect revisited: merger of biochemistry and molecular biology. , 1981, Science.

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

[41]  T. Morita,et al.  Clastogenicity of low pH to various cultured mammalian cells. , 1991, Mutation research.

[42]  Natarajan Raghunand,et al.  In vivo imaging of extracellular pH using 1H MRSI , 1999, Magnetic resonance in medicine.

[43]  A. Giaccia,et al.  Hypoxia activates a platelet-derived growth factor receptor/phosphatidylinositol 3-kinase/Akt pathway that results in glycogen synthase kinase-3 inactivation. , 2001, Cancer research.

[44]  R. Gillies,et al.  A stirred bath technique for diffusivity measurements in cell matrices , 1988, Biotechnology and bioengineering.

[45]  R. Gillies,et al.  31P-MRS measurements of extracellular pH of tumors using 3-aminopropylphosphonate. , 1994, The American journal of physiology.

[46]  R. Nuccitelli,et al.  The ionic components of the current pulses generated by developing fucoid eggs. , 1976, Developmental biology.