This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Helmlinger, G. Articles by Jain, R. K. Search for Related Content PubMed PubMed Citation Articles by Helmlinger, G. Articles by Jain, R. K.

Acid Production in Glycolysis-impaired Tumors Provides New Insights into Tumor Metabolism¹

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

Purpose: Low extracellular pH is a hallmark of solid tumors. It has long been thought that this acidity is mainly attributable to the production of lactic acid. In this study, we tested the hypothesis that lactate is not the only source of acidification in solid tumors and explored the potential mechanisms underlying these often-observed high rates of acid production.

Experimental Design: We compared the metabolic profiles of glycolysis-impaired (phosphoglucose isomerase-deficient) and parental cells in both in vitro and two in vivo models (dorsal skinfold chamber and Gullino chamber).

Results: We demonstrated that CO₂, in addition to lactic acid, was a significant source of acidity in tumors. We also found evidence supporting the hypothesis that tumor cells rely on glutaminolysis for energy production and that the pentose phosphate pathway is highly active within tumor cells. Our results also suggest that the tricarboxylic acid cycle is saturable and that different metabolic pathways are activated to provide for energy production and biosynthesis.

Conclusions: These results are consistent with the paradigm that tumor metabolism is determined mainly by substrate availability and not by the metabolic demand of tumor cells per se. In particular, it appears that the local glucose and oxygen availabilities each independently affect tumor acidity. These findings have significant implications for cancer treatment.

This article has been cited by other articles:

				A. S. Silva, J. A. Yunes, R. J. Gillies, and R. A. Gatenby The Potential Role of Systemic Buffers in Reducing Intratumoral Extracellular pH and Acid-Mediated Invasion Cancer Res., March 15, 2009; 69(6): 2677 - 2684. [Abstract] [Full Text] [PDF]

				P. Swietach, S. Wigfield, P. Cobden, C. T. Supuran, A. L. Harris, and R. D. Vaughan-Jones Tumor-associated Carbonic Anhydrase 9 Spatially Coordinates Intracellular pH in Three-dimensional Multicellular Growths J. Biol. Chem., July 18, 2008; 283(29): 20473 - 20483. [Abstract] [Full Text] [PDF]

				R. J. Gillies, I. Robey, and R. A. Gatenby Causes and Consequences of Increased Glucose Metabolism of Cancers J. Nucl. Med., June 1, 2008; 49(Suppl_2): 24S - 42S. [Abstract] [Full Text] [PDF]

				L. Stuwe, M. Muller, A. Fabian, J. Waning, S. Mally, J. Noel, A. Schwab, and C. Stock pH dependence of melanoma cell migration: protons extruded by NHE1 dominate protons of the bulk solution J. Physiol., December 1, 2007; 585(2): 351 - 360. [Abstract] [Full Text] [PDF]

				P. Provent, M. Benito, B. Hiba, R. Farion, P. Lopez-Larrubia, P. Ballesteros, C. Remy, C. Segebarth, S. Cerdan, J. A. Coles, et al. Serial In vivo Spectroscopic Nuclear Magnetic Resonance Imaging of Lactate and Extracellular pH in Rat Gliomas Shows Redistribution of Protons Away from Sites of Glycolysis Cancer Res., August 15, 2007; 67(16): 7638 - 7645. [Abstract] [Full Text] [PDF]

				R. Benoliel, J. Epstein, E. Eliav, R. Jurevic, and S. Elad Orofacial Pain in Cancer: Part I--Mechanisms Journal of Dental Research, June 1, 2007; 86(6): 491 - 505. [Abstract] [Full Text] [PDF]

				E. Bullitt, P.A. Wolthusen, L. Brubaker, W. Lin, D. Zeng, and T. Van Dyke Malignancy-Associated Vessel Tortuosity: A Computer-Assisted, MR Angiographic Study of Choroid Plexus Carcinoma in Genetically Engineered Mice AJNR Am. J. Neuroradiol., March 1, 2006; 27(3): 612 - 619. [Abstract] [Full Text] [PDF]

				R. Cairns, I. Papandreou, and N. Denko Overcoming Physiologic Barriers to Cancer Treatment by Molecularly Targeting the Tumor Microenvironment Mol. Cancer Res., February 1, 2006; 4(2): 61 - 70. [Abstract] [Full Text] [PDF]

				C. Stock, B. Gassner, C. R Hauck, H. Arnold, S. Mally, J. A Eble, P. Dieterich, and A. Schwab Migration of human melanoma cells depends on extracellular pH and Na+/H+ exchange J. Physiol., August 15, 2005; 567(1): 225 - 238. [Abstract] [Full Text] [PDF]

				Y. Kato, C. A. Lambert, A. C. Colige, P. Mineur, A. Noel, F. Frankenne, J.-M. Foidart, M. Baba, R.-I. Hata, K. Miyazaki, et al. Acidic Extracellular pH Induces Matrix Metalloproteinase-9 Expression in Mouse Metastatic Melanoma Cells through the Phospholipase D-Mitogen-activated Protein Kinase Signaling J. Biol. Chem., March 25, 2005; 280(12): 10938 - 10944. [Abstract] [Full Text] [PDF]

				N. Kokkonen, A. Rivinoja, A. Kauppila, M. Suokas, I. Kellokumpu, and S. Kellokumpu Defective Acidification of Intracellular Organelles Results in Aberrant Secretion of Cathepsin D in Cancer Cells J. Biol. Chem., September 17, 2004; 279(38): 39982 - 39988. [Abstract] [Full Text] [PDF]

				A. A. Komissarov, P. J. Declerck, and J. D. Shore Protonation State of a Single Histidine Residue Contributes Significantly to the Kinetics of the Reaction of Plasminogen Activator Inhibitor-1 with Tissue-type Plasminogen Activator J. Biol. Chem., May 28, 2004; 279(22): 23007 - 23013. [Abstract] [Full Text] [PDF]

				R. Rossignol, R. Gilkerson, R. Aggeler, K. Yamagata, S. J. Remington, and R. A. Capaldi Energy Substrate Modulates Mitochondrial Structure and Oxidative Capacity in Cancer Cells Cancer Res., February 1, 2004; 64(3): 985 - 993. [Abstract] [Full Text] [PDF]

				M. L. Wahl, T. L. Moser, and S. V. Pizzo Angiostatin and Anti-angiogenic Therapy in Human Disease Recent Prog. Horm. Res., January 1, 2004; 59(1): 73 - 104. [Abstract] [Full Text]