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 Gatenby, R. A. Articles by Gillies, R. J. Search for Related Content PubMed PubMed Citation Articles by Gatenby, R. A. Articles by Gillies, R. J.

Acid-Mediated Tumor Invasion: a Multidisciplinary Study

Departments of ¹ Radiology, ² Applied Mathematics, and ³ Optical Sciences, University of Arizona, Tucson Arizona; and ⁴ Department of Physics, Temple University, Philadelphia, Pennsylvania

Requests for reprints: Robert A. Gatenby, Department of Radiology, University Medical Center, 1501 North Campbell Avenue, Tucson, AZ 85718. Phone: 520-626-5725; Fax: 520-626-9981; E-mail: rgatenby{at}radiology.arizona.edu.

The acid-mediated tumor invasion hypothesis proposes altered glucose metabolism and increased glucose uptake, observed in the vast majority of clinical cancers by fluorodeoxyglucose-positron emission tomography, are critical for development of the invasive phenotype. In this model, increased acid production due to altered glucose metabolism serves as a key intermediate by producing H⁺ flow along concentration gradients into adjacent normal tissue. This chronic exposure of peritumoral normal tissue to an acidic microenvironment produces toxicity by: (a) normal cell death caused by the collapse of the transmembrane H⁺ gradient inducing necrosis or apoptosis and (b) extracellular matrix degradation through the release of cathepsin B and other proteolytic enzymes. Tumor cells evolve resistance to acid-induced toxicity during carcinogenesis, allowing them to survive and proliferate in low pH microenvironments. This permits them to invade the damaged adjacent normal tissue despite the acid gradients. Here, we describe theoretical and empirical evidence for acid-mediated invasion. In silico simulations using mathematical models provide testable predictions concerning the morphology and cellular and extracellular dynamics at the tumor-host interface. In vivo experiments confirm the presence of peritumoral acid gradients as well as cellular toxicity and extracellular matrix degradation in the normal tissue exposed to the acidic microenvironment. The acid-mediated tumor invasion model provides a simple mechanism linking altered glucose metabolism with the ability of tumor cells to form invasive cancers. (Cancer Res 2006; 66(10): 5216-23)

This article has been cited by other articles:

				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]

				H. Jo, Y. Jia, K. K. Subramanian, H. Hattori, and H. R. Luo Cancer Cell-Derived Clusterin Modulates the Phosphatidylinositol 3'-Kinase-Akt Pathway through Attenuation of Insulin-Like Growth Factor 1 during Serum Deprivation Mol. Cell. Biol., July 1, 2008; 28(13): 4285 - 4299. [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. A Kingsley, P. G J Fournier, J. M Chirgwin, and T. A Guise Molecular Biology of Bone Metastasis Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 443 - 457. [Abstract] [Full Text] [PDF]

				K. C. Rice and K. W. Bayles Molecular Control of Bacterial Death and Lysis Microbiol. Mol. Biol. Rev., March 1, 2008; 72(1): 85 - 109. [Abstract] [Full Text] [PDF]

				K. Glunde, T. Shah, P. T. Winnard Jr., V. Raman, T. Takagi, F. Vesuna, D. Artemov, and Z. M. Bhujwalla Hypoxia Regulates Choline Kinase Expression through Hypoxia-Inducible Factor-1{alpha} Signaling in a Human Prostate Cancer Model Cancer Res., January 1, 2008; 68(1): 172 - 180. [Abstract] [Full Text] [PDF]

				L. A. Kingsley, P. G.J. Fournier, J. M. Chirgwin, and T. A. Guise Molecular Biology of Bone Metastasis Mol. Cancer Ther., October 1, 2007; 6(10): 2609 - 2617. [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]

				J. Yang, H. Chen, I. R. Vlahov, J.-X. Cheng, and P. S. Low Characterization of the pH of Folate Receptor-Containing Endosomes and the Rate of Hydrolysis of Internalized Acid-Labile Folate-Drug Conjugates J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 462 - 468. [Abstract] [Full Text] [PDF]