Acid-mediated tumor invasion: A multidisciplinary study

Robert A. Gatenby, Edward T. Gawlinski, Arthur F Gmitro, Brant Kaylor, Robert J. Gillies

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)5216-5223
Number of pages8
JournalCancer Research
Volume66
Issue number10
DOIs
StatePublished - May 15 2006

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Acids
Neoplasms
Glucose
Extracellular Matrix
Cathepsin B
Positron-Emission Tomography
Computer Simulation
Carcinogenesis
Peptide Hydrolases
Cell Death
Theoretical Models
Necrosis
Apoptosis
Phenotype

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Gatenby, R. A., Gawlinski, E. T., Gmitro, A. F., Kaylor, B., & Gillies, R. J. (2006). Acid-mediated tumor invasion: A multidisciplinary study. Cancer Research, 66(10), 5216-5223. https://doi.org/10.1158/0008-5472.CAN-05-4193

Acid-mediated tumor invasion : A multidisciplinary study. / Gatenby, Robert A.; Gawlinski, Edward T.; Gmitro, Arthur F; Kaylor, Brant; Gillies, Robert J.

In: Cancer Research, Vol. 66, No. 10, 15.05.2006, p. 5216-5223.

Research output: Contribution to journalArticle

Gatenby, RA, Gawlinski, ET, Gmitro, AF, Kaylor, B & Gillies, RJ 2006, 'Acid-mediated tumor invasion: A multidisciplinary study', Cancer Research, vol. 66, no. 10, pp. 5216-5223. https://doi.org/10.1158/0008-5472.CAN-05-4193
Gatenby, Robert A. ; Gawlinski, Edward T. ; Gmitro, Arthur F ; Kaylor, Brant ; Gillies, Robert J. / Acid-mediated tumor invasion : A multidisciplinary study. In: Cancer Research. 2006 ; Vol. 66, No. 10. pp. 5216-5223.
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