Cited by 771Cancer, Hypoxia, and MetabolismMathematical Biology Tumor GrowthCancer Cells and Metastasis

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Acid-Mediated Tumor Invasion: a Multidisciplinary Study

Gatenby, Robert A., Gawlinski, Edward T., Gmitro, Arthur F., Kaylor, Brant, Gillies, Robert J.·2006·Cancer Research

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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. (Cancer Res 2006; 66(10): 5216-23)

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Authors: Gatenby, R. A., Gawlinski, E. T., Gmitro, A. F., Kaylor, B., & Gillies, R. J.
Affiliations: University of Arizona (US)
Temple University (US)
ORCID: Gatenby, Robert A.
Gillies, Robert J.
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2006-05-15
Volume: 66
Issue: 10
Pages: 5216-5223
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-05-4193
OpenAlex: W2118604693
Cited by: 771
References: 37
Citations by year: 2026: 19 · 2025: 18 · 2024: 25 · 2023: 31 · 2022: 42 · 2021: 47 · 2020: 54 · 2019: 46 · 2018: 36 · 2017: 48 · 2016: 48 · 2015: 48 · 2014: 41 · 2013: 44 · 2012: 36
FWCI: 12.90
Type: journal article
Language: en
Open access: closed
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (U56CA113004, R01CA093650)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords: tumor acidosis, extracellular matrix degradation, cathepsin B, normal tissue toxicity, tumor-host interface, carcinogenesis, acid resistance
MeSH terms: Acidosis, Animals, Breast Neoplasms, Cell Movement, Glucose, Glycolysis, Humans, Hydrogen-Ion Concentration, Male, Models, Biological, Neoplasm Invasiveness, Neoplasm Metastasis, Prostatic Neoplasms, Mice, SCID, Cell Line, Tumor, Cell Growth Processes, Mice

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Acid-Mediated Tumor Invasion: a Multidisciplinary Study

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