Acid treatment of melanoma cells selects for invasive phenotypes

Solid tumors become acidic due to hypoxia and upregulated glycolysis. We have hypothesized that this acidosis leads to more aggressive invasive behavior during carcinogenesis (Nature Reviews Cancer 4:891–899, 2004). Previous work on this subject has shown mixed results. While some have observed an i...

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Bibliographic Details
Published in:Clinical & experimental metastasis 2008-06, Vol.25 (4), p.411-425
Main Authors: Moellering, Raymond E., Black, Kvar C., Krishnamurty, Chetan, Baggett, Brenda K., Stafford, Phillip, Rain, Matthew, Gatenby, Robert A., Gillies, Robert J.
Format: Article
Language:English
Subjects:
Biomedical and Life Sciences
Biomedicine
Cancer Research
Cell Line, Tumor
Cell Movement
Gene Expression Profiling
Hematology
Humans
Hydrogen-Ion Concentration
Melanoma - pathology
Melanoma - secondary
Neoplasm Invasiveness
Oncology
Phenotype
Research Paper
Surgical Oncology
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Summary:Solid tumors become acidic due to hypoxia and upregulated glycolysis. We have hypothesized that this acidosis leads to more aggressive invasive behavior during carcinogenesis (Nature Reviews Cancer 4:891–899, 2004). Previous work on this subject has shown mixed results. While some have observed an induction of metastasis and invasion with acid treatments, others have not. To investigate this, human melanoma cells were acclimated to low pH growth conditions. Significant cell mortality occurred during acclimation, suggesting that acidosis selected for resistant phenotypes. Cells maintained under acidic conditions exhibited a greater range of motility, a reduced capacity to form flank tumors in SCID mice and did not invade more rapidly in vitro, compared to non-selected control cells. However, re-acclimation of these selected cells to physiological pH gave rise to stable populations with significantly higher in vitro invasion. These re-acclimated cells maintained higher invasion and higher motility for multiple generations. Transcriptomic analyses of these three phenotypes revealed significant differences, including upregulation of relevant pathways important for tissue remodeling, cell cycle control and proliferation. These results reinforce the hypothesis that acidosis promotes selection of stable, more invasive phenotypes, rather than inductive changes, which would be reversible.
ISSN:0262-0898
1573-7276
DOI:10.1007/s10585-008-9145-7