Abstract
Malignant gliomas are lethal cancers that display cellular hierarchies with cancer stem cells at the apex. Glioma stem cells (GSCs) are not uniformly distributed, but rather located in specialized niches, suggesting that the cancer stem cell phenotype is regulated by the tumor microenvironment. Indeed, recent studies show that hypoxia and its molecular responses regulate cancer stem cell maintenance. We now demonstrate that acidic conditions, independent of restricted oxygen, promote the expression of GSC markers, self-renewal and tumor growth. GSCs exert paracrine effects on tumor growth through elaboration of angiogenic factors, and low pH conditions augment this expression associated with induction of hypoxia inducible factor 2α (HIF2α), a GSC-specific regulator. Induction of HIF2α and other GSC markers by acidic stress can be reverted by elevating pH in vitro, suggesting that raising intratumoral pH may be beneficial for targeting the GSC phenotype. Together, our results suggest that exposure to low pH promotes malignancy through the induction of a cancer stem cell phenotype, and that culturing cancer cells at lower pH reflective of endogenous tumor conditions may better retain the cellular heterogeneity found in tumors.
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Abbreviations
- DFX:
-
desferrioxamine
- DMEM:
-
Dulbecco's Modified Eagle Medium
- EGF:
-
epidermal growth factor
- ELISA:
-
enzyme-linked immunosorbent assay
- FBS:
-
fetal bovine serum
- FGF:
-
fibroblast growth factor
- GBM:
-
glioblastoma
- GFAP:
-
glial fibrillary acidic protein
- GSC:
-
glioma stem cell
- HIF:
-
hypoxia inducible factor
- PCR:
-
polymerase chain reaction
- IL-8:
-
interleukin 8
- TIMP:
-
tissue inhibitor of metalloproteinase
- VEGF:
-
vascular endothelial growth factor
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Acknowledgements
Financial support was provided by the Goldhirsh Foundation, McDonnell Foundation, and NIH grants NS054276, CA116659, CA129958, CA154130 (JR). AH is supported by a grant from the National Brain Tumor Association and by NIH grant CA151522. JDL is supported by a National Research Service Award (CA142159) and an American Brain Tumor Association Fellowship (Sponsored by the Joelle Syverson Fund).
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Hjelmeland, A., Wu, Q., Heddleston, J. et al. Acidic stress promotes a glioma stem cell phenotype. Cell Death Differ 18, 829–840 (2011). https://doi.org/10.1038/cdd.2010.150
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DOI: https://doi.org/10.1038/cdd.2010.150
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