Acidic stress promotes a glioma stem cell phenotype.
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.
Departments of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. hjelmea@ccf.org
A B
AB
Hjelmeland
Q
Q
Wu
J M
JM
Heddleston
G S
GS
Choudhary
J
J
MacSwords
J D
JD
Lathia
R
R
McLendon
D
D
Lindner
A
A
Sloan
J N
JN
Rich
D000138:Acidosis; D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D051272:Glucose Transporter Type 1 / Q000235:genetics; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D000071317:Nanog Homeobox Protein; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D010641:Phenotype; D015843:Serpins / Q000235:genetics; D013312:Stress, Physiological; D014158:Transcription, Genetic; D059016:Tumor Microenvironment / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D043925:Angiogenesis Inducing Agents; D000943:Antigens, Differentiation; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D051272:Glucose Transporter Type 1; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071317:Nanog Homeobox Protein; D009419:Nerve Tissue Proteins; D050814:Octamer Transcription Factor-3; D000076104:Oligodendrocyte Transcription Factor 2; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C486780:NANOG protein, human; C405708:OLIG2 protein, human; C494173:POU5F1 protein, human; C102316:SERPINB9 protein, human; C495677:SLC2A1 protein, human