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.

[1]  R. Gillies,et al.  Why do cancers have high aerobic glycolysis? , 2004, Nature Reviews Cancer.

[2]  K. Seeger,et al.  Hypoxia upregulates the histone demethylase JMJD1A via HIF-1. , 2008, Biochemical and biophysical research communications.

[3]  R. Jain,et al.  Acidic Extracellular pH Induces Vascular Endothelial Growth Factor (VEGF) in Human Glioblastoma Cells via ERK1/2 MAPK Signaling Pathway , 2002, The Journal of Biological Chemistry.

[4]  Å. Borg,et al.  Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. , 2006, Cancer cell.

[5]  A. Harris,et al.  Role of Hypoxia‐Inducible Factors in Epigenetic Regulation via Histone Demethylases , 2009, Annals of the New York Academy of Sciences.

[6]  P. Vaupel,et al.  pH distributions in spontaneous and isotransplanted rat tumours. , 1988, British Journal of Cancer.

[7]  P. Okunieff,et al.  Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. , 1989, Cancer research.

[8]  I. Bayazitov,et al.  A perivascular niche for brain tumor stem cells. , 2007, Cancer cell.

[9]  Robert J Gillies,et al.  The potential role of systemic buffers in reducing intratumoral extracellular pH and acid-mediated invasion. , 2009, Cancer research.

[10]  Jeffrey M. Rosen,et al.  The Increasing Complexity of the Cancer Stem Cell Paradigm , 2009, Science.

[11]  L. Gerweck,et al.  Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. , 1996, Cancer research.

[12]  T. Tsuruo,et al.  Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions , 2009, Oncogene.

[13]  L. Chin,et al.  Malignant astrocytic glioma: genetics, biology, and paths to treatment. , 2007, Genes & development.

[14]  J. Pouysségur,et al.  Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer , 2009, Journal of cellular and molecular medicine.

[15]  Zang Ai-hua,et al.  Stem Cells,Cancer and Cancer Stem Cells , 2005 .

[16]  R K Jain,et al.  Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. , 2001, Cancer research.

[17]  Qiulian Wu,et al.  Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. , 2006, Cancer research.

[18]  Brian Keith,et al.  Hypoxia-Inducible Factors, Stem Cells, and Cancer , 2007, Cell.

[19]  Tarik Tihan,et al.  The hypoxic response of tumors is dependent on their microenvironment. , 2003, Cancer cell.

[20]  M. Weller,et al.  Modulation of growth and radiochemosensitivity of human malignant glioma cells by acidosis , 2002, Cancer.

[21]  L. Gunaratnam,et al.  HIF activation by pH-dependent nucleolar sequestration of VHL , 2004, Nature Cell Biology.

[22]  S. Caldeira,et al.  Na+/H+ exchanger‐dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation‐associated phenotypes , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[23]  Brian Keith,et al.  HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. , 2006, Genes & development.

[24]  P. Ratcliffe,et al.  Regulation of Jumonji-domain-containing histone demethylases by hypoxia-inducible factor (HIF)-1alpha. , 2008, The Biochemical journal.

[25]  Martin J. van den Bent,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[26]  E. Rankin,et al.  Regulation of the Histone Demethylase JMJD1A by Hypoxia-Inducible Factor 1α Enhances Hypoxic Gene Expression and Tumor Growth , 2009, Molecular and Cellular Biology.

[27]  J. Wilcox,et al.  Cerebral microenvironment influences expression of the vitronectin gene in astrocytic tumors. , 1995, Journal of cell science.

[28]  Deric M. Park,et al.  Biology of glioma cancer stem cells , 2009, Molecules and cells.

[29]  W. Cavenee,et al.  Vascular endothelial growth factor isoforms display distinct activities in promoting tumor angiogenesis at different anatomic sites. , 2001, Cancer research.

[30]  J. Engh,et al.  Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1α , 2009, Oncogene.

[31]  C. Gundy,et al.  Expression of the Apoptosis Inhibitor Protease Inhibitor 9 Predicts Clinical Outcome in Vaccinated Patients with Stage III and IV Melanoma , 2005, Clinical Cancer Research.

[32]  Hui Wang,et al.  Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. , 2009, Cancer cell.

[33]  Harikrishna Nakshatri,et al.  CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis , 2006, Breast Cancer Research.

[34]  M. Wolter,et al.  A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha. , 2010, Brain : a journal of neurology.

[35]  J. Best,et al.  Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer , 2005, Journal of cellular physiology.

[36]  W. Boron,et al.  Long-term expression of c-H-ras stimulates Na-H and Na(+)-dependent Cl-HCO3 exchange in NIH-3T3 fibroblasts. , 1994, The Journal of biological chemistry.

[37]  Bonnie F. Sloane,et al.  Bicarbonate increases tumor pH and inhibits spontaneous metastases. , 2009, Cancer research.

[38]  Mark W. Dewhirst,et al.  Glioma stem cells promote radioresistance by preferential activation of the DNA damage response , 2006, Nature.

[39]  R. McLendon,et al.  The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype , 2009, Cell cycle.

[40]  R. McLendon,et al.  Integrin alpha 6 regulates glioblastoma stem cells. , 2010, Cell stem cell.