2. Academic Validation
  3. The Adenosine A₃ Receptor Regulates Differentiation of Glioblastoma Stem-Like Cells to Endothelial Cells under Hypoxia

The Adenosine A₃ Receptor Regulates Differentiation of Glioblastoma Stem-Like Cells to Endothelial Cells under Hypoxia

  • Int J Mol Sci. 2018 Apr 18;19(4):1228. doi: 10.3390/ijms19041228.
René Rocha 1,  Ángelo Torres 2,  Karina Ojeda 3,  Daniel Uribe 4,  Dellis Rocha 5,  José Erices 6,  Ignacio Niechi 7,  Pamela Ehrenfeld 8,  Rody San Martín 9,  Claudia Quezada 10
Affiliations

Affiliations

  • 1 Laboratorio de Patología Molecular, Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile. [email protected].
  • 2 Laboratorio de Patología Molecular, Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile. [email protected].
  • 3 Laboratorio de Patología Molecular, Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile. [email protected].
  • 4 Laboratorio de Patología Molecular, Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile. [email protected].
  • 5 Laboratorio de Patología Molecular, Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile. [email protected].
  • 6 Laboratorio de Patología Molecular, Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile. [email protected].
  • 7 Laboratorio de Patología Molecular, Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile. [email protected].
  • 8 Instituto de Anatomía, Histología y Patología, Universidad Austral de Chile, Valdivia 5090000, Chile. [email protected].
  • 9 Laboratorio de Patología Molecular, Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile. [email protected].
  • 10 Laboratorio de Patología Molecular, Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile. [email protected].
PMID: 29670017 DOI: 10.3390/ijms19041228
Abstract

Glioblastoma (GBM) is a neoplasm characterized by an extensive blood vessel network. Hypoxic niches of GBM can induce tumorigenic properties of a small cell subpopulation called Glioblastoma stem-like cells (GSCs) and can also increase extracellular adenosine generation which activates the A₃ Adenosine Receptor (A₃AR). Moreover, GSCs potentiates the persistent neovascularization in GBM. The aim of this study was to determine if A₃AR blockade can reduce the vasculogenesis mediated by the differentiation of GSCs to Endothelial Cells (ECs) under hypoxia. We evaluated the expression of endothelial cell markers (CD31, CD34, CD144, and vWF) by fluorescence-activated cell sorting (FACS), and vascular endothelial growth factor (VEGF) secretion by ELISA using MRS1220 (A₃AR antagonist) under hypoxia. We validate our results using U87MG-GSCs A₃AR knockout (GSCsA3-KO). The effect of MRS1220 on blood vessel formation was evaluated in vivo using a subcutaneous GSCs-tumor model. GSCs increased extracellular adenosine production and A₃AR expression under hypoxia. Hypoxia also increased the percentage of GSCs positive for endothelial cell markers and VEGF secretion, which was in turn prevented when using MRS1220 and in GSCsA3-KO. Finally, in vivo treatment with MRS1220 reduced tumor size and blood vessel formation. Blockade of A₃AR decreases the differentiation of GSCs to ECs under hypoxia and in vivo blood vessel formation.

Keywords

A3 adenosine receptor; adenosine; endothelial cells; glioblastoma stem-like cells; neovascularization.

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