MGMT hypermethylation and MDR system in glioblastoma cancer stem cells

Cancer Genomics Proteomics. 2012 Jul-Aug;9(4):171-8.

Abstract

Background: Cancer stem cells (CSCs) in gliomas are associated with resistance to radio- and chemotherapy, based on O(6)-methylguanine-DNA methyltransferase (MGMT) hypermethylation and the Multidrug resistance (MDR) system activation.

Materials and methods: Samples from 21 glioblastomas (GBMs) were put in culture with growth factors or serum in order to obtain neurospheres or adherent cells. Both were genetically and immunohistochemically characterized for ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1), ATP-binding cassette, sub-family C (CFTR/MRP), member 1 (ABCC1) and MGMT expression together with primary tumors.

Results: ABCB1 expression was positive in endothelial cells of primary tumors. ABCC1 expression was variably positive in tumor cells and positive in neurospheres, and less expressed in adherent cells. MGMT was methylated and unmethylated in primary tumors and in neurospheres, respectively, and unmethylated in adherent cells.

Conclusion: Methylation is an epigenetic event affecting progenitors before the separation of the two glia lineages and maximally the future initiating cells. ABCB1 expression is limited to endothelial cells, whereas ABCC1 expression could mark a minority of tumor cells approaching a stem-like status.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1* / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1* / metabolism
  • Adult
  • Aged
  • Aged, 80 and over
  • Brain Neoplasms / metabolism*
  • Cells, Cultured
  • DNA Methylation
  • DNA Modification Methylases* / genetics
  • DNA Modification Methylases* / metabolism
  • DNA Repair Enzymes* / genetics
  • DNA Repair Enzymes* / metabolism
  • Drug Resistance, Multiple / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / metabolism*
  • Humans
  • Male
  • Middle Aged
  • Multidrug Resistance-Associated Proteins* / genetics
  • Multidrug Resistance-Associated Proteins* / metabolism
  • Neoplastic Stem Cells / metabolism
  • Promoter Regions, Genetic
  • Tumor Suppressor Proteins* / genetics
  • Tumor Suppressor Proteins* / metabolism

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Multidrug Resistance-Associated Proteins
  • Tumor Suppressor Proteins
  • DNA Modification Methylases
  • MGMT protein, human
  • DNA Repair Enzymes
  • multidrug resistance-associated protein 1