4.7 Article

O6-Methylguanine-Methyltransferase (MGMT) Promoter Methylation Status in Glioma Stem-Like Cells is Correlated to Temozolomide Sensitivity Under Differentiation-Promoting Conditions

Journal

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 13, Issue 6, Pages 6983-6994

Publisher

MDPI
DOI: 10.3390/ijms13066983

Keywords

MGMT methylation; glioma stem-like cells; temozolomide; differentiation

Funding

  1. Ligue contre le Cancer de la Vienne et des Deux-Sevres
  2. Region Poitou-Charentes
  3. Canceropole Grand Ouest (Reseau Gliomes)
  4. Institut National du Cancer
  5. Sport et Collection foundation
  6. Rotary Club de Civray foundation

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Glioblastoma (GBM) is the most malignant type of primary brain tumor with a very poor prognosis. The actual standard protocol of treatment for GBM patients consists of radiotherapy and concomitant temozolomide (TMZ). However, the therapeutic efficacy of this treatment is limited due to tumor recurrence and TMZ resistance. Recently isolated, glioma stem-like cells (GSCs) are thought to represent the population of tumorigenic cells responsible for GBM resistance and recurrence following surgery and chemotherapy. In addition, MGMT (O6-methylguanine-methyltransferase) methylation is considered as one of the principal mechanisms contributing to TMZ sensitivity of GBM. In this study we have isolated GSCs from 10 adult GBM patients and investigated the relationship between MGMT methylation status and Temozolomide (TMZ) sensitivity of these lines grown either in stem-like or differentiation promoting conditions. Sensitivity to TMZ was significantly associated with MGMT methylation status in cells committed to differentiation but not in stem-like cells. In addition, patients harboring highly methylated MGMT promoters had a longer overall survival. These results reveal the importance of the differentiation process when considering the predictive value of MGMT status in GSCs for clinical response to TMZ.

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