gms | German Medical Science

60. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit den Benelux-Ländern und Bulgarien

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

24. - 27.05.2009, Münster

Impact of differentiation resistance on tumor stem cell phenotype in gliomas

Meeting Abstract

  • B. Campos - Neurochirurgische Klinik, Universitätsklinikum Heidelberg
  • F. Wan - Neurochirurgische Klinik, Universitätsklinikum Heidelberg
  • R. Ahmadi - Neurochirurgische Klinik, Universitätsklinikum Heidelberg
  • N. Becker - Neurochirurgische Klinik, Universitätsklinikum Heidelberg
  • C. Herold-Mende - Neurochirurgische Klinik, Universitätsklinikum Heidelberg
  • A. Unterberg - Neurochirurgische Klinik, Universitätsklinikum Heidelberg

Deutsche Gesellschaft für Neurochirurgie. 60. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit den Benelux-Ländern und Bulgarien. Münster, 24.-27.05.2009. Düsseldorf: German Medical Science GMS Publishing House; 2009. DocMI.06-01

doi: 10.3205/09dgnc202, urn:nbn:de:0183-09dgnc2027

Veröffentlicht: 20. Mai 2009

© 2009 Campos et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen ( Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.



Objective: The so-called brain tumor stem cell concept postulates that immature cell populations reside within a given tumor and seem to be irresponsive to physiological differentiation stimuli, persisting in an undifferentiated state associated with high tumorigenicity and therapy resistance. Such a loss of differentiation capacity could occur at multiple levels involving for instance loss of specific receptors for endogenous differentiation inducers like bone morphogenetic proteins (BMP) and retinoic acid (RA) or upregulation of enzymes like CYP26 participating in the degradation of the latter. Here we investigated potential mechanisms that could lead to a loss of differentiation capacity in glioma and analyzed their influence on patient outcome.

Methods: To address these questions, we used of a tissue-microarray (TMA) consisting of 281 astrocytic gliomas WHO° II-IV to study the expression of key receptors belonging to major differentiation pathways such as RA and BMP signaling. Protein expression was correlated with tumor grades and patient survival data. Subsequently expression of differentiation receptors was analyzed in several stem-like glioma cell (SLGC) lines (n=5). Induction of CYP26 enzymes after treatment with RA was studied with quantitative PCR.

Results: Expression analysis of BMP and RA -pathway receptors revealed a negative correlation with WHO° for retinoid X receptor alpha (RXRalpha, p<0.0001), retinoid X receptor gamma (RXRgamma, p<0.0001) and BMP receptor 1B (BMPR1B, p<0.0001). Furthermore, in multivariate analysis, loss of RXRalpha expression proved to be a significant predictor of poor patient outcome. Screening of SLGC lines showed that the tumor stem cell phenotype was associated with a loss of RARbeta and BMPR1B on the mRNA level, which was of particular interest since these receptors were widely distributed on normal glioma tissues. Finally we found that SLGCs can induce CYP26B1 molecules up to 6-fold in the presence of RA and might thus render SLGCs resistant to the differentiation effect of this natural substrate. Interestingly, the process could be partly reversed in the presence of Liarozol, an unspecific CYP inhibitor.

Conclusions: Our data support the notion that different mechanisms involved in the loss of differentiation capacity might be involved in the maintenance of an undifferentiated tumor stem cell phenotype in glioma and that such a differentiation resistance might influence the clinical prognosis of glioma patients.