gms | German Medical Science

59. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
3. Joint Meeting mit der Italienischen Gesellschaft für Neurochirurgie (SINch)

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

01. - 04.06.2008, Würzburg

Differentiation therapy impacts on malignancy-related properties of brain tumor stem cell-derived tumors

Differenzierungstherapie beeinflusst malignitätsassoziierte Eigenschaften von Glioblastomstammzellen

Meeting Abstract

  • corresponding author B. Campos - Sektion Neurochirurgische Forschung, Neurochirurgische Klinik, Universitätsklinikum Heidelberg
  • F. Wan - Sektion Neurochirurgische Forschung, Neurochirurgische Klinik, Universitätsklinikum Heidelberg
  • R. Ahmadi - Sektion Neurochirurgische Forschung, Neurochirurgische Klinik, Universitätsklinikum Heidelberg
  • M. Farhadi - Sektion Neurochirurgische Forschung, Neurochirurgische Klinik, Universitätsklinikum Heidelberg
  • A. Unterberg - Sektion Neurochirurgische Forschung, Neurochirurgische Klinik, Universitätsklinikum Heidelberg
  • C. C. Herold-Mende - Sektion Neurochirurgische Forschung, Neurochirurgische Klinik, Universitätsklinikum Heidelberg

Deutsche Gesellschaft für Neurochirurgie. Società Italiana di Neurochirurgia. 59. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC), 3. Joint Meeting mit der Italienischen Gesellschaft für Neurochirurgie (SINch). Würzburg, 01.-04.06.2008. Düsseldorf: German Medical Science GMS Publishing House; 2008. DocDI.04.04

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dgnc2008/08dgnc170.shtml

Veröffentlicht: 30. Mai 2008

© 2008 Campos et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Objective: Tumor stem cells (TSCs) are hold responsible for tumor initiation and therapy resistance in a variety of cancers, including leukemia, carcinomas of breast and colon as well as several types of brain tumors. Differentiation of TSCs has been discussed as a possible approach to eradicate the tumor-driving cell population disrooting the actively proliferating tumor bulk. Since all-trans retinoic acid (ATRA) is known as a modulator of differentiation and proliferation, we sought to elucidate whether ATRA induces differentiation of glioblastoma-derived TSC, so-called brain tumor stem cells (BTSCs) and if tumor-relevant properties of these cells are affected by differentiation.

Methods: BTSC lines (n=3) with high CD133 content (68-93%) were treated with ATRA-containing medium. Change in proliferation and CD133 content was monitored by BrdU-incorporation assay and FACS-analysis, respectively. Impact of differentiation on the angiogenic capacity of BTSCs was measured by quantification of angiogenic cytokines and assessed in a HUVEC-based tube formation assay. Potential effects on BTSC invasiveness were studied in a 3D-collagen invasion model. Finally, we studied whether in vitro effects could be confirmed in vivo using a NOD/SCID-mouse xenograft model.

Results: We present evidence that BTSCs exposed to ATRA increase their proliferative activity and simultaneously lower the expression of stem cell-related antigen CD133 by up to 75% in favor of incremented linage markers GFAP, MBP and beta3-tubulin. Furthermore, we report on significantly reduced VEGF and bFGF secretion by 70-82% and 95-99% respectively, as well as significantly lowered tube-formation by up to 55% following differentiation. Additionally, we show that differentiation elicits strong anti-invasive effects reducing collagen invasion by up to 46% and that these effects are associated with a marked downregulation of invasion-related MMP2 protein (up to sevenfold). Finally, we report that xenografted tumors of differentiated BTSCs are significantly smaller (only 15% of BTSC tumor volume) and less invasive than undifferentiated BTSC tumor xenografts. Correspondingly, animals bearing differentiated cells show both significantly better PFS and OS than mice with BTSC xenografts (p<0,016).

Conclusions: Altogether, these results highlight the potential of differentiation treatment to target the tumor-driving compartment in glioblastoma and point out a potential therapeutic value in the eradication of TSCs.