Highly infiltrative brain tumours show reduced chemosensitivity associated with a stem cell-like phenotype

T. C.A. Johannessen, J. Wang, K. O. Skaftnesmo, P. Sakariassen, P. Enger, K. Petersen, A. M. Øyan, K. H. Kalland, R. Bjerkvig, B. B. Tysnes

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43 Citations (Scopus)

Abstract

Aims: Cancer stem-like cells might have important functions in chemoresistance. We have developed a model where highly infiltrative brain tumours with a stem-like phenotype were established by orthotopic transplantation of human glioblastomas to immunodeficient rats. Serial passaging gradually transformed the tumours into a less invasive and more angiogenic phenotype (high-generation tumours). The invasive phenotype (low-generation tumours) was characterized by an increase in stem cell markers and increased phosphorylation of kinases in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. These markers were reduced in the serially passaged vascular tumours. The present study was aimed at investigating how the two phenotypes responded in vitro to doxorubicin, a clinically potent cytotoxic drug for solid tumours. Methods: Biopsy spheroids were implanted and passaged intracranially in nude rats. Gene expression and protein analyses were performed, and drug sensitivity was assessed. Results: Microarray analysis revealed gene ontology categories connected to developmental aspects and negative regulators of differentiation, especially in the infiltrative stem cell-like tumours. The highly invasive stem-like phenotype was chemoresistant compared with the angiogenic phenotype. By interfering with the PI3K it was possible to sensitize tumour spheroids to chemotherapy. Real-time quantitative polymerase chain reaction showed downregulation of the stem cell markers Nestin and Musashi-1 in low-generation biopsy spheroids following PI3K inhibition. Conclusions: Highly invasive tumours with a stem-like phenotype are more chemoresistant than angiogenic tumours derived from the same patients. We suggest that treatment resistance in glioblastomas can be related to PI3K/AKT activity in stem-like tumour cells, and that targeted interference with the PI3K/AKT pathway might differentiate and sensitize this subpopulation to chemotherapy.

Original languageEnglish
Pages (from-to)380-393
Number of pages14
JournalNeuropathology and Applied Neurobiology
Volume35
Issue number4
DOIs
Publication statusPublished - Aug 2009
Externally publishedYes

Keywords

  • Brain tumour
  • Cancer stem-like cell
  • Differentiation
  • Stem cells
  • Treatment resistance

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