Tumor stem cells from glioblastoma multiforme

Abstract

Glioblastoma multiforme, a World Health Organization grade IV malignant glioma, is the most common and lethal primary brain tumor with the median survival of approximately 15–25 months after treatment. Glioblastoma multiforme has been shown to be resistant to radiotherapy and chemotherapy and invariably recurs following surgical resection and chemoradiation. The characteristics of this tumor are exemplified by heterogeneous cell population with diverse biologic properties and genetic changes, the ability to form cancer stem cells (CSC) and divided into four molecular subtypes – proneural, neural, classical and mesenchymal. Despite some success, the mechanisms leading to the formation of the most malignant tumor subtype are unclear. The aim of this review was a synthesis of modern information about the role and biological characteristics of tumor stem cells in tumor progression and the pathogenesis of glioblastoma multiforme. CSCs reside in niches, which are anatomically distinct regions within the tumor microenvironment. These niches maintain the principle properties of CSCs, preserve their phenotypic plasticity, adhesion, survival, resistance to standard cancer treatment and metastatic potential. The presence of aberrant signaling pathways (Notch, Hedgehog-Gli, Wnt/β-catenin, TGF-β/SMAD, PI3K/Akt/mTOR), both in the tumor and in the population of CSC, the dysregulation of microRNAs (miR-21, miR-128, miR-326, miR-34a), influence of epithelial-to-mesenchymal transition explains the availability of typical biological characteristics of the CSC. One needs to consider the influence of the therapy on normal stem cells in the development of drugs directed against the CSC. Regulatory mechanisms and markers found over the last decade can be used as the basis for creation of the new drugs with targeted action in the treatment of glioblastoma multiforme.

Keywords

• glioblastoma multiforme
• cancer stem cell
• cd 133+ marker
• notch-signaling pathway
• hedgehog-gli-signaling pathway
• wnt/ β-catenin-signaling pathway
• tgf-β/smad-signaling pathway
• epithelial – mesenchymal transition
• microrna