Ella L. Kim
The Translational Neurooncology Research Group, Department of Neurosurgery, University Medical Centre, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
Glioblastoma multiforme (GBM) is one of the most challenging human cancers. The current standard of care for GBM consists of surgical de-bulking followed by combined radio- and cytotoxic chemotherapy. Despite this multimodal therapy, post-treatment recurrence is almost inevitable and is a major cause of GBM patient lethality. There has been a growing realization that malignant gliomas have a hierarchical structure, whereby distinct populations of cells within the same tumour vary in their capacity to promote tumour growth and ability to withstand the effects of cytotoxic treatments The pronounced intrinsic radioresistance of GBMs is partially linked to the existence of stem-like cells, also called glioblastomainitiating cells (GICs), in these malignancies. There has been a growing realization that intrinsic resistance of GICs to cytotoxic agents is the underlying reason for the poor efficacy of conventional cytotoxic therapy. The elucidation of molecular mechanisms that render GICs resistant to clinically relevant doses of ionizing radiation is of pivotal importance for improving the effectiveness of cytotoxic therapies and development of individualized approaches to the treatment of GBM. While the GIC paradigm is rapidly gaining widespread acceptance, there is still considerable uncertainty as to the identity of GICs and their precise roles in the initiation, maintenance and progression of GBM. Fundamental remaining questions include: Is there a universal type of stem-like glioma cells? What criteria define glioma cell stemness? How does the degree of glioma cell stemness relate to the clinicopathological criteria of glioma aggressiveness? To address these questions, the relationship between tumorigenicity, proliferative potential and differentiation was examined through a combinatorial approach based on in vitro, in vivo and in silico analyses of different types of stem-like glioma cells. Our research indicates that glioma cells collectively called GICs comprise a heterogeneous group of phenotypically and functionally distinct cell types with varying tumorigenic potential. Our findings indicate that the phenomenon of glioma radioresistance involves a global gene expression reprogramming in GICs and urge the necessity of transcriptional profiling as a means of monitoring the recurrence of GBM under conventional cytotoxic therapy.