The role of sub-ventricular zone in gliomagenesis

are incurable diseases characterised by high inter-and intra-tumor heterogeneity (ITH), diffuse brain infiltration and treatment resistance. Over the last fifteen years, studies at the interface between stem cell biology and cancer research have established the existence of cancer stem-like populations in GBM and other brain tumors (reviewed in [1]). These data have been accompanied by speculation about neural stem cells being the cell of origin of these malignancies. In support of this hypothesis, mouse models studies have repeatedly suggested that GBM can originate from transformed neural stem/precursor cells [2-4]. However, similar evidence in human was still missing. Recently, we have developed a real-time fluorescence-guided multiple sampling (FGMS) strategy to investigate the extent of spatial ITH in human GBM [5]. This approach stems from an initial proof-of-concept study aimed at assessing the use of a fluorescent marker (5-Aminolevulinic acid, 5-ALA) to investigate the distribution of cancer stem-like cells (alternatively named tumor propagating cells) at the core and margin of human GBM [6]. In our recent publication [7] we have used FGMS to identify visible fluorescence in the adult sub-ventricular zone (SVZ), a germinal region of the human brain and, for the first time, we have started to reveal its role in gliomagenesis and treatment resistance in humans. Fluorescent disease was present in the SVZ of 65% of the GBM patients (in [7] we refer to this region as sub-ependymal zone because we could distinguish the ependymal layer separating the tissue from the ventricle by using an intra-operative fluorescent microscope). It is well established that 5-ALA fluorescence is specific to tumor cells in GBM. Therefore we hypothesised that visible fluorescence in the SVZ would identify malignant cells. The most common genetic alterations of GBM identified by The Cancer Genome Atlas (TCGA) were present in this region of all the analysed patients and genomic analysis showed ITH between the SVZ and matched tumor mass (T), thus confirming that the SVZ represents a niche of malignant cells. Interestingly, clustering of gene expression profiles revealed a marked predominance of mesenchymal signatures in almost 80% of the SVZ samples irrespec-Editorial tive of the subtype of the corresponding T suggesting that the SVZ might nurture tumor growth. To address the functional role of SVZ tumor cell populations, we characterised matched T-and SVZ-tumor propagating cells in vitro and in vivo. We tested three drugs commonly used in GBM treatment: temozolomide (an alkylating agent that represents the standard of …