Glioblastoma remains the most aggressive and devastating form of primary brain tumor with universally dismal survival outcomes despite multi-modality management, essentially rendering it incurable in contemporary neuro-oncologic practice. It displays all the classical hallmarks of cancer including i

Transl Cancer Res 2016;5(Suppl 4):S738-S741 tcr.amegroups. com Glioblastoma remains the most aggressive and devastating form of primary brain tumor with universally dismal survival outcomes despite multi-modality management, essentially rendering it incurable in contemporary neuro-oncologic practice. It displays all the classical hallmarks of cancer including immune suppression, sustained proliferative signalling, inhibition of apoptosis, angiogenesis and invasion (1,2). Glioblastoma is biologically very heterogeneous; this intra-tumoral heterogeneity is explained by the stochastic model (2,3), wherein the tumor arises from a single clone of cells with further progression resulting from random accumulation of somatic mutations in genetically unstable cell population and sequential selection of malignant subclones through micro-environment cues. The current standard of care for newly-diagnosed glioblastoma comprising maximal safe resection followed by postoperative focal conformal radiotherapy to the tumor bed with concurrent and adjuvant temozolomide chemotherapy, results in a median survival of around 15 months and a 5-year overall survival rarely exceeding 8–10% (4). Recent research suggests that glioblastomas may be organized hierarchically with a small number of progenitor cells (5-7), so called glioblastoma stem cells (GSCs) that have self-renewal capacity, multi-lineage potency, as well as properties of tumor initiation and propagation responsible for relapse, recurrence and/or progression in glioblastoma. It is widely believed, that GSCs reside preferentially within the hypoxic core of the glioblastoma tumour mass, while more differentiated cells are mainly localized along the peripheral and more vascularized part of the tumour (8). These GSCs have a selective tropism (9,10) for the subventricular zone (SVZ), the largest reservoir of neural stem cells in the adult brain (11). In addition to the established role of SVZ-derived cells towards olfactory function and neurogenesis for brain repair in response to injury, there is increasing evidence of its role in gliomagenesis (12,13). The identification of GSCs spawned a slew of experimental model systems to understand and characterize the relationship between SVZ and glioblastoma. The notion of SVZ as a potential oncogenic niche originated from an early study (14) suggesting that brain tumors in contact with ventricular walls might be arising from the embryonic rests present in the SVZ. This was followed by studies demonstrating mitoses occurring in the sub-ependymal layer of rodent and primate brain (15). In mice, it was initially shown that undifferentiated (precursor) cells are more easily transformed compared to cells that are terminally differentiated (16), thus corroborating the hypothesis that precursor or neural stem cells might represent the target of malignant transformation. In addition, another study (17) comparing cultures of astrocytes versus neurosphere precursor cells showed that dedifferentiation of astrocytes makes these cells susceptible to malignant transformation similarly to neural stem cells, by combining loss of critical tumor suppressors. Importantly, the phylogenetic relationship between SVZ and glioblastoma clearly establishes SVZ as a reservoir of GSCs (either early tumor clones or late-emergent clones) that are largely resistant to standard radiotherapy and chemotherapy, resulting in disease progression and treatment failure. In this context, GSCs isolated from SVZ could be used for unravelling and understanding mechanisms of resistance in glioblastoma. Editorial