Abstract
The niche concept was originally developed to describe the location of normal neural stem cells (NSCs) in the subependymal layer of the sub-ventricular zone. In this paper, its significance has been extended to the location of tumor stem cells in glioblastoma (GB) to discuss the relationship between GB stem cells (GSCs) and endothelial cells (ECs). Their interaction is basically conceived as responsible for tumor growth, invasion and recurrence. Niches are described as the points of utmost expression of the tumor microenvironment (TME), therefore including everything in the tumor except for tumor cells: NSCs, reactive astrocytes, ECs, glioma-associated microglia/macrophages (GAMs), myeloid cells, pericytes, fibroblasts, etc. and all intrinsic and extrinsic signaling pathways. Perivascular (PVNs), perinecrotic (PNNs) and invasive niches were described from the pathological point of view, highlighting the basic significance of the EC/tumor stem cell couple. PNN development was reinterpreted based on the concept that hyperproliferative areas of GB are composed of GSCs/progenitors. TME was depicted in its function as the main regulator of everything that happens in the tumor. A particular emphasis was given to GAMs, pericytes and reactive astrocytes as important elements affecting proliferation, growth, invasion and resistance to therapies of tumor cells.
Highlights
Glioblastoma (GB) is the most aggressive primary brain tumor in adults accounting for >50% of the tumors of the brain
Its significance has been extended to the location of tumor stem cells in glioblastoma (GB) to discuss the relationship between GB stem cells (GSCs) and endothelial cells (ECs)
Niches are described as the points of utmost expression of the tumor microenvironment (TME), including everything in the tumor except for tumor cells: neural stem cells (NSCs), reactive astrocytes, ECs, glioma-associated microglia/macrophages (GAMs), myeloid cells, pericytes, fibroblasts, etc. and all intrinsic and extrinsic signaling pathways
Summary
Glioblastoma (GB) is the most aggressive primary brain tumor in adults accounting for >50% of the tumors of the brain. Three main properties of the tumor hampers its successful treatment: (i) The occurrence of GB stem cells (GSCs); (ii) the tumor heterogeneity; (iii) the microenvironment and the niches. There is a general agreement that GSCs in the tumor reside in niches that are similar to those hosting normal neural stem cells (NSCs) in the subventricular zone (SVZ) [20]. In these niches, neuroblasts, quiescent NSCs and transit-amplifying cells (A, B and C cells, respectively) occur [21]. GSCs/progenitors in different differentiation stages populate solid proliferative areas of GB, apparently not associated with necrosis or vessels; their differentiation stage is regulated by the TME
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