Cancer stem-like cells (CSCs) may be the long sought answer to the questions puzzling scientists for over 50 years: recurrence and treatment resistance in glioblastoma multiforme (GBM). The endothelium might be the exponential player in the complex cellular milieu that regulates tumor behavior and growth. Going deeper into the perivascular stem cell niche and understanding the molecular mechanisms underlying the crosstalk between different components, may uncover innovative and more efficient therapeutic options. Eradicating the cancer stem-like cells, not only directly but also by targeting the endothelial niche, seems to be a topic of high interest in cancer research today. Recent work published by Zhu et al (Cancer Research, September 2011) tackles the problem of NOTCH ligands (DLL1, DLL4 and JAG1) of endothelial origin as the juxtacrine driving mechanism for CSC self-renewal, similar to the one seen in the normal neural stem cells of the subventricular zone. Interestingly, differentiated tumor cells seem to also contribute by providing additional NOTCH ligands, specifically JAG1. One of the three quintessential stem cell properties, self-renewal, is viewed by the authors as the main cause of tumor growth and relapse. The paper shows that the ligands directly promote neurosphere growth in vitro in a dose dependent manner by maintaining this intrinsic self-renewal capacity. Authors also conclude that these ligands do not increase the overall culture proliferation rate, as assessed by PCNA and Ki-67 levels, when mediated by the endothelium (see Figure, hBMCs–human brain microvascular endothelial cells). Ligand knockdown studies further show their diminishing growth capacity as intracranial xenografts and the impoverishing effect on CSC markers such as CD133.Figure: Human brain microvascular endothelial cells.By using the putative glioblastoma stem cell marker NESTIN, authors first demonstrate that NOTCH1 receptors are predominantly localized on CSCs and that JAG1/DLL expressing cells are placed in the vicinity of NOTCH activated cells. Having solved the problem of proximity they move on to elucidate the nature of NOTCH ligand expressing cells. DLL4 seems to be primarily linked to CD31 positive endothelial cells within the GBM. On the other hand, DLL1 is much more characteristic for tumor cells, being a marker for well differentiated GBM cells with reduced CD133 levels and reduced proliferation. By losing stemness and NOTCH activity, these later more mature cells seem to be having more of a supportive and structural role as part of the niche, with a much lower capacity to induce tumors in vivo when compared to fully functional CSCs. Blockage of the NOTCH pathway seemingly has a dual effect: depletion of the CSC pool in vitro and inhibition of tumor progression in vivo, which are probably interrelated phenomena. The authors postulate that CD 133 positive stem cells induce VEGF that further leads to DLL4 production, thereby closing a CSC-endothelium loop. The promising results seen with angiogenesis inhibitors such as bevacizumab in recurrent GBMs might therefore also be explained through this mechanistic loop, although more refined studies on the molecular effects of bevacizumab are deemed necessary. Granted that other molecules looming around the niche are also involved in CSC self-renewal, such as NO and HIF2α, and more targeted and specific antibody inhibition of each pathway might be more efficient, further studies are warranted to clearly identify all crosstalk channels of the stem cell niche and to decide upon the best mode of action to completely eradicate cancer stem cells.