Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells

One important function of endothelial cells in glioblastoma multiforme (GBM) is to create a niche that helps promote self-renewal of cancer stem-like cells (CSLC). However, the underlying molecular mechanism for this endothelial function is not known. Since activation of NOTCH signaling has been found to be required for propagation of GBM CSLCs, we hypothesized that the GBM endothelium may provide the source of NOTCH ligands. Here, we report a corroboration of this concept with a demonstration that NOTCH ligands are expressed in endothelial cells adjacent to NESTIN and NOTCH receptor-positive cancer cells in primary GBMs. Coculturing human brain microvascular endothelial cells (hBMEC) or NOTCH ligand with GBM neurospheres promoted GBM cell growth and increased CSLC self-renewal. Notably, RNAi-mediated knockdown of NOTCH ligands in hBMECs abrogated their ability to induce CSLC self-renewal and GBM tumor growth, both in vitro and in vivo. Thus, our findings establish that NOTCH activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells and their surrounding endothelial cells in the tumor microenvironment, suggesting that targeting both CSLCs and their niche may provide a novel strategy to deplete CSLCs and improve GBM treatment

Measurement of the higher-order anisotropic flow coefficients for identified hadrons in Au++Au collisions at sNN\sqrt{s_{_{NN}}} = 200 GeV

International audienceMeasurements of the anisotropic flow coefficients v2{Ψ2},v3{Ψ3},v4{Ψ4}, and v4{Ψ2} for identified particles (π±,K±, and p+p¯) at midrapidity, obtained relative to the event planes Ψm at forward rapidities in Au + Au collisions at sNN=200GeV, are presented as a function of collision centrality and particle transverse momenta pT. The vn coefficients show characteristic patterns consistent with hydrodynamical expansion of the matter produced in the collisions. For each harmonic n, a modified valence quark-number Nq scaling [plotting vn{Ψm}/(Nq)n/2 versus transverse kinetic energies (KET)/Nq] is observed to yield a single curve for all the measured particle species for a broad range of KET. A simultaneous blast-wave model fit to the observed vn{Ψm}(pT) coefficients and published particle spectra identifies radial flow anisotropies ρn{Ψm} and spatial eccentricities sn{Ψm} at freeze-out. These are generally smaller than the initial-state participant-plane geometric eccentricities ɛn{ΨmPP} as also observed in the final eccentricity from quantum interferometry measurements with respect to the event plane