Molecular properties of CD133+ glioblastoma stem cells derived from treatment-refractory recurrent brain tumors

Abstract

Glioblastoma multiforme (GBM) remains refractory to conventional therapy. CD133+ GBM cells have been recently isolated and characterized as chemo-/radio-resistant tumor-initiating cells and are hypothesized to be responsible for post-treatment recurrence. In order to explore the molecular properties of tumorigenic CD133+ GBM cells that resist treatment, we isolated CD133+ GBM cells from tumors that are recurrent and have previously received chemo-/radio-therapy. We found that the purified CD133+ GBM cells sorted from the CD133+ GBM spheres express SOX2 and CD44 and are capable of clonal self-renewal and dividing to produce fast-growing CD133− progeny, which form the major cell population within GBM spheres. Intracranial injection of purified CD133+, not CD133− GBM daughter cells, can lead to the development of YKL-40+ infiltrating tumors that display hypervascularity and pseudopalisading necrosis-like features in mouse brain. The molecular profile of purified CD133+ GBM cells revealed characteristics of neuroectoderm-like cells, expressing both radial glial and neural crest cell developmental genes, and portraying a slow-growing, non-differentiated, polarized/migratory, astrogliogenic, and chondrogenic phenotype. These data suggest that at least a subset of treated and recurrent GBM tumors may be seeded by CD133+ GBM cells with neural and mesenchymal properties. The data also imply that CD133+ GBM cells may be clinically indolent/quiescent prior to undergoing proliferative cell division (PCD) to produce CD133− GBM effector progeny. Identifying intrinsic and extrinsic cues, which promote CD133+ GBM cell self-renewal and PCD to support ongoing tumor regeneration may highlight novel therapeutic strategies to greatly diminish the recurrence rate of GBM.Electronic supplementary materialThe online version of this article (doi:10.1007/s11060-009-9919-z) contains supplementary material, which is available to authorized users.

HIF-1α is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway

“…41 Recent study showed that FABP7 preferentially expresses in CD133-positive glioblastoma cells. 42,43 Here, we also found that FABP7 is highly expressed in U251 sphere cells and respond to hypoxia-induced activation of Notch signaling. What remains to be explored is whether FABP7 serves as a marker for GSC and its role in the hypoxiamediated maintenance.…”

Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1

“…This led to the identification of 12 phosphatases potentially involved in the stem-like phenotype of GSCs (Figures 1c and d). Six of the twelve candidate genes (PPEF1, ENPP1, PTPN9, PPP4C, PPP2R2A and DUSP5) were found to be highly expressed in astrocytic gliomas compared with adult normal brain and/or to be essential for stem cell maintenance (Supplementary Figure S2A) [17][18][19][20][21][22] and hence selected for validation studies. Decreased CD133 level 6 days posttransduction was confirmed in NCH421k (GSCs used in the primary screen) and in additional GSCs (NCH441, NCH644) in two independent experiments using the two shRNAs that showed the strongest CD133 reduction in the primary screen (Figure 1e; Supplementary Figure S2B).…”

Gap junctions in human glioblastomas: implications for suicide gene therapy

“…In our study, the TK gene was delivered into cells with a lentiviral vector that has the ability to infect non-dividing cells, rendering it more suitable than the oncoretroviral vector to target slow-growing CD133 þ glioblastoma stem cells. 33 Except for the Cx43-negative GBM9 cells, all the other cell lines displayed a BE with values within the 10-30% range ( Figure 5). The BE intensities did not correlate with the localization of Cx43, and did not reflect the gap-junctional intercellular communication measured by calcein transfer.…”