VEGF promotes tumorigenesis and angiogenesis of human glioblastoma stem cells

Oka, Naoki; Soeda, Akio; Inagaki, Akihito; Onodera, Masafumi; Maruyama, Hidekazu; Hara, Akira; Kunisada, Takahiro; Mori, Hideki; Iwama, Toru

doi:10.1016/j.bbrc.2007.06.094

Cited by 130 publications

(96 citation statements)

References 22 publications

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“…These cells express the neural stem/progenitor markers such as nestin, musashi-1 and CD133 in the presence of EGF in serum-free medium. Transplantation of 100-1000 CD133-positive cells into the brains of immunodeficient mice recapitulates the original tumor (Oka et al, 2007). These cells also express markers of neuronal, astrocytic and oligodendroglial lineages in serum containing differentiation medium (Supplementary Figure 1).…”

Section: Resultsmentioning

confidence: 71%

“…Hypoxia enhances CD133 þ CSC self-renewal and proliferation All experiments were performed with previously established malignant-glioma-derived CSC lines from freshly resected surgical specimens under a protocol approved by the local Institutional Review Board (Oka et al, 2007;Soeda et al, 2008). These CSC lines express markers of the undifferentiated phenotype, show selfrenewal and are multipotent.…”

Section: Resultsmentioning

confidence: 99%

“…Tumor-sphere cultures were performed as described earlier, with some modifications, in medium containing Dulbecco's modified Eagle's medium-F12 (Gibco-Invitrogen, La Jolla, CA, USA), penicillin G, streptomycin sulfate, B-27 (GibcoInvitrogen), and recombinant human EGF (20 ng/ml; R&D Systems, Minneapolis, MN, USA) (Singh et al, 2004;Oka et al, 2007;Soeda et al, 2008). Cells were cultured in HERAcell incubators (Thermo Electronic Corporation, Asheville, NC, USA) at 37 1C, 95% relative humidity, and 5% CO 2 with 20% oxygen or 1% oxygen conditions.…”

Section: Cell Culturementioning

confidence: 99%

“…Immunocytochemistry of CSCs was performed as described (Oka et al, 2007;Park et al, 2007). Primary antibodies used were as follows: anti-b-III-tubulin (Tuj1; mouse mAb, 1:200; Chemicon, Temecula, CA, USA) and anti-glial fibrillary acidic protein (GFAP; rabbit pAb, 1:500; DAKO, Glostrup, Denmark).…”

Section: Indirect Immunofluorescence Microscopymentioning

confidence: 99%

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Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1α

et al. 2009

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Hypoxia contributes to the progression of a variety of cancers by activating adaptive transcriptional programs that promote cell survival, motility and tumor angiogenesis. Although the importance of hypoxia and subsequent hypoxia-inducible factor-1a (HIF-1a) activation in tumor angiogenesis is well known, their role in the regulation of glioma-derived stem cells is unclear. In this study, we show that hypoxia (1% oxygen) promotes the self-renewal capacity of CD133-positive human glioma-derived cancer stem cells (CSCs). Propagation of the glioma-derived CSCs in a hypoxic environment also led to the expansion of cells bearing CXCR4 (CD184), CD44 low and A2B5 surface markers. The enhanced self-renewal activity of the CD133-positive CSCs in hypoxia was preceded by upregulation of HIF-1a. Knockdown of HIF-1a abrogated the hypoxia-mediated CD133-positive CSC expansion. Inhibition of the phosphatidylinositol 3-kinase (PI3K)-Akt or ERK1/2 pathway reduced the hypoxiadriven CD133 expansion, suggesting that these signaling cascades may modulate the hypoxic response. Finally, CSCs propagated at hypoxia robustly retained the undifferentiated phenotype, whereas CSCs cultured at normoxia did not. These results suggest that response to hypoxia by CSCs involves the activation of HIF-1a to enhance the self-renewal activity of CD133-positive cells and to inhibit the induction of CSC differentiation. This study illustrates the importance of the tumor microenvironment in determining cellular behavior.

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Section: Resultsmentioning

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

Section: Indirect Immunofluorescence Microscopymentioning

confidence: 99%

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Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1α

et al. 2009

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“…The term "tumor initiating cells" (TIC) is frequently used to describe such cells (4), and we shall use it throughout this article to indicate cells with cancer stem cell capacity. Due to the fact that TICs promote the tumor chemoresistance (5,6), radioresistance (3,7), and angiogenesis (5,8), it is conceivable that finding a manner to kill them would improve GBM therapy (9,10).…”

Section: Introductionmentioning

confidence: 99%

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

Monticone

Biollo

Fabiano

et al. 2009

Molecular Cancer Research

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γ-secretase inhibitors have been proposed as drugs able to kill cancer cells by targeting the NOTCH pathway. Here, we investigated two of such inhibitors, the Benzyloxicarbonyl-Leu-Leu-Nle-CHO (LLNle) and the N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), to assess whether they were effective in killing human glioblastoma tumor-initiating cells (GBM TIC) in vitro. We found that only LLNle was able at the micromolar range to induce the death of GBM TICs by apoptosis. To determine the cellular processes that were activated in GBM TICs by treatment with LLNle, we analyzed the amount of the NOTCH intracellular domain and the gene expression profiles following treatment with LLNle, DAPT, and DMSO (vehicle). We found that LLNIe, beside inhibiting the generation of the NOTCH intracellular domain, also induces proteasome inhibition, proteolytic stress, and mitotic arrest in these cells by repressing genes required for DNA synthesis and mitotic progression and by activating genes acting as mitotic inhibitors. DNA content flow cytometry clearly showed that cells treated with LLNle undergo arrest in the G 2 -M phases of the cell cycle. We also found that DAPT and L-685,458, another selective Notch inhibitor, were unable to kill GBM TICs, whereas lactacystin, a pure proteasome inhibitor, was effective although at a much less extent than LLNle. These data show that LLNle kills GBM TIC cells by inhibiting the proteasome activity. We suggest that LLNle, being able to target two relevant pathways for GBM TIC survival, may have a potential therapeutic value that deserves further investigation in animal models.

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Hypoxia‐inducible factor 1α inhibits the fibroblast‐like markers type I and type III collagen during hypoxia‐induced chondrocyte redifferentiation: Hypoxia not only induces type II collagen and aggrecan, but it also inhibits type I and type III collagen in the hypoxia‐inducible factor 1α–dependent redifferentiation of chondrocytes

Duval¹,

Leclercq²,

Elissalde³

et al. 2009

Arthritis & Rheumatism

137

127

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Objective. Autologous chondrocyte implantation requires expansion of cells ex vivo, leading to dedifferentiation of chondrocytes (loss of aggrecan and type II collagen to the profit of type I and type III collagens). Several approaches have been described for redifferentiation of these cells. Among them, low oxygen tension has been exploited to restore the differentiated chondrocyte phenotype, but molecular mechanisms of this process remain unclear. However, under conditions of hypoxia, one of the major factors involved is hypoxiainducible factor 1␣ (HIF-1␣). The purpose of this study was to investigate the role of HIF-1␣ during human chondrocyte redifferentiation.Methods. We used complementary approaches to achieving HIF-1␣ loss (inhibition by cadmium ions and dominant-negative expression) or gain (ectopic expression and cobalt ion treatment) of function. Expression of chondrocyte, as well as fibroblast-like, phenotype markers was determined using real-time reverse transcription-polymerase chain reaction and Western blot analyses. Binding activities of HIF-1␣ and SOX9, a pivotal transcription factor of chondrogenesis, were evaluated by electrophoretic mobility shift assays and by chromatin immunoprecipitation assay.Results. We found that hypoxia and HIF-1␣ not only induced the expression of SOX9, COL2A1, and aggrecan, but they simultaneously inhibited the expression of COL1A1, COL1A2, and COL3A1. In addition, we identified the binding of HIF-1␣ to the aggrecan promoter, the first such reported demonstration of this binding.Conclusion. This study is the first to show a bimodal role of HIF-1␣ in cartilage homeostasis, since HIF-1␣ was shown to favor specific markers and to impair dedifferentiation. This suggests that manipulation of HIF-1␣ could represent a promising approach to the treatment of osteoarthritis.

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VEGF promotes tumorigenesis and angiogenesis of human glioblastoma stem cells

Cited by 130 publications

References 22 publications

Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1α

Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1α

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

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