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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Animal studies have demonstrated that selective tropism of mesenchymal stem cells (MSC) for glioma may be used as a means of selective delivery of cytotoxic payloads. Endometrial Regenerative Cells (ERC) are a population of mesenchymal-like cells which possesse pluripotent differentiation capacity and is characterized by unique surface markers and growth factor production. In this study we sought to determine whether unmanipulated ERC would alter the growth of glioma using the aggressive C6/LacZ7 (C6) into Sprague Dawley rat model. ERC administration by intravenous (i.v.) or intratumoral (i.t.) showed significant inhibition of glioma: volume reduction of 49% after i.v. treatment (p < 0.05), and about 46% i.t. treatment (p < 0.05). Tumor reduction was associated with inhibition of angiogenesis and reduced numbers of CD133 positive cells in the incranial tumor. Despite the angiogenic potential of ERC in the hindlimb ischemia model, these data support a paradoxical tumor inhibitory activity of ERC. Further studies are needed to determine the qualitative differences between physiological angiogenesis, which seems to be supported by ERC and tumor angiogenesis which appeared to be inhibited.
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PMID:Inhibition of intracranial glioma growth by endometrial regenerative cells. 1919 54

Glioblastoma is the most common primary brain tumor, characterized by its resistance to treatments. To define efficient therapy, the origin of tumor-forming cells needs to be elucidated in order to search for new therapeutic pathways. The objective of this study was to determine the different cell populations constituting a human glioblastoma cell line, U-87 MG and their sensitivity to apoptosis induced through the activation of Fas, a membranous death receptor. By a cell sorting method, the sedimentation field flow fractionation, two major cell subpopulations were identified, a most differentiated cell fraction, containing large and adherent cells, sensitive to Fas-induced apoptosis and another one, characterized by small cells forming aggregates, expressing CD133, a marker of stem cells and more resistant to Fas-activated apoptosis. By using a selective method of culture, adapted for neural stem cell cultures, we have verified that the U-87 MG cell line contained cancer stem cells similar to the immature ones obtained by the cell sorting method. Interestingly, while these tumor stem cells, expressing CD133, were resistant to Fas-induced apoptosis, monomeric form of Fas protein was detected predominantly in these cells. In contrast, the most mature cells, responsive to Fas-activated apoptosis, collected in another cell fraction, contained oligomeric aggregates of Fas protein, a pre-signalling form of the Fas receptor, essential for the initiation of apoptosis through its activation. These results suggest that these immature stem cells in glioma could be an important factor of resistance to chemotherapy requiring apoptosis through Fas signalling system. Indeed, future strategies of treatment, inducing differentiation of these stem cells need to be considered to enhance therapeutic efficiency.
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PMID:Cancer stem cells from human glioma cell line are resistant to Fas-induced apoptosis. 1921 77

Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) is a promising cancer drug. However, many tumours are resistant to TRAIL-based therapies. Glioma cells with stem cell features (SCG), such as CD133 expression and neurosphere formation, have been recently identified to be more resistant to cytotoxic drugs than glioma cells lacking stem-cell-like features (NSCGs). Here we report that SCGs are completely resistant to 100-2,000 ng/ml TRAIL, whereas NSCGs revealed a moderate sensitivity to TRAIL. We found that SCGs exhibited only low levels of caspase-8 mRNA and protein, known to be indispensable for TRAIL-induced apoptosis. In addition, we detected hypermethylation of CASP8 promoter in SCGs, whereas NSCGs exhibited a non-methylated CASP8 promoter. Reexpression of caspase-8 by 5-Aza-2'-deoxycytidine was not sufficient to restore TRAIL sensitivity in SCGs cells, suggesting that additional factors cause TRAIL resistance in SCGs. Our data suggest that therapy with TRAIL, either as monotherapy or in combination with demethylating agents, is not effective in treating glioblastoma because SCGs are not targeted by such treatment.
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PMID:Stem-cell-like glioma cells are resistant to TRAIL/Apo2L and exhibit down-regulation of caspase-8 by promoter methylation. 1921 42

The poor prognosis of patients with aggressive and invasive cancers combined with toxic effects and short half-life of currently available treatments necessitate development of more effective tumor selective therapies. Mesenchymal stem cells (MSCs) are emerging as novel cell-based delivery agents; however, a thorough investigation addressing their therapeutic potential and fate in different cancer models is lacking. In this study, we explored the engineering potential, fate, and therapeutic efficacy of human MSCs in a highly malignant and invasive model of glioblastoma. We show that engineered MSC retain their "stem-like" properties, survive longer in mice with gliomas than in the normal brain, and migrate extensively toward gliomas. We also show that MSCs are resistant to the cytokine tumor necrosis factor apoptosis ligand (TRAIL) and, when engineered to express secreted recombinant TRAIL, induce caspase-mediated apoptosis in established glioma cell lines as well as CD133-positive primary glioma cells in vitro. Using highly malignant and invasive human glioma models and employing real-time imaging with correlative neuropathology, we demonstrate that MSC-delivered recombinant TRAIL has profound anti-tumor effects in vivo. This study demonstrates the efficacy of diagnostic and therapeutic MSC in preclinical glioma models and forms the basis for developing stem cell-based therapies for different cancers.
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PMID:Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy. 1926 68

It has been reported that cancer stem cells may contribute to glioma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. We have examined DNA repair in five stem and nonstem glioma cell lines. The population doubling time was significantly increased in stem compared with nonstem cells, and enhanced activation of Chk1 and Chk2 kinases was observed in untreated CD133(+) compared with CD133(-) cells. Neither DNA base excision or single-strand break repair nor resolution of pH2AX nuclear foci were increased in CD133(+) compared with CD133(-) cells. We conclude that glioma stem cells display elongated cell cycle and enhanced basal activation of checkpoint proteins that might contribute to their radioresistance, whereas enhanced DNA repair is not a common feature of these cells.
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PMID:Comparative analysis of DNA repair in stem and nonstem glioma cell cultures. 1927 80

The current study was designed to critically evaluate the notion that cancer stem cell (CSC)-like cells constitute a subpopulation of cells within experimental gliomas. Virtually all cells within the N29 and N32 rat glioma models homogenously expressed CD133, the stem/progenitor marker nestin as well as the neural lineage markers glial fibrillary acidic protein, betaIII-tubulin, and CNPase in vitro. The phenotype was largely retained on exposure to conditions promoting differentiation in vitro and after intracranial implantation of tumor cells into syngeneic hosts. Unsorted adherently grown cells displayed very high clonogenicity in vitro and robust tumorigenicity in vivo. Single N29 and N32 tumor cells invariably formed clones in vitro, and intracerebral inoculation of as few as 10 adherently growing N29 and N32 tumor cells, respectively, gave rise to a tumor. These results provide an alternative view on CSC-like cells in glioma models: sphere-formation is not a prerequisite for accumulation of tumorigenic cells, and CSC-like cells do not reside within a rare subpopulation of cells in these glioma models. N29 and N32 gliomas may accordingly be used for the development of treatment strategies directed specifically against a practically pure population of brain tumor-initiating CSC-like cells.
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PMID:CD133+ and nestin+ tumor-initiating cells dominate in N29 and N32 experimental gliomas. 1929 92

Future breakthroughs in cancer therapy must accompany targeted agents that will neutralize cancer stem cells response to circulating growth factors. Since the brain tissue microenvironmental niche is a prerequisite for expression of the stem cell marker CD133 antigen in brain tumors, we investigated the invasion mechanisms specific to CD133(+) U87 glioblastoma cells in response to lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), two circulating bioactive lysophospholipids and potent inducers of cancer. A CD133(+) U87 glioma cell population was isolated from parental U87 glioblastoma cells using magnetic cell sorting technology. The CD133(+)-enriched cell population grew as neurospheres and showed enhanced maximal response to both LPA (approximately 5.0-fold) and S1P (approximately 2.5-fold) at 1 microM when compared to parental U87 cells. The increased response to LPA in CD133(+) cells, reflected by increased levels of phosphorylated ERK, was found independent of the cooperative functions of the membrane-type-1 matrix metalloproteinase (MT1-MMP), while this cooperativity was essential to the S1P response. Quantitative RT-PCR was performed and we found higher gene expression levels of the S1P receptors S1P1 and S1P2, and of the LPA receptor LPA1 in CD133(+) cells than in their parental U87 cells. These increased levels reflected those observed from in vivo experimental U87 tumor implants. Our data suggest that the CD133(+) cell subpopulation evokes most of the lysophospholipid response within brain tumors through a combined regulation of S1P/LPA cell surface receptors signaling and by MT1-MMP. The emergence of lead compounds targeting the stem cell niche and S1P/LPA signaling in CD133(+) cancer cells is warranted.
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PMID:Modulation of invasive properties of CD133+ glioblastoma stem cells: a role for MT1-MMP in bioactive lysophospholipid signaling. 1932 72

In human gliomas, self-renewing and tumor-initiating cells are characterized by the expression marker CD133. Although, widely used, the validity of CD133 is debated as recent data show that CD133(+) and CD133(-) cells share similar stemness and tumorigenic properties. To clarify this "CD133 controversy", we reexamined the methods of purification and the stem behavior of both CD133 compartments in fresh gliomas and gliomasphere cultures. Using human anti-CD133-coupled microbeads and magnetic activated cell sorting, we observed a nonspecific sorting of glioma cells irrespective of their CD133 expression. In contrast, when purified by fluorescence activating cell sorting, a specific expression and enrichment of CD133 was successfully observed in fresh human gliomas and gliomasphere cultures. However, neither the expression of stemness genes nor the long-term self-renewal capacities of CD133(+) and CD133(-) cells were significantly different, even after fresh isolation. Altogether, our data show that purification of CD133(+) glioma cells using hCD133-microbeads presents a lack of specificity and demonstrate that the use of CD133 as a unique glioma stem cell marker is likely not sufficient to tag the whole self-renewing tumor cell reservoir.
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PMID:Limits of CD133 as a marker of glioma self-renewing cells. 1935 Jun 31

Glioblastoma, the most malignant type of primary brain tumor, is one of the solid cancers where cancer stem cells have been isolated, and studies have suggested resistance of those cells to chemotherapy and radiotherapy. Here, we report the establishment of CSC-enriched cultures derived from human glioblastoma specimens. They grew as neurospheres in serum-free medium with epidermal growth factor and fibroblast growth factor 2, varied in the level of CD133 expression and very efficiently formed highly invasive and/or vascular tumors upon intracerebral implantation into immunodeficient mice. As a novel therapeutic strategy for glioblastoma-derived cancer stem-like cells (GBM-SC), we have tested oncolytic herpes simplex virus (oHSV) vectors. We show that although ICP6 (UL39)-deleted mutants kill GBM-SCs as efficiently as wild-type HSV, the deletion of gamma34.5 significantly attenuated the vectors due to poor replication. However, this was significantly reversed by the additional deletion of alpha47. Infection with oHSV G47Delta (ICP6(-), gamma34.5(-), alpha47(-)) not only killed GBM-SCs but also inhibited their self-renewal as evidenced by the inability of viable cells to form secondary tumor spheres. Importantly, despite the highly invasive nature of the intracerebral tumors generated by GBM-SCs, intratumoral injection of G47Delta significantly prolonged survival. These results for the first time show the efficacy of oHSV against human GBM-SCs, and correlate this cytotoxic property with specific oHSV mutations. This is important for designing new oHSV vectors and clinical trials. Moreover, the new glioma models described in this study provide powerful tools for testing experimental therapeutics and studying invasion and angiogenesis.
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PMID:Human glioblastoma-derived cancer stem cells: establishment of invasive glioma models and treatment with oncolytic herpes simplex virus vectors. 1935 38

Various malignant cancers have been found to contain a sub-population of stem cell-like tumour cells, or cancer stem cells (CSCs), however, culture methods for CSCs and the size of the fraction of CSCs in C6, which is a commonly used glioma cell line, remain controversial. In this study, we demonstrated that the C6 cell line contains a fraction of tumour cells that can form tumour spheres in a simplified serum-free neural stem cell medium and express CD133 and nestin, which are widely-used markers for brain CSCs. Immunohistochemistry and immunofluorescence confirmed the existence of CSCs both in the C6 cell line and C6 xenografts. Flow cytometry demonstrated that 4.02% of cells in the C6 cell line and 4.21% in the C6 xenografts presented as CSCs. These results confirm the fraction of CSCs in the C6 cell line and provide a simple and effective method for isolation of CSCs to study the initiation and progression of human glioma and, possibly, other malignant tumours.
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PMID:Detection of cancer stem cells from the C6 glioma cell line. 1938 45


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