Highly infiltrative brain tumours show reduced chemosensitivity associated with a stem cell-like phenotype

Johannessen, Tor‐Christian; Wang, Jian; Skaftnesmo, Kai-Ove; Sakariassen, Per Øystein; Enger, Per Øyvind; Petersen, Kjell; Øyan, Anne Margrete; Kalland, Karl‐Henning; Bjerkvig, Rolf; Tysnes, Berit Bølge

doi:10.1111/j.1365-2990.2008.01008.x

Cited by 26 publications

(27 citation statements)

References 91 publications

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“…As far as Msi-1 is concerned, this is a complex multifunctional protein crucial for the maintenance of the stemness state in normal tissues, and strongly expressed together with Nestin in highly invasive tumors [55], [56] as well as in reactive astrocytes and in cells that differentiate into astrocytes [57]. Msi-1 cell localization changed during clone maintenance in differentiating medium from cytoplasm to nucleus.…”

Section: Discussionmentioning

confidence: 99%

Isolation of Cancer Stem Cells from Three Human Glioblastoma Cell Lines: Characterization of Two Selected Clones

et al. 2014

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Cancer stem cells (CSC) were isolated via a non-adherent neurosphere assay from three glioma cell lines: LI, U87, and U373. Using a clonal assay, two clones (D2 and F11) were selected from spheres derived from LI cells and were characterized for the: expression of stem cell markers (CD133, Nestin, Musashi-1 and Sox2); proliferation; differentiation capability (determined by the expression of GalC, βIII-Tubulin and GFAP); Ca2+ signaling and tumorigenicity in nude mice. Both D2 and F11 clones expressed higher levels of all stem cell markers with respect to the parental cell line. Clones grew more slowly than LI cells with a two-fold increase in duplication time. Markers of differentiation (βIII-Tubulin and GFAP) were expressed at high levels in both LI cells and in neurospheres. The expression of Nestin, Sox2, and βIII-Tubulin was down-regulated in D2 and F11 when cultured in serum-containing medium, whereas Musashi-1 was increased. In this condition, duplication time of D2 and F11 increased without reaching that of LI cells. D2, F11 and parental cells did not express voltage-dependent Ca2+-channels but they exhibited increased intracellular Ca2+ levels in response to ATP. These Ca2+ signals were larger in LI cells and in spheres cultured in serum-containing medium, while they were smaller in serum-free medium. The ATP treatment did not affect cell proliferation. Both D2 and F11 induced the appearance of tumors when ortotopically injected in athymic nude mice at a density 50-fold lower than that of LI cells. All these data indicate that both clones have characteristics of CSC and share the same stemness properties. The findings regarding the expression of differentiation markers and Ca2+-channels show that both clones are unable to reach the terminal differentiation. Both D2 and F11 might represent a good model to improve the knowledge on CSC in glioblastoma and to identify new therapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

Isolation of Cancer Stem Cells from Three Human Glioblastoma Cell Lines: Characterization of Two Selected Clones

et al. 2014

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“…glioma cells and show similar characteristics to neural stem cells, including capacities for neurosphere formation, proliferation, self-renewal, and multi-lineage differentiation (Galli et al 2004;Hadjipanayis and Van Meir 2009;Singh et al 2003;Singh et al 2004). Some researchers believe that GSCs are responsible for resistance to radiotherapy and chemotherapy and for glioma relapse (Bao et al 2006a, b;Johannessen et al 2009;Liu et al 2006;Palm and Schwamborn 2010). Thus, strategies targeting GSCs may provide a new approach to the treatment of gliomas.…”

Section: Introductionmentioning

confidence: 91%

MicroRNA-107 Inhibits U87 Glioma Stem Cells Growth and Invasion

Chen

et al. 2013

Cell Mol Neurobiol

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Glioma stem cells (GSCs) are thought to be critical for resistance to radiotherapy and chemotherapy and for tumor recurrence after surgery in glioma patients. Identification of new therapeutic strategies that can target GSCs may thus be critical for improving patient survival. MicroRNAs (miRNAs) are small non-coding RNAs that function as tumor suppressors or oncogenes. In this study, we confirmed that miR-107 was down-regulated in GSCs. To investigate the role of miR-107 in tumorigenesis of GSCs, a lentiviral vector over-expressing miR-107 in U87GSCs was constructed. We found that over-expression of miR-107 suppressed proliferation and down-regulated Notch2 protein and stem cell marker (CD133 and Nestin) expression in U87GSCs. Furthermore, enhanced miR-107 expression significantly inhibited U87GSC invasion and reduced matrix metalloproteinase-12 expression. miR-107 also suppressed U87GSCs xenograft growth in vivo. These findings suggest that miR-107 is involved in U87GSCs growth and invasion and may provide a potential therapeutic target for glioma treatment.

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“…Importantly, they have been implicated in resistance to both radiotherapy and chemotherapy [72][73][74]. We have previously identified a potential link between a cancer stem-like phenotype, increased survival signaling and chemoresistance in GBM xenografts [74]. Moreover, a stem-like phenotype based on a leukemic self-renewal gene expression signature has been identified as an independent predictor of poor outcome in GBM patients receiving temozolomide chemoradiation [75].…”

Section: Cancer Stem-like Cellsmentioning

confidence: 99%

“…Cancer stem-like cells derived from GBMs display self-renewal in serial passage neurosphere assays, demonstrate increased tumorigenic potential in vivo compared with corresponding non-stem tumor cells and can be differentiated to cells expressing astrocytic, oligodendrocytic and neuronal markers [64][65][66]71]. Importantly, they have been implicated in resistance to both radiotherapy and chemotherapy [72][73][74]. We have previously identified a potential link between a cancer stem-like phenotype, increased survival signaling and chemoresistance in GBM xenografts [74].…”

Section: Cancer Stem-like Cellsmentioning

confidence: 99%

Molecular mechanisms of temozolomide resistance in glioblastoma multiforme

Johannessen¹,

Bjerkvig²

2012

Expert Review of Anticancer Therapy

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113

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Glioblastoma multiforme (GBM; WHO astrocytoma grade IV) is considered incurable owing to its inherently profound resistance towards current standards of therapy. Considerable effort is being devoted to identifying the molecular basis of temozolomide resistance in GBMs and exploring novel therapeutic regimens that may improve overall survival. Several independent DNA repair mechanisms that normally safeguard genome integrity can facilitate drug resistance and cancer cell survival by removing chemotherapy-induced DNA adducts. Furthermore, subpopulations of cancer stem-like cells have been implicated in the treatment resistance of several malignancies including GBMs. Thus, a growing number of molecular mechanisms contributing to temozolomide resistance are being uncovered in preclinical studies and, consequently, we are being presented with a broad range of potentially novel targets for therapy. A substantial future challenge is to successfully exploit the increasing molecular knowledge contributing to temozolomide resistance in robust clinical trials and to ultimately improve overall survival for GBM patients.

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Highly infiltrative brain tumours show reduced chemosensitivity associated with a stem cell-like phenotype

Cited by 26 publications

References 91 publications

Isolation of Cancer Stem Cells from Three Human Glioblastoma Cell Lines: Characterization of Two Selected Clones

Isolation of Cancer Stem Cells from Three Human Glioblastoma Cell Lines: Characterization of Two Selected Clones

MicroRNA-107 Inhibits U87 Glioma Stem Cells Growth and Invasion

Molecular mechanisms of temozolomide resistance in glioblastoma multiforme

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