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  1. Artikel ; Online: Correction: Engraftment of Human Glioblastoma Cells in Immunocompetent Rats through Acquired Immunosuppression.

    Huszthy, Peter C / Sakariassen, Per Ø / Espedal, Heidi / Brokstad, Karl A / Bjerkvig, Rolf / Miletic, Hrvoje

    PloS one

    2015  Band 10, Heft 10, Seite(n) e0140303

    Sprache Englisch
    Erscheinungsdatum 2015
    Erscheinungsland United States
    Dokumenttyp Published Erratum
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0140303
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  2. Artikel ; Online: Engraftment of Human Glioblastoma Cells in Immunocompetent Rats through Acquired Immunosuppression.

    Huszthy, Peter C / Sakariassen, Per Ø / Espedal, Heidi / Brokstad, Karl A / Bjerkvig, Rolf / Miletic, Hrvoje

    PloS one

    2015  Band 10, Heft 8, Seite(n) e0136089

    Abstract: Transplantation of glioblastoma patient biopsy spheroids to the brain of T cell-compromised Rowett (nude) rats has been established as a representative animal model for human GBMs, with a tumor take rate close to 100%. In immunocompetent littermates ... ...

    Abstract Transplantation of glioblastoma patient biopsy spheroids to the brain of T cell-compromised Rowett (nude) rats has been established as a representative animal model for human GBMs, with a tumor take rate close to 100%. In immunocompetent littermates however, primary human GBM tissue is invariably rejected. Here we show that after repeated passaging cycles in nude rats, human GBM spheroids are enabled to grow in the brain of immunocompetent rats. In case of engraftment, xenografts in immunocompetent rats grow progressively and host leukocytes fail to enter the tumor bed, similar to what is seen in nude animals. In contrast, rejection is associated with massive infiltration of the tumor bed by leukocytes, predominantly ED1+ microglia/macrophages, CD4+ T helper cells and CD8+ effector cells, and correlates with elevated serum levels of pro-inflammatory cytokines IL-1α, IL-18 and TNF-α [corrected]. We observed that in nude rat brains, an adaptation to the host occurs after several in vivo passaging cycles, characterized by striking attenuation of microglial infiltration. Furthermore, tumor-derived chemokines that promote leukocyte migration and their entry into the CNS such as CXCL-10 and CXCL-12 are down-regulated, and the levels of TGF-β2 increase. We propose that through serial in vivo passaging in nude rats, human GBM cells learn to avoid and or/ suppress host immunity. Such adapted GBM cells are in turn able to engraft in immunocompetent rats without signs of an inflammatory response.
    Mesh-Begriff(e) Animals ; Brain Neoplasms/immunology ; Chemokine CXCL10/physiology ; Chemokine CXCL12/physiology ; Disease Models, Animal ; Female ; Glioblastoma/immunology ; Graft Rejection/immunology ; Graft Rejection/prevention & control ; Humans ; Immune Tolerance/immunology ; Immunocompetence/immunology ; Interleukin-18/blood ; Interleukin-1beta/blood ; Male ; Neoplasm Transplantation/methods ; Polymerase Chain Reaction ; Rats ; Rats, Nude ; Spheroids, Cellular ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha/blood
    Chemische Substanzen CXCL12 protein, rat ; Chemokine CXCL10 ; Chemokine CXCL12 ; Cxcl10 protein, rat ; Interleukin-18 ; Interleukin-1beta ; Tumor Necrosis Factor-alpha
    Sprache Englisch
    Erscheinungsdatum 2015
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0136089
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  3. Artikel ; Online: Cancer stem cells as mediators of treatment resistance in brain tumors: status and controversies.

    Sakariassen, Per Ø / Immervoll, Heike / Chekenya, Martha

    Neoplasia (New York, N.Y.)

    2007  Band 9, Heft 11, Seite(n) 882–892

    Abstract: Malignant primary brain tumors are characterized by a short median survival and an almost 100% tumor-related mortality. Despite the addition of new chemotherapy regimes, the overall survival has improved marginally, and radiotherapy is only transiently ... ...

    Abstract Malignant primary brain tumors are characterized by a short median survival and an almost 100% tumor-related mortality. Despite the addition of new chemotherapy regimes, the overall survival has improved marginally, and radiotherapy is only transiently effective, illustrating the profound impact of treatment resistance on prognosis. Recent studies suggest that a small subpopulation of cancer stem cells (CSCs) has the capacity to repopulate tumors and drive malignant progression and mediate radio- and chemoresistance. This implies that future therapies should turn from the elimination of the rapidly dividing, but differentiated tumor cells, to specifically targeting the minority of tumor cells that repopulate the tumor. Although there exists some support for the CSC hypothesis, there remain many uncertainties regarding theoretical, technical, and interpretational aspects of the data supporting it. If correct, the CSC hypothesis could have profound implications for the way tumors are classified and treated. In this review of the literature, we provide original data and hypotheses supporting alternative explanations and outline some of the therapeutic implications that can be derived.
    Mesh-Begriff(e) AC133 Antigen ; Animals ; Antigens/analysis ; Antigens, CD/analysis ; Antigens, CD/physiology ; Brain Neoplasms/drug therapy ; Brain Neoplasms/pathology ; CD24 Antigen/analysis ; Disease Progression ; Drug Resistance, Neoplasm ; Glycoproteins/analysis ; Glycoproteins/physiology ; Humans ; Hyaluronan Receptors/analysis ; Mice ; Mutation ; Neoplastic Stem Cells/physiology ; Peptides/analysis ; Peptides/physiology ; Proteoglycans/analysis
    Chemische Substanzen AC133 Antigen ; Antigens ; Antigens, CD ; CD24 Antigen ; Glycoproteins ; Hyaluronan Receptors ; PROM1 protein, human ; Peptides ; Prom1 protein, mouse ; Proteoglycans ; chondroitin sulfate proteoglycan 4
    Sprache Englisch
    Erscheinungsdatum 2007-11-21
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1483840-0
    ISSN 1476-5586 ; 1522-8002
    ISSN (online) 1476-5586
    ISSN 1522-8002
    DOI 10.1593/neo.07658
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Bevacizumab treatment for human glioblastoma. Can it induce cognitive impairment?

    Fathpour, Pakzad / Obad, Nina / Espedal, Heidi / Stieber, Daniel / Keunen, Olivier / Sakariassen, Per Ø / Niclou, Simone P / Bjerkvig, Rolf

    Neuro-oncology

    2014  Band 16, Heft 5, Seite(n) 754–756

    Abstract: Recent results from 2 double-blind, placebo-controlled phase III trials (RTOG 0825) and (AVAglio) for first-line treatment of glioblastoma patients with the VEGF antibody bevacizumab, showed similar results, related to overall and progression-free ... ...

    Abstract Recent results from 2 double-blind, placebo-controlled phase III trials (RTOG 0825) and (AVAglio) for first-line treatment of glioblastoma patients with the VEGF antibody bevacizumab, showed similar results, related to overall and progression-free survival. The RTOG 0825 trial indicated, opposed to the AVAglio trial, that patients treated with bevacizumab showed a decline in global neurocognitive function compared to untreated patients, -a decline that was most obvious after prolonged treatment. At present, there is a considerably controversy related to these observations. In the present work we point at the possibility that bevacizumab treatment of the normal brain can reduce synaptic plasticity in the hippocampus. We believe that such a phenomenon may partly explain the reduced cognitive function observed in patients in the RTOG 0825 trial. Since the same effects were not clearly defined in the AVAglio trial, further studies on putative neurocognitive effects after bevacizumab treatment are warranted.
    Mesh-Begriff(e) Angiogenesis Inhibitors/adverse effects ; Angiogenesis Inhibitors/pharmacology ; Animals ; Antibodies, Monoclonal, Humanized/adverse effects ; Antibodies, Monoclonal, Humanized/pharmacology ; Bevacizumab ; Brain Neoplasms/drug therapy ; Cognition Disorders/chemically induced ; Glioblastoma/drug therapy ; Hippocampus/drug effects ; Humans ; Neuronal Plasticity/drug effects ; Rats
    Chemische Substanzen Angiogenesis Inhibitors ; Antibodies, Monoclonal, Humanized ; Bevacizumab (2S9ZZM9Q9V)
    Sprache Englisch
    Erscheinungsdatum 2014-04-14
    Erscheinungsland England
    Dokumenttyp Letter ; Research Support, Non-U.S. Gov't
    ZDB-ID 2028601-6
    ISSN 1523-5866 ; 1522-8517
    ISSN (online) 1523-5866
    ISSN 1522-8517
    DOI 10.1093/neuonc/nou013
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: Lack of functional normalisation of tumour vessels following anti-angiogenic therapy in glioblastoma.

    Obad, Nina / Espedal, Heidi / Jirik, Radovan / Sakariassen, Per Oystein / Brekke Rygh, Cecilie / Lund-Johansen, Morten / Taxt, Torfinn / Niclou, Simone P / Bjerkvig, Rolf / Keunen, Olivier

    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

    2017  Band 38, Heft 10, Seite(n) 1741–1753

    Abstract: Neo-angiogenesis represents an important factor for the delivery of oxygen and nutrients to a growing tumour, and is considered to be one of the main pathodiagnostic features of glioblastomas (GBM). Anti-angiogenic therapy by vascular endothelial growth ... ...

    Abstract Neo-angiogenesis represents an important factor for the delivery of oxygen and nutrients to a growing tumour, and is considered to be one of the main pathodiagnostic features of glioblastomas (GBM). Anti-angiogenic therapy by vascular endothelial growth factor (VEGF) blocking agents has been shown to lead to morphological vascular normalisation resulting in a reduction of contrast enhancement as seen by magnetic resonance imaging (MRI). Yet the functional consequences of this normalisation and its potential for improved delivery of cytotoxic agents to the tumour are not known. The presented study aimed at determining the early physiologic changes following bevacizumab treatment. A time series of perfusion MRI and hypoxia positron emission tomography (PET) scans were acquired during the first week of treatment, in two human GBM xenograft models treated with either high or low doses of bevacizumab. We show that vascular morphology was normalised over the time period investigated, but vascular function was not improved, resulting in poor tumoural blood flow and increased hypoxia.
    Mesh-Begriff(e) Angiogenesis Inhibitors/pharmacology ; Animals ; Bevacizumab/pharmacology ; Brain Neoplasms/pathology ; Female ; Glioblastoma/pathology ; Humans ; Male ; Mice, Nude ; Neovascularization, Pathologic/pathology ; Xenograft Model Antitumor Assays
    Chemische Substanzen Angiogenesis Inhibitors ; Bevacizumab (2S9ZZM9Q9V)
    Sprache Englisch
    Erscheinungsdatum 2017-06-19
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604628-9
    ISSN 1559-7016 ; 0271-678X
    ISSN (online) 1559-7016
    ISSN 0271-678X
    DOI 10.1177/0271678X17714656
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel ; Online: Cancer Stem Cells as Mediators of Treatment Resistance in Brain Tumors

    Per Ø. Sakariassen / Heike Immervoll / Martha Chekenya

    Neoplasia : An International Journal for Oncology Research, Vol 9, Iss 11, Pp 882-

    Status and Controversies

    2007  Band 892

    Abstract: Malignant primary brain tumors are characterized by a short median survival and an almost 100% tumorrelated mortality. Despite the addition of new chemotherapy regimes, the overall survival has improved marginally, and radiotherapy is only transiently ... ...

    Abstract Malignant primary brain tumors are characterized by a short median survival and an almost 100% tumorrelated mortality. Despite the addition of new chemotherapy regimes, the overall survival has improved marginally, and radiotherapy is only transiently effective, illustrating the profound impact of treatment resistance on prognosis. Recent studies suggest that a small subpopulation of cancer stem cells (CSCs) has the capacity to repopulate tumors and drive malignant progression and mediate radio- and chemoresistance. This implies that future therapies should turn from the elimination of the rapidly dividing, but differentiated tumor cells, to specifically targeting the minority of tumor cells that repopulate the tumor. Although there exists some support for the CSC hypothesis, there remain many uncertainties regarding theoretical, technical, and interpretational aspects of the data supporting it. If correct, the CSC hypothesis could have profound implications for the way tumors are classified and treated. In this review of the literature, we provide original data and hypotheses supporting alternative explanations and outline some of the therapeutic implications that can be derived.
    Schlagwörter Neural stem cell ; CD133 ; glioblastoma ; chemoresistance ; radioresistance ; Medicine ; R ; Internal medicine ; RC31-1245 ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
    Erscheinungsdatum 2007-11-01T00:00:00Z
    Verlag Elsevier
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  7. Artikel ; Online: Correction

    Peter C Huszthy / Per Ø Sakariassen / Heidi Espedal / Karl A Brokstad / Rolf Bjerkvig / Hrvoje Miletic

    PLoS ONE, Vol 10, Iss 10, p e

    Engraftment of Human Glioblastoma Cells in Immunocompetent Rats through Acquired Immunosuppression.

    2015  Band 0140303

    Schlagwörter Medicine ; R ; Science ; Q
    Sprache Englisch
    Erscheinungsdatum 2015-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
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  8. Artikel ; Online: Engraftment of Human Glioblastoma Cells in Immunocompetent Rats through Acquired Immunosuppression.

    Peter C Huszthy / Per Ø Sakariassen / Heidi Espedal / Karl A Brokstad / Rolf Bjerkvig / Hrvoje Miletic

    PLoS ONE, Vol 10, Iss 8, p e

    2015  Band 0136089

    Abstract: Transplantation of glioblastoma patient biopsy spheroids to the brain of T cell-compromised Rowett (nude) rats has been established as a representative animal model for human GBMs, with a tumor take rate close to 100%. In immunocompetent littermates ... ...

    Abstract Transplantation of glioblastoma patient biopsy spheroids to the brain of T cell-compromised Rowett (nude) rats has been established as a representative animal model for human GBMs, with a tumor take rate close to 100%. In immunocompetent littermates however, primary human GBM tissue is invariably rejected. Here we show that after repeated passaging cycles in nude rats, human GBM spheroids are enabled to grow in the brain of immunocompetent rats. In case of engraftment, xenografts in immunocompetent rats grow progressively and host leukocytes fail to enter the tumor bed, similar to what is seen in nude animals. In contrast, rejection is associated with massive infiltration of the tumor bed by leukocytes, predominantly ED1+ microglia/macrophages, CD4+ T helper cells and CD8+ effector cells, and correlates with elevated serum levels of pro-inflammatory cytokines IL-1α, IL-18 and TNF-α [corrected]. We observed that in nude rat brains, an adaptation to the host occurs after several in vivo passaging cycles, characterized by striking attenuation of microglial infiltration. Furthermore, tumor-derived chemokines that promote leukocyte migration and their entry into the CNS such as CXCL-10 and CXCL-12 are down-regulated, and the levels of TGF-β2 increase. We propose that through serial in vivo passaging in nude rats, human GBM cells learn to avoid and or/ suppress host immunity. Such adapted GBM cells are in turn able to engraft in immunocompetent rats without signs of an inflammatory response.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 610
    Sprache Englisch
    Erscheinungsdatum 2015-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  9. Artikel ; Online: In vivo models of primary brain tumors: pitfalls and perspectives.

    Huszthy, Peter C / Daphu, Inderjit / Niclou, Simone P / Stieber, Daniel / Nigro, Janice M / Sakariassen, Per Ø / Miletic, Hrvoje / Thorsen, Frits / Bjerkvig, Rolf

    Neuro-oncology

    2012  Band 14, Heft 8, Seite(n) 979–993

    Abstract: Animal modeling for primary brain tumors has undergone constant development over the last 60 years, and significant improvements have been made recently with the establishment of highly invasive glioblastoma models. In this review we discuss the ... ...

    Abstract Animal modeling for primary brain tumors has undergone constant development over the last 60 years, and significant improvements have been made recently with the establishment of highly invasive glioblastoma models. In this review we discuss the advantages and pitfalls of model development, focusing on chemically induced models, various xenogeneic grafts of human cell lines, including stem cell-like cell lines and biopsy spheroids. We then discuss the development of numerous genetically engineered models available to study mechanisms of tumor initiation and progression. At present it is clear that none of the current animal models fully reflects human gliomas. Yet, the various model systems have provided important insight into specific mechanisms of tumor development. In particular, it is anticipated that a combined comprehensive knowledge of the various models currently available will provide important new knowledge on target identification and the validation and development of new therapeutic strategies.
    Mesh-Begriff(e) Animals ; Brain Neoplasms ; Disease Models, Animal ; Glioblastoma ; Humans
    Sprache Englisch
    Erscheinungsdatum 2012-06-07
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2028601-6
    ISSN 1523-5866 ; 1522-8517
    ISSN (online) 1523-5866
    ISSN 1522-8517
    DOI 10.1093/neuonc/nos135
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  10. Artikel ; Online: Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma.

    Svendsen, Agnete / Verhoeff, Joost J C / Immervoll, Heike / Brøgger, Jan C / Kmiecik, Justyna / Poli, Aurelie / Netland, Inger A / Prestegarden, Lars / Planagumà, Jesús / Torsvik, Anja / Kjersem, Anneli Bohne / Sakariassen, Per Ø / Heggdal, Jan I / Van Furth, Wouter R / Bjerkvig, Rolf / Lund-Johansen, Morten / Enger, Per Ø / Felsberg, Joerg / Brons, Nicolaas H C /
    Tronstad, Karl J / Waha, Andreas / Chekenya, Martha

    Acta neuropathologica

    2011  Band 122, Heft 4, Seite(n) 495–510

    Abstract: ... received and hypermethylation of the O(6)-methylguanine methyltransferase (MGMT) DNA repair gene promoter ...

    Abstract Glioblastoma (GBM) is a highly aggressive brain tumour, where patients respond poorly to radiotherapy and exhibit dismal survival outcomes. The mechanisms of radioresistance are not completely understood. However, cancer cells with an immature stem-like phenotype are hypothesised to play a role in radioresistance. Since the progenitor marker neuron-glial-2 (NG2) has been shown to regulate several aspects of GBM progression in experimental systems, we hypothesised that its expression would influence the survival of GBM patients. Quantification of NG2 expression in 74 GBM biopsies from newly diagnosed and untreated patients revealed that 50% express high NG2 levels on tumour cells and associated vessels, being associated with significantly shorter survival. This effect was independent of age at diagnosis, treatment received and hypermethylation of the O(6)-methylguanine methyltransferase (MGMT) DNA repair gene promoter. NG2 was frequently co-expressed with nestin and vimentin but rarely with CD133 and the NG2 positive tumour cells harboured genetic aberrations typical for GBM. 2D proteomics of 11 randomly selected biopsies revealed upregulation of an antioxidant, peroxiredoxin-1 (PRDX-1), in the shortest surviving patients. Expression of PRDX-1 was associated with significantly reduced products of oxidative stress. Furthermore, NG2 expressing GBM cells showed resistance to ionising radiation (IR), rapidly recognised DNA damage and effectuated cell cycle checkpoint signalling. PRDX-1 knockdown transiently slowed tumour growth rates and sensitised them to IR in vivo. Our data establish NG2 as an important prognostic factor for GBM patient survival, by mediating resistance to radiotherapy through induction of ROS scavenging enzymes and preferential DNA damage signalling.
    Mesh-Begriff(e) Aged ; Antigens/biosynthesis ; Antigens/genetics ; Antigens/radiation effects ; Biomarkers, Tumor/metabolism ; Biomarkers, Tumor/radiation effects ; Brain Neoplasms/genetics ; Brain Neoplasms/pathology ; Brain Neoplasms/radiotherapy ; DNA Damage/genetics ; DNA Damage/radiation effects ; Female ; Glioblastoma/genetics ; Glioblastoma/pathology ; Glioblastoma/radiotherapy ; Humans ; Male ; Middle Aged ; Predictive Value of Tests ; Prognosis ; Proteoglycans/biosynthesis ; Proteoglycans/genetics ; Proteoglycans/radiation effects ; Radiation Tolerance ; Radiation, Ionizing ; Stem Cells/metabolism ; Stem Cells/pathology ; Stem Cells/radiation effects ; Survival Rate/trends
    Chemische Substanzen Antigens ; Biomarkers, Tumor ; Proteoglycans ; chondroitin sulfate proteoglycan 4
    Sprache Englisch
    Erscheinungsdatum 2011-08-24
    Erscheinungsland Germany
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1079-0
    ISSN 1432-0533 ; 0001-6322
    ISSN (online) 1432-0533
    ISSN 0001-6322
    DOI 10.1007/s00401-011-0867-2
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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