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  1. Article ; Online: Tumor-penetrating peptide for systemic targeting of Tenascin-C

    Prakash Lingasamy / Allan Tobi / Kaarel Kurm / Sergei Kopanchuk / Aleksander Sudakov / Markko Salumäe / Tõnu Rätsep / Toomas Asser / Rolf Bjerkvig / Tambet Teesalu

    Scientific Reports, Vol 10, Iss 1, Pp 1-

    2020  Volume 13

    Abstract: Abstract Extracellular matrix in solid tumors has emerged as a specific, stable, and abundant target for affinity-guided delivery of anticancer drugs. Here we describe the homing peptide that interacts with the C-isoform of Tenascin-C (TNC-C) upregulated ...

    Abstract Abstract Extracellular matrix in solid tumors has emerged as a specific, stable, and abundant target for affinity-guided delivery of anticancer drugs. Here we describe the homing peptide that interacts with the C-isoform of Tenascin-C (TNC-C) upregulated in malignant tissues. TNC-C binding PL3 peptide (amino acid sequence: AGRGRLVR) was identified by in vitro biopanning on recombinant TNC-C. Besides TNC-C, PL3 interacts via its C-end Rule (CendR) motif with cell-and tissue penetration receptor neuropilin-1 (NRP-1). Functionalization of iron oxide nanoworms (NWs) and metallic silver nanoparticles (AgNPs) with PL3 peptide increased tropism of systemic nanoparticles towards glioblastoma (GBM) and prostate carcinoma xenograft lesions in nude mice (eight and five-fold respectively). Treatment of glioma-bearing mice with proapoptotic PL3-guided NWs improved the survival of the mice, whereas treatment with untargeted particles had no effect. PL3-coated nanoparticles were found to accumulate in TNC-C and NRP-1-positive areas in clinical tumor samples, suggesting a translational relevance. The systemic tumor-targeting properties and binding of PL3-NPs to the clinical tumor sections, suggest that the PL3 peptide may have applications as a targeting moiety for the selective delivery of imaging and therapeutic agents to solid tumors.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2020-04-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma

    Mingzhi Han / Shuai Wang / Ning Yang / Xu Wang / Wenbo Zhao / Halala Sdik Saed / Thomas Daubon / Bin Huang / Anjing Chen / Gang Li / Hrvoje Miletic / Frits Thorsen / Rolf Bjerkvig / Xingang Li / Jian Wang

    EMBO Molecular Medicine, Vol 12, Iss 1, Pp n/a-n/a (2020)

    2020  

    Abstract: Abstract Dysregulated cholesterol metabolism is a hallmark of many cancers, including glioblastoma (GBM), but its role in disease progression is not well understood. Here, we identified cholesterol 24‐hydroxylase (CYP46A1), a brain‐specific enzyme ... ...

    Abstract Abstract Dysregulated cholesterol metabolism is a hallmark of many cancers, including glioblastoma (GBM), but its role in disease progression is not well understood. Here, we identified cholesterol 24‐hydroxylase (CYP46A1), a brain‐specific enzyme responsible for the elimination of cholesterol through the conversion of cholesterol into 24(S)‐hydroxycholesterol (24OHC), as one of the most dramatically dysregulated cholesterol metabolism genes in GBM. CYP46A1 was significantly decreased in GBM samples compared with normal brain tissue. A reduction in CYP46A1 expression was associated with increasing tumour grade and poor prognosis in human gliomas. Ectopic expression of CYP46A1 suppressed cell proliferation and in vivo tumour growth by increasing 24OHC levels. RNA‐seq revealed that treatment of GBM cells with 24OHC suppressed tumour growth through regulation of LXR and SREBP signalling. Efavirenz, an activator of CYP46A1 that is known to penetrate the blood–brain barrier, inhibited GBM growth in vivo. Our findings demonstrate that CYP46A1 is a critical regulator of cellular cholesterol in GBM and that the CYP46A1/24OHC axis is a potential therapeutic target.
    Keywords 24OHC ; cholesterol homeostasis ; CYP46A1 ; efavirenz ; glioblastoma ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
    Subject code 616
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Protocol for derivation of organoids and patient-derived orthotopic xenografts from glioma patient tumors

    Anaïs Oudin / Virginie Baus / Vanessa Barthelemy / Carina Fabian / Eliane Klein / Monika Dieterle / May Wantz / Ann-Christin Hau / Claire Dording / Amandine Bernard / Alessandro Michelucci / Yahaya A. Yabo / Georgia Kanli / Olivier Keunen / Rolf Bjerkvig / Simone P. Niclou / Anna Golebiewska

    STAR Protocols, Vol 2, Iss 2, Pp 100534- (2021)

    2021  

    Abstract: Summary: Tumor organoids and patient-derived orthotopic xenografts (PDOXs) are some of the most valuable pre-clinical tools in cancer research. In this protocol, we describe efficient derivation of organoids and PDOX models from glioma patient tumors. We ...

    Abstract Summary: Tumor organoids and patient-derived orthotopic xenografts (PDOXs) are some of the most valuable pre-clinical tools in cancer research. In this protocol, we describe efficient derivation of organoids and PDOX models from glioma patient tumors. We provide detailed steps for organoid culture, intracranial implantation, and detection of tumors in the brain. We further present technical adjustments for standardized functional assays and drug testing.For complete details on the use and execution of this protocol, please refer to Golebiewska et al. (2020).
    Keywords Cell Biology ; Cell culture ; Cell isolation ; Cancer ; Model Organisms ; Neuroscience ; Science (General) ; Q1-390
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Spontaneous Transformation of Stem Cells In Vitro and the Issue of Cross-Contamination

    Anja Torsvik, Gro V. Røsland, Rolf Bjerkvig

    International Journal of Biological Sciences, Vol 8, Iss 7, Pp 1051-

    2012  Volume 1052

    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Ivyspring International Publisher
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors

    Synnøve Nymark Aasen / Himalaya Parajuli / Tuyen Hoang / Zichao Feng / Krister Stokke / Jiwei Wang / Kislay Roy / Rolf Bjerkvig / Stian Knappskog / Frits Thorsen

    International Journal of Molecular Sciences, Vol 20, Iss 17, p

    2019  Volume 4235

    Abstract: Malignant melanoma is the most aggressive type of skin cancer and is closely associated with the development of brain metastases. Despite aggressive treatment, the prognosis has traditionally been poor, necessitating improved therapies. In melanoma, the ... ...

    Abstract Malignant melanoma is the most aggressive type of skin cancer and is closely associated with the development of brain metastases. Despite aggressive treatment, the prognosis has traditionally been poor, necessitating improved therapies. In melanoma, the mitogen activated protein kinase and the phosphoinositide 3-kinase signaling pathways are commonly altered, and therapeutically inhibiting one of the pathways often upregulates the other, leading to resistance. Thus, combined treatment targeting both pathways is a promising strategy to overcome this. Here, we studied the in vitro and in vivo effects of the PI3K inhibitor buparlisib and the MEK1/2 inhibitor trametinib, used either as targeted monotherapies or in combination, on patient-derived melanoma brain metastasis cell lines. Scratch wound and trans-well assays were carried out to assess the migratory capacity of the cells upon drug treatment, whereas flow cytometry, apoptosis array and Western blots were used to study apoptosis. Finally, an in vivo treatment experiment was carried out on NOD/SCID mice. We show that combined therapy was more effective than monotherapy. Combined treatment also more effectively increased apoptosis, and inhibited tumor growth in vivo. This suggests a clinical potential of combined treatment to overcome ceased treatment activity which is often seen after monotherapies, and strongly encourages the evaluation of the treatment strategy on melanoma patients with brain metastases.
    Keywords melanoma ; brain metastasis ; BRAF ; MAPK ; PI3K ; combined treatment ; apoptosis ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 610 ; 616
    Language English
    Publishing date 2019-08-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis

    Joris Guyon / Ignacio Fernandez‐Moncada / Claire M Larrieu / Cyrielle L Bouchez / Antonio C Pagano Zottola / Johanna Galvis / Tiffanie Chouleur / Audrey Burban / Kevin Joseph / Vidhya M Ravi / Heidi Espedal / Gro Vatne Røsland / Boutaina Daher / Aurélien Barre / Benjamin Dartigues / Slim Karkar / Justine Rudewicz / Irati Romero‐Garmendia / Barbara Klink /
    Konrad Grützmann / Marie‐Alix Derieppe / Thibaut Molinié / Nina Obad / Céline Léon / Giorgio Seano / Hrvoje Miletic / Dieter Henrik Heiland / Giovanni Marsicano / Macha Nikolski / Rolf Bjerkvig / Andreas Bikfalvi / Thomas Daubon

    EMBO Molecular Medicine, Vol 14, Iss 12, Pp n/a-n/a (2022)

    2022  

    Abstract: Abstract Lactate is a central metabolite in brain physiology but also contributes to tumor development. Glioblastoma (GB) is the most common and malignant primary brain tumor in adults, recognized by angiogenic and invasive growth, in addition to its ... ...

    Abstract Abstract Lactate is a central metabolite in brain physiology but also contributes to tumor development. Glioblastoma (GB) is the most common and malignant primary brain tumor in adults, recognized by angiogenic and invasive growth, in addition to its altered metabolism. We show herein that lactate fuels GB anaplerosis by replenishing the tricarboxylic acid (TCA) cycle in absence of glucose. Lactate dehydrogenases (LDHA and LDHB), which we found spatially expressed in GB tissues, catalyze the interconversion of pyruvate and lactate. However, ablation of both LDH isoforms, but not only one, led to a reduction in tumor growth and an increase in mouse survival. Comparative transcriptomics and metabolomics revealed metabolic rewiring involving high oxidative phosphorylation (OXPHOS) in the LDHA/B KO group which sensitized tumors to cranial irradiation, thus improving mouse survival. When mice were treated with the antiepileptic drug stiripentol, which targets LDH activity, tumor growth decreased. Our findings unveil the complex metabolic network in which both LDHA and LDHB are integrated and show that the combined inhibition of LDHA and LDHB strongly sensitizes GB to therapy.
    Keywords antiepileptic drug ; energy metabolism ; glioblastoma ; invasion ; lactate dehydrogenases ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
    Subject code 570
    Language English
    Publishing date 2022-12-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; 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  Volume 0140303

    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2015-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; 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  Volume 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.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2015-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Deciphering the complex role of thrombospondin-1 in glioblastoma development

    Thomas Daubon / Céline Léon / Kim Clarke / Laetitia Andrique / Laura Salabert / Elodie Darbo / Raphael Pineau / Sylvaine Guérit / Marlène Maitre / Stéphane Dedieu / Albin Jeanne / Sabine Bailly / Jean-Jacques Feige / Hrvoje Miletic / Marco Rossi / Lorenzo Bello / Francesco Falciani / Rolf Bjerkvig / Andréas Bikfalvi

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 15

    Abstract: Thrombospondin-1 (THSB1) is a component of the ECM with a role in regulating cancer development and tumour vasculature. Here, the authors show that TGF-beta-induced THBS1 expression contributes to the invasive behaviour of GBM cells and promotes ... ...

    Abstract Thrombospondin-1 (THSB1) is a component of the ECM with a role in regulating cancer development and tumour vasculature. Here, the authors show that TGF-beta-induced THBS1 expression contributes to the invasive behaviour of GBM cells and promotes resistance to antiangiogenic therapy partially through interaction with CD47.
    Keywords Science ; Q
    Language English
    Publishing date 2019-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Deciphering the complex role of thrombospondin-1 in glioblastoma development

    Thomas Daubon / Céline Léon / Kim Clarke / Laetitia Andrique / Laura Salabert / Elodie Darbo / Raphael Pineau / Sylvaine Guérit / Marlène Maitre / Stéphane Dedieu / Albin Jeanne / Sabine Bailly / Jean-Jacques Feige / Hrvoje Miletic / Marco Rossi / Lorenzo Bello / Francesco Falciani / Rolf Bjerkvig / Andréas Bikfalvi

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 15

    Abstract: Thrombospondin-1 (THSB1) is a component of the ECM with a role in regulating cancer development and tumour vasculature. Here, the authors show that TGF-beta-induced THBS1 expression contributes to the invasive behaviour of GBM cells and promotes ... ...

    Abstract Thrombospondin-1 (THSB1) is a component of the ECM with a role in regulating cancer development and tumour vasculature. Here, the authors show that TGF-beta-induced THBS1 expression contributes to the invasive behaviour of GBM cells and promotes resistance to antiangiogenic therapy partially through interaction with CD47.
    Keywords Science ; Q
    Language English
    Publishing date 2019-03-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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