| 1. |
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| 2. |
- Jiang, Yiwen, et al.
(författare)
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Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin
- 2017
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 18:4, s. 977-990
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Tidskriftsartikel (refereegranskat)abstract
- The identity of the glioblastoma (GBM) cell of origin and its contributions to disease progression and treatment response remain largely unknown. We have analyzed how the phenotypic state of the initially transformed cell affects mouse GBM development and essential GBM cell (GC) properties. We find that GBM induced in neural stem-cell-like glial fibrillary acidic protein (GFAP)-expressing cells in the subventricular zone of adult mice shows accelerated tumor development and produces more malignant GCs (mGC1GFAP) that are less resistant to cancer drugs, compared with those originating from more differentiated nestin- (mGC2NES) or 2,'3'-cyclic nucleotide 3'-phosphodiesterase (mGC3CNP)-expressing cells. Transcriptome analysis of mouse GCs identified a 196 mouse cell origin (MCO) gene signature that was used to partition 61 patient-derived GC lines. Human GC lines that clustered with the mGC1GFAP cells were also significantly more self-renewing, tumorigenic, and sensitive to cancer drugs compared with those that clustered with mouse GCs of more differentiated origin.
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| 3. |
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| 4. |
- Kärrlander, Maria, et al.
(författare)
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Histidine-rich glycoprotein can prevent development of mouse experimental glioblastoma
- 2009
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:12, s. e8536-
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Tidskriftsartikel (refereegranskat)abstract
- Extensive angiogenesis, formation of new capillaries from pre-existing blood vessels, is an important feature of malignant glioma. Several antiangiogenic drugs targeting vascular endothelial growth factor (VEGF) or its receptors are currently in clinical trials as therapy for high-grade glioma and bevacizumab was recently approved by the FDA for treatment of recurrent glioblastoma. However, the modest efficacy of these drugs and emerging problems with anti-VEGF treatment resistance welcome the development of alternative antiangiogenic therapies. One potential candidate is histidine-rich glycoprotein (HRG), a plasma protein with antiangiogenic properties that can inhibit endothelial cell adhesion and migration. We have used the RCAS/TV-A mouse model for gliomas to investigate the effect of HRG on brain tumor development. Tumors were induced with platelet-derived growth factor-B (PDGF-B), in the presence or absence of HRG. We found that HRG had little effect on tumor incidence but could significantly inhibit the development of malignant glioma and completely prevent the occurrence of grade IV tumors (glioblastoma).
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| 5. |
- Landegren, Nils, et al.
(författare)
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Autoantibodies Targeting a Collecting Duct-Specific Water Channel in Tubulointerstitial Nephritis
- 2016
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Ingår i: Journal of the American Society of Nephrology: JASN. - 1533-3450 .- 1046-6673. ; 27:10, s. 3220-3228
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Tidskriftsartikel (refereegranskat)abstract
- Tubulointerstitial nephritis is a common cause of kidney failure and may have diverse etiologies. This form of nephritis is sometimes associated with autoimmune disease, but the role of autoimmune mechanisms in disease development is not well understood. Here, we present the cases of three patients with autoimmune polyendocrine syndrome type 1 who developed tubulointerstitial nephritis and ESRD in association with autoantibodies against kidney collecting duct cells. One of the patients developed autoantibodies targeting the collecting duct-specific water channel aquaporin 2, whereas autoantibodies of the two other patients reacted against the HOXB7 or NFAT5 transcription factors, which regulate the aquaporin 2 promoter. Our findings suggest that tubulointerstitial nephritis developed in these patients as a result of an autoimmune insult on the kidney collecting duct cells.
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| 6. |
- Lindberg, Nanna, 1982-
(författare)
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Cellular Origin and Development of Glioma
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Gliomas are the most common primary tumors of the central nervous system believed to arise from glial cells. Invasive growth and inherent propensity for malignant progression make gliomas incurable despite extensive treatment. I have developed a life-like orthotopic glioma model and used this and other in vivo models to study basic mechanisms of glioma development and treatment. Previous studies had indicated that experimental gliomas could arise from glial stem cells and astrocytes. The present thesis describes the making and characterization of a novel mouse model, Ctv-a, where gliomas are induced from oligodendrocyte progenitor cells (OPCs). Our study shows that OPCs have the capacity to give rise to gliomas and suggests in light of previous data that the differentiation state of the cell of origin affects tumor malignancy. CDKN2A encodes p16INK4a and p14ARF (p19Arf in mouse) commonly inactivated in malignant glioma. Their roles in experimental glioma have been extensively studied and both proteins have tumor suppressor functions in glial stem cells and astrocytes. Here, we demonstrate that p19Arf only could suppress gliomagenesis in OPCs while p16Ink4a had no tumor suppressive effect. Functional DNA repair is pivotal for maintaining genome integrity, eliminating unsalvageable cells and inhibiting tumorigenesis. We have studied how RAD51, a central protein of homology-directed repair, affected experimental glioma development and have found that expression of RAD51 may protect against genomic instability and tumor development. Angiogenesis, the formation of new blood vessels from pre-existing ones, is a central feature of malignant progression in glioma. Antiangiogenic treatment by inhibition of vascular endothelial growth factor receptor signaling is used in the clinic for treatment of some cancers. We have investigated the effect of an alternative antiangiogenic protein, histidine-rich glycoprotein (HRG), on glioma development and found that HRG could inhibit the formation of malignant gliomas and completely prevent the formation of glioblastoma.
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| 7. |
- Lindberg, Nanna, et al.
(författare)
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Differential roles of p16Ink4a and p19Arf in suppressing gliomagenesis from oligodendrocyte progenitor cells
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Version:1.0 StartHTML:0000000226 EndHTML:0000029504 StartFragment:0000002830 EndFragment:0000029468 SourceURL:file://localhost/Users/nannalindberg/Ctva%20tumor%20suppressors/Manuskript/MS%20Ctva%20knockar%20091013NL.doc CDKN2a encodes the tumor suppressor proteins p16INK4a and p14ARF (p19Arf in mouse) whose functions are frequently lost in human glioblastoma. From previous studies using the RCAS/TV-Atv-a mouse model we have shown that p16Ink4a and p19Arf individually and combined couldan suppress glioma development in Nestin expressing cells (in Ntv-a mice) and in Gfap expressing cells (in Gtv-a mice) (Uhrbom, Dai et al. 2002; Uhrbom, Kastemar et al. 2005; Tchougounova, Kastemar et al. 2007). Recently, we showed that oligodendrocyte progenitor cells (OPCs) could act as cell of origin for glioma by making a Ctv-a mouse in which CNPase expressing cells couldan be targeted by retroviral infection (Lindberg, Kastemar et al. 2009). Here In the current study we have investigated the roles of p16Ink4a and p19Arf in tumor development from OPCs. Unexpectedly, we found that p19Arf only only could suppress oncogene induced gliomagenesis. Loss of Arf caused significantly increased incidence and malignancy of PDGF-B induced tumors and decreased survival compared to Ctv-a wt mice. In addition, Arf deficiency facilitated K-RAS+AKT induced glioma development. Loss of Ink4a, however, lead to nocould not enable tumor induction by (K-RAS++AKT and caused a slight decrease in (PDGF-B) induced tumor incidence. Similarly, wWhen inducing tumors in adult Ctv-a mice we found that Arf loss but not Ink4a loss enabled tumor induction. Taken together, our data suggest that p19Arf but not p16Ink4a is a tumor suppressor in OPCs of both newborn and adult mice.
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| 8. |
- Lindberg, Nanna, 1982-, et al.
(författare)
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Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma
- 2009
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 28:23, s. 2266-2275
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Tidskriftsartikel (refereegranskat)abstract
- Gliomas are primary brain tumors mainly affecting adults. The cellular origin is unknown. The recent identification of tumor-initiating cells in glioma, which share many similarities with normal neural stem cells, has suggested the cell of origin to be a transformed neural stem cell. In previous studies, using the RCAS/tv-a mouse model, platelet-derived growth factor B (PDGF-B)-induced gliomas have been generated from nestin or glial fibrillary acidic protein-expressing cells, markers of neural stem cells. To investigate if committed glial progenitor cells could be the cell of origin for glioma, we generated the Ctv-a mouse where tumor induction would be restricted to myelinating oligodendrocyte progenitor cells (OPCs) expressing 2',3'-cyclic nucleotide 3'-phosphodiesterase. We showed that PDGF-B transfer to OPCs could induce gliomas with an incidence of 33%. The majority of tumors resembled human WHO grade II oligodendroglioma based on close similarities in histopathology and expression of cellular markers. Thus, with the Ctv-a mouse we have showed that the cell of origin for glioma may be a committed glial progenitor cell.
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| 9. |
- Lindberg, Nanna, et al.
(författare)
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Oligodendroglioma models
- 2013
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Ingår i: Animal Models of Brain Tumors. - Totowa, NJ : Humana Press. - 9781627032087 ; , s. 57-82
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Bokkapitel (refereegranskat)abstract
- Oligodendroglial tumors are primary tumors of the central nervous system that largely affect adults. The cell of origin is undefined, but the tumors display many features reminiscent of oligodendrocytes or oligodendrocyte progenitor cells. Here, we briefly recapitulate the history of oligodendroglial tumor research, discuss the current knowledge concerning the biology of oligodendroglial tumors, and thoroughly review the various mouse models that have been used and that are currently in use to study oligodendroglial tumor development.
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| 10. |
- Lindberg, Nanna, et al.
(författare)
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Oncogenic Signaling Is Dominant to Cell of Origin and Dictates Astrocytic or Oligodendroglial Tumor Development from Oligodendrocyte Precursor Cells
- 2014
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 34:44, s. 14644-14651
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Tidskriftsartikel (refereegranskat)abstract
- Stem cells, believed to be the cellular origin of glioma, are able to generate gliomas, according to experimental studies. Here we investigated the potential and circumstances of more differentiated cells to generate glioma development. We and others have shown that oligodendrocyte precursor cells (OPCs) can also be the cell of origin for experimental oligodendroglial tumors. However, the question of whether OPCs have the capacity to initiate astrocytic gliomas remains unanswered. Astrocytic and oligodendroglial tumors represent the two most common groups of glioma and have been considered as distinct disease groups with putatively different origins. Here we show that mouse OPCs can give rise to both types of glioma given the right circumstances. We analyzed tumors induced by K-RAS and AKT and compared them to oligodendroglial platelet-derived growth factor B-induced tumors in Ctv-a mice with targeted deletions of Cdkn2a (p16(Ink4a-/-), p19(Arf-/-), Cdkn2a(-/-)). Our results showed that glioma can originate from OPCs through overexpression of K-RAS and AKT when combined with p19(Arf) loss, and these tumors displayed an astrocytic histology and high expression of astrocytic markers. We argue that OPC shave the potential to develop both astrocytic and oligodendroglial tumors given loss of p19(Arf), and that oncogenic signaling is dominant to cell of origin in determining glioma phenotype. Our mouse data are supported by the fact that human astrocytoma and oligodendroglioma display a high degree of overlap in global gene expression with no clear distinctions between the two diagnoses.
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| 11. |
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| 12. |
- Sagrén, Cecilia, 1959-, et al.
(författare)
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Framtidsfrågor Restaureringskonst 2016-2017 Kungl Konsthögskolan
- 2017
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Rapport (populärvet., debatt m.m.)abstract
- Restaureringskonst vid Kungl Konsthögskolan i Stockholm har läsåret 2016-2017 haft temat Framtidsfrågor. Utöver professionskunskap och teori har fronten och framtidsfrågor inom ämnet studerats. Publikationen visar en del av årets arbete i form av artiklar. Praktisk träning i dokumentation och värdering avspeglas liksom gemensamma studieresor, föreläsningar och milstolpar inom restaurering. Framtidsfrågor har inga enkla svar med för att kunskapsuppbyggnaden ska ligga i fronten är Restaureringskonst en aktiv deltagare i diskussionen.
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| 13. |
- Tchougounova, Elena, et al.
(författare)
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Sox5 can suppress platelet-derived growth factor B-induced glioma development in Ink4a-deficient mice through induction of acute cellular senescence
- 2009
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 28:12, s. 1537-1548
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Tidskriftsartikel (refereegranskat)abstract
- SOX5 is a member of the high-mobility group superfamily of architectural non-histone proteins involved in gene regulation and maintenance of chromatin structure in a wide variety of developmental processes. Sox5 was identified as a brain tumor locus in a retroviral insertional mutagenesis screen of platelet-derived growth factor B (PDGFB)-induced mouse gliomas. Here we have investigated the role of Sox5 in PDGFB-induced gliomagenesis in mice. We show that Sox5 can suppress PDGFB-induced glioma development predominantly upon Ink4a-loss. In human glioma cell lines and tissues, we found very low levels of SOX5 compared with normal brain. Overexpression of Sox5 in human glioma cells led to a reduction in clone formation and inhibition of proliferation. Combined expression of Sox5 and PDGFB in primary brain cell cultures caused decreased proliferation and an increased number of senescent cells in the Ink4a-/- cells only. Protein analyses showed a reduction in the amount and activation of Akt and increased levels of p27(Kip1) upon Sox5 expression that was dominant to PDGFB signaling and specific to Ink4a-/- cells. Upon inhibition of p27(Kip1), the effects of Sox5 on proliferation and senescence could be reversed. Our data suggest a novel pathway, where Sox5 may suppress the oncogenic effects of PDGFB signaling during glioma development by regulating p27(Kip1) in a p19(Arf)-dependent manner, leading to acute cellular senescence.
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| 14. |
- Westermark, Ulrica K, et al.
(författare)
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RAD51 can inhibit PDGFB-induced gliomagenesis and genomic instability
- 2011
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Ingår i: Neuro-Oncology. - : Oxford University Press (OUP). - 1522-8517 .- 1523-5866. ; 13:12, s. 1277-1287
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Tidskriftsartikel (refereegranskat)abstract
- Faithful replication and DNA repair are vital for maintenance of genome integrity. RAD51 is a central protein in homologous recombination repair and during replication, when it protects and restarts stalled replication forks. Aberrant RAD51 expression occurs in glioma, and high expression has been shown to correlate with prolonged survival. Furthermore, genes involved in DNA damage response (DDR) are mutated or deleted in human glioblastomas, corroborating the importance of proper DNA repair to suppress gliomagenesis. We have analyzed DDR and genomic instability in PDGF-B-induced gliomas and investigated the role of RAD51 in glioma development. We show that PDGF-B-induced gliomas display genomic instability and that co-expression of RAD51 can suppress PDGF-B-induced tumorigenesis and prolong survival. Expression of RAD51 inhibited proliferation and genomic instability of tumor cells independent of Arf status. Our results demonstrate that the RAD51 pathway can prevent glioma initiation and maintain genome integrity of induced tumors, suggesting reactivation of the RAD51 pathway as a potential therapeutic avenue.
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| 15. |
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| 16. |
- Xie, Yuan, et al.
(författare)
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The Human Glioblastoma Cell Culture Resource : Validated Cell Models Representing All Molecular Subtypes
- 2015
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 2:10, s. 1351-1363
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma (GBM) is the most frequent and malignant form of primary brain tumor. GBM is essentially incurable and its resistance to therapy is attributed to a subpopulation of cells called gliomastem cells (GSCs). To meet the present shortage of relevant GBM cell (GC) lines we developed a library of annotated and validated cell lines derived from surgical samples of GBM patients, maintained under conditions to preserve GSC characteristics. This collection, which we call the Human Glioblastoma Cell Culture (HGCC) resource, consists of a biobank of 48 GC lines and an associated database containing high-resolution molecular data. We demonstrate that the HGCC lines are tumorigenic, harbor genomic lesions characteristic of GBMs, and represent all four transcriptional sub-types. The HGCC panel provides an open resource for in vitro and in vivo modeling of a large part of GBM diversity useful to both basic and translational GBM research.
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