| 1. |
- Bexell, Daniel, et al.
(author)
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Bone Marrow Multipotent Mesenchymal Stroma Cells Act as Pericyte-like Migratory Vehicles in Experimental Gliomas.
- 2009
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In: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 2008:Nov 4., s. 183-190
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Journal article (peer-reviewed)abstract
- Bone marrow-derived multipotent mesenchymal stroma cells (MSCs) have emerged as cellular vectors for gene therapy of solid cancers. We implanted enhanced green fluorescent protein-expressing rat MSCs directly into rat malignant gliomas to address their migratory capacity, phenotype, and effects on tumor neovascularization and animal survival. A single intratumoral injection of MSCs infiltrated the majority of invasive glioma extensions (72 +/- 14%) and a substantial fraction of distant tumor microsatellites (32 +/- 6%). MSC migration was highly specific for tumor tissue. Grafted MSCs integrated into tumor vessel walls and expressed pericyte markers alpha-smooth muscle actin, neuron-glia 2, and platelet-derived growth factor receptor-beta but not endothelial cell markers. The pericyte marker expression profile and perivascular location of grafted MSCs indicate that these cells act as pericytes within tumors. MSC grafting did not influence tumor microvessel density or survival of tumor-bearing animals. The antiangiogenic drug Sunitinib markedly reduced the numbers of grafted MSCs migrating within tumors. We found no MSCs within gliomas following intravenous (i.v.) injections. Thus, MSCs should be administered by intratumoral implantations rather than by i.v. injections. Intratumorally grafted pericyte-like MSCs might represent a particularly well-suited vector system for delivering molecules to affect tumor angiogenesis and for targeting cancer stem cells within the perivascular niche.Molecular Therapy (2008); doi:10.1038/mt.2008.229.
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| 2. |
- Bexell, Daniel, et al.
(author)
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CD133+ and nestin+ tumor-initiating cells dominate in N29 and N32 experimental gliomas.
- 2009
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 125:1, s. 15-22
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Journal article (peer-reviewed)abstract
- 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. (c) 2009 Wiley-Liss, Inc.
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| 3. |
- Bexell, Daniel, et al.
(author)
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Characterization of the subventricular zone neurogenic response to rat malignant brain tumors
- 2007
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In: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 147:3, s. 824-832
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Journal article (peer-reviewed)abstract
- The subventricular zone (SVZ) is one of the neurogenic regions of the adult brain. We characterized the neurogenic response of the SVZ to the growth of brain tumors in the rat striatum. Abundant nestin positive cells, most likely representing reactive astrocytes, were found surrounding the tumor. However, we observed no substantial migration of nestin positive cells from the SVZ toward the tumor. Tumor growth resulted in decreased numbers of bromodeoxyuridine positive and Ki-67 positive proliferating cells and a concomitant increase in doublecortin and polysialylated neural cell adhesion molecule immunoreactivity within the SVZ. Neuroblasts were observed in high numbers in the area between the SVZ and the tumor, most likely pointing to the SVZ as the principal source of these cells. Neuroblasts located between the SVZ and the tumor expressed the transcription factor Pbx, a marker for immature striatal neurons. However, no evidence of neuroblast differentiation into fully mature neurons was found. This study thus demonstrates increased neuroblast immunoreactivity within the SVZ ipsilateral to a brain tumor in the striatum. SVZ-derived neuroblasts attracted by the tumor adopt an immature striatal phenotype indicating a region specific reparative mechanism in response to a malignant tumor. (C) 2007 IBRO. Published by Elsevier Ltd. All rights reserved.
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| 4. |
- Bexell, Daniel, et al.
(author)
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Rat Multipotent Mesenchymal Stromal Cells Lack Long-Distance Tropism to 3 Different Rat Glioma Models
- 2012
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In: Neurosurgery. - 0148-396X. ; 70:3, s. 731-739
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Journal article (peer-reviewed)abstract
- BACKGROUND: Viral gene therapy of malignant brain tumors has been restricted by the limited vector distribution within the tumors. Multipotent mesenchymal stromal cells (MSCs) and other precursor cells have shown tropism for gliomas, and these cells are currently being explored as potential vehicles for gene delivery in glioma gene therapy. OBJECTIVE: To investigate MSC migration in detail after intratumoral and extratumoral implantation through syngeneic and orthotopic glioma models. METHODS: Adult rat bone marrow-derived MSCs were transduced to express enhanced green fluorescent protein and implanted either directly into or at a distance from rat gliomas. RESULTS: We found no evidence of long-distance MSC migration through the intact striatum toward syngeneic D74(RG2), N32, and N29 gliomas in the ipsilateral hemisphere or across the corpus callosum to gliomas located in the contralateral hemisphere. After intratumoral injection, MSCs migrated extensively, specifically within N32 gliomas. The MSCs did not proliferate within tumors, suggesting a low risk of malignant transformation of in vivo grafted cell vectors. Using a model for surgical glioma resection, we found that intratumorally grafted MSCs migrate efficiently within glioma remnants after partial surgical resection. CONCLUSION: The findings point to limitations for the use of MSCs as vectors in glioma gene therapy, although intratumoral MSC implantation provides a dense and tumor-specific vector distribution.
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| 5. |
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| 6. |
- Gunnarsson, Salina, et al.
(author)
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Intratumoral IL-7 delivery by mesenchymal stromal cells potentiates IFNgamma-transduced tumor cell immunotherapy of experimental glioma.
- 2010
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In: Journal of Neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 218:1-2, s. 140-144
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Journal article (peer-reviewed)abstract
- The present study reports regression of pre-established experimental rat gliomas as a result of combining peripheral immunization using interferon gamma (IFNgamma) transduced autologous tumor cells with local intratumoral delivery of interleukin 7 (IL-7) by mesenchymal stromal cells. IL-7 alone significantly decreased the tumor area and this effect was enhanced with IFNgamma immunization. A higher density of intratumoral T-cells was observed in animals receiving combined therapies compared to rats receiving either cytokine alone suggesting that the therapeutic effect is dependent on a T-cell response.
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| 7. |
- Gunnarsson, Salina
(author)
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Synergistic effects of mesenchymal stromal cells and immunotherapy in experimental brain tumors
- 2010
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Doctoral thesis (other academic/artistic)abstract
- Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain tumor. In spite of surgical resection, combined radiation therapy and chemotherapy, the mean survival is less than 15 months following diagnosis. Using the established N29 and N32 animal models of glioma, shown to have many similarities with the human tumor, we are able to study and develop therapeutic strategies against GBM. The tumor models were first characterized according to cancer-initiating capacity. It was established that both models concomitantly and homogenously express several immature and mature markers of neural origin. Furthermore, the glioma cells were highly clonogenic in vitro and showed a robust tumorigenicity in vivo. Next multipotent mesenchymal stromal cells (MSCs) were compared to neural precursor cells (NPCs) in capacity of survival and migration following intratumoral grafting, which revealed that MSCs were superior to NPCs as potential vectors in tumor therapy. It was also concluded that MSCs do not migrate towards a pre-established tumor when grafted behind it or in contact with the corpus callosum. Neither do the MSCs proliferate following grafting, further confirming that MSCs are suitable as cellular vehicles. MSCs derived from adult rat bone marrow are relatively easily isolated and cultured as well as able to be stably transduced to express a therapeutic gene/drug. When MSCs are grafted intratumorally following peripheral immunizations with IFNγ-secreting autologous irradiated tumor cells, a synergistic effect on anti-tumor immunity is noticed with a prolonged survival and an increased tumor infiltration of immune cells. Rat MSCs were modified to produce the cytokine interleukin 7 (IL-7), a growth factor for immune cells. IL-7 secreting MSCs injected intratumorally resulted in a decreased tumor area compared to control. When combined with peripheral immunization the mean area of pre-established tumors was further decreased. The effect on tumor was coupled to an increase of tumor-infiltrating T cells. In conclusion this thesis points to a synergistic effect of intratumorally located MSCs and peripheral immunotherapy with IFNγ-producing tumor cells. Hopefully this combination might be further developed into a clinically useful treatment strategy.
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| 8. |
- Janelidze, Shorena, et al.
(author)
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Immunizations With IFN gamma Secreting Tumor Cells can Eliminate Fully Established and Invasive Rat Gliomas
- 2009
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In: Journal of Immunotherapy. - 1524-9557. ; 32:6, s. 593-601
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Journal article (peer-reviewed)abstract
- Immunotherapy of malignant primary brain tumors holds the potential to improve the dismal prognosis after current clinical therapy. Although immunotherapy of experimental gliomas has been demonstrated to have the capacity to cure intracerebral tumors no convincing effects of immunotherapy have been shown in clinical trials. One reason for this could be that some of the models used do not display full features of human glioblastomas. The N29 rat gliomas exhibited all the histologic features of human glioblastoma multiforme including nuclear atypia, mitotic figures, necrosis, and diffuse infiltration into the normal brain tissue. Surprisingly, immunotherapy with autologous interferon gamma producing tumor cells against preestablished intracerebral N29 turners yielded a higher cure rate than immunotherapy against less invasive tumors. Furthermore, when immunizations were postponed until day 5 after tumor establishment 50% of the animals survived. When immunizations were postponed until day 11 after tumor establishment no glioma-bearing animals were cured but survival was significantly prolonged. The superior effect of immunotherapy in the invasive N29 model compared with the less invasive tumors could depend oil combined effects of up-regulation of major histocompatibility complex I and induction of major histocompatibility complex II plus CD80 after transfection and irradiation of the tumor cells used for immunizations. This study demonstrates that immunotherapy against experimental brain tumors indeed is feasible even against highly invasive and established tumors. These results strengthen the translational potential of immunotherapy against malignant brain tumors.
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