| 1. |
|
|
| 2. |
- Caglayan, Demet, et al.
(författare)
-
Induction of Glioblastoma Multiforme and Gliomatosis Cerebri with a Sleeping Beauty gene transfer system, implications for T regulatory cell involvement during glioma formation.
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Glioblastoma Multiforme (GBM), the most malignant and common neoplasm of the central nervous system (CNS), has been classified into subgroups with gene-expression profile as the basis for categorization. Among these the mesenchymal subgroup is most greatly associated with inflammatory infiltrates and increased expression of inflammatory associated genes. GBMs exhibit T cell infiltration to a varying degree and today the degree of infiltration is not used in prognostics. The Sleeping Beauty (SB) system was used to introduce AKT, a mutant variant of NRAS and a shp53 coupled to green fluorescent protein (GFP) into mice that are fully immunocomptetent, lack mature T cells or have reduced regulatory T (Treg) cell function respectively. We report, for the first time, the induction of Gliomatosis Cerebri with the SB system. Tumors that originated were either GBM or Gliomatosis Cerebri with a similar incidence. There was no difference in survival, grade or incidence of induced tumors in wild type mice and mice that lack mature T cells.
|
|
| 3. |
- Caglayan, Demet, et al.
(författare)
-
Sox21 inhibits glioma progression in vivo by forming complexes with Sox2 and stimulating aberrant differentiation
- 2013
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 133:6, s. 1345-1356
-
Tidskriftsartikel (refereegranskat)abstract
- Sox2 is a transcription factor in neural stem cells and keeps the cells immature and proliferative. Sox2 is expressed in primary human glioma such as glioblastoma multiforme (GBM), primary glioma cells and glioma cell lines and is implicated in signaling pathways in glioma connected to malignancy. Sox21, the counteracting partner of Sox2, has the same expression pattern as Sox2 in glioma but in general induces opposite effects. In this study, Sox21 was overexpressed by using a tetracycline-regulated expression system (tet-on) in glioma cells. The glioma cells were injected subcutaneously into immunodeficient mice. The control tumors were highly proliferative, contained microvascular proliferation and large necrotic areas typical of human GBM. Induction of Sox21 in the tumor cells resulted in a significant smaller tumor size, and the effect correlated with the onset of treatment, where earlier treatment gave smaller tumors. Mice injected with glioma cells orthotopically into the brain survived significantly longer when Sox21 expression was induced. Tumors originating from glioma cells with an induced expression of Sox21 exhibited an increased formation of Sox2:Sox21 complexes and an upregulation of S100, CNPase and Tuj1. Sox21 appears to decrease the stem-like cell properties of the tumor cells and initiate aberrant differentiation of glioma cells in vivo. Taken together our results indicate that Sox21 can function as a tumor suppressor during gliomagenesis mediated by a shift in the balance between Sox2 and Sox21. The wide distribution of Sox2 and Sox21 in GBM makes the Sox2/Sox21 axis a very interesting target for novel therapy of gliomas. What's new? Glioma formation is driven by brain tumor-initiating cells with stem cell-like properties. Here the authors show for the first time that the transcription factor Sox21 can act as a suppressor gene in gliomagenesis. Induced expression of Sox21 in human glioma cells results in reduced tumor growth and prolonged survival of xenotranplanted mice. Sox21 reduces the stem-cell like properties of the tumor cells, leading to abnormal differentiation, induced apoptosis, and decreased proliferation. The results point to a shift in balance between the counteracting and widely distributed Sox2 and Sox21, revealing the Sox2/Sox21 axis as a target for novel therapy of gliomas.
|
|
| 4. |
- Caglayan, Demet, et al.
(författare)
-
Sox21 inhibits glioma progression in vivo by reducing Sox2 and stimulating aberrant differentiation
- 2013
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 133:6, s. 1345-1356
-
Tidskriftsartikel (refereegranskat)abstract
- Sox2 is a transcription factor in neural stem cells and keeps the cells immature and proliferative. Sox2 is expressed in primary human glioma such as glioblastoma multiforme (GBM), primary glioma cells and glioma cell lines and is implicated in signaling pathways in glioma connected to malignancy. Sox21, the counteracting partner of Sox2, has the same expression pattern as Sox2 in glioma but in general induces opposite effects. In this study, Sox21 was overexpressed by using a tetracycline-regulated expression system (tet-on) in glioma cells. The glioma cells were injected subcutaneously into immunodeficient mice. The control tumors were highly proliferative, contained microvascular proliferation and large necrotic areas typical of human GBM. Induction of Sox21 in the tumor cells resulted in a significant smaller tumor size, and the effect correlated with the onset of treatment, where earlier treatment gave smaller tumors. Mice injected with glioma cells orthotopically into the brain survived significantly longer when Sox21 expression was induced. Tumors originating from glioma cells with an induced expression of Sox21 exhibited an increased formation of Sox2:Sox21 complexes and an upregulation of S100β, CNPase and Tuj1. Sox21 appears to decrease the stem-like cell properties of the tumor cells and initiate aberrant differentiation of glioma cells in vivo. Taken together our results indicate that Sox21 can function as a tumor suppressor during gliomagenesis mediated by a shift in the balance between Sox2 and Sox21. The wide distribution of Sox2 and Sox21 in GBM makes the Sox2/Sox21 axis a very interesting target for novel therapy of gliomas.
|
|
| 5. |
- Ferletta, Maria, 1973-, et al.
(författare)
-
Forced expression of Sox21 inhibits Sox2 and induces apoptosis in human glioma cells
- 2011
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 129:1, s. 45-60
-
Tidskriftsartikel (refereegranskat)abstract
- Numerous studies support a role for Sox2 to keep stem cells and progenitor cells in an immature and proliferative state. Coexpression of Sox2 and GFAP has been found in regions of the adult brain where neural stem cells are present and in human glioma cells. In our study, we have investigated the roles of Sox2 and its counteracting partner Sox21 in human glioma cells. We show for the first time that Sox21 is expressed in both primary glioblastoma and in human glioma cell lines. We found that coexpression of Sox2, GFAP and Sox21 was mutually exclusive with expression of fibronectin. Our result suggests that glioma consists of at least two different cell populations: Sox2+/GFAP+/Sox21+/FN- and Sox2-/GFAP-/Sox21-/FN1+. Reduction of Sox2 expression by using siRNA against Sox2 or by overexpressing Sox21 using a tetracyclineregulated expression system (Tet-on) caused decreased GFAP expression and a reduction in cell number due to induction of apoptosis. We suggest that Sox21 can negatively regulate Sox2 in glioma. Our findings imply that Sox2 and Sox21 may be interesting targets for the development of novel glioma therapy.
|
|
| 6. |
|
|
| 7. |
- Hägerstrand, Daniel, et al.
(författare)
-
Characterization of an imatinib-sensitive subset of high-grade human glioma cultures
- 2006
-
Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 25:35, s. 4913-4922
-
Tidskriftsartikel (refereegranskat)abstract
- High-grade gliomas, including glioblastomas, are malignant brain tumors for which improved treatment is urgently needed. Genetic studies have demonstrated the existence of biologically distinct subsets. Preliminary studies have indicated that platelet-derived growth factor (PDGF) receptor signaling contributes to the growth of some of these tumors. In this study, human high-grade glioma primary cultures were analysed for sensitivity to treatment with the PDGF receptor inhibitor imatinib/Glivec/Gleevec/STI571. Six out of 15 cultures displayed more than 40% growth inhibition after imatinib treatment, whereas seven cultures showed less than 20% growth inhibition. In the sensitive cultures, apoptosis contributed to growth inhibition. Platelet-derived growth factor receptor status correlated with imatinib sensitivity. Supervised analyses of gene expression profiles and real-time PCR analyses identified expression of the chemokine CXCL12/SDF-1 (stromal cell-derived factor 1) as a predictor of imatinib sensitivity. Exogenous addition of CXCL12 to imatinib-insensitive cultures conferred some imatinib sensitivity. Finally, coregulation of CXCL12 and PDGF alpha-receptor was observed in glioblastoma biopsies. We have thus defined the characteristics of a novel imatinib-sensitive subset of glioma cultures, and provided evidence for a functional relationship between imatinib sensitivity and chemokine signaling. These findings will assist in the design and evaluation of clinical trials exploring therapeutic effects of imatinib on malignant brain tumors.
|
|
| 8. |
|
|
| 9. |
- Kärrlander, Maria, et al.
(författare)
-
Histidine-rich glycoprotein can prevent development of mouse experimental glioblastoma
- 2009
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:12, s. e8536-
-
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).
|
|
| 10. |
- Lindberg, Nanna, et al.
(författare)
-
Differential roles of p16Ink4a and p19Arf in suppressing gliomagenesis from oligodendrocyte progenitor cells
-
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.
|
|
