| 1. |
- Elsir, Tamador, et al.
(författare)
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A study of embryonic stem cell-related proteins in human astrocytomas : Identification of Nanog as a predictor of survival
- 2014
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 134:5, s. 1123-1131
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies suggest that the regulatory networks controlling the functions of stem cells during development may be abnormally active in human cancers. An embryonic stem cell (ESC) gene signature was found to correlate with a more undifferentiated phenotype of several human cancer types including gliomas, and associated with poor prognosis in breast cancer. In the present study, we used tissue microarrays of 80 low-grade (WHO grade II) and 98 high-grade human gliomas (WHO grade III and IV) to investigate the presence of the ESC-related proteins Nanog, Klf4, Oct4, Sox2 and c-Myc by immunohistochemistry. While similar patterns of co-expressed proteins between low- and high-grade gliomas were present, we found up-regulated protein levels of Nanog, Klf4, Oct4 and Sox2 in high-grade gliomas. Survival analysis by Kaplan-Meier analysis revealed a significant shorter survival in the subgroups of low-grade astrocytomas (n=42) with high levels of Nanog protein (p=0.0067) and of Klf4 protein (p=0.0368), in high-grade astrocytomas (n=85) with high levels of Nanog (p=0.0042), Klf4 (p=0.0447), and c-Myc (p=0.0078) and in glioblastomas only (n=71) with high levels of Nanog (p=0.0422) and of c-Myc (p= 0.0256). In the multivariate model, Nanog was identified as an independent prognostic factor in the subgroups of low-grade astrocytomas (p=0.0039), high-grade astrocytomas (p=0.0124) and glioblastomas only (p=0.0544), together with established clinical variables in these tumors. These findings provide further evidence for the joint regulatory pathways of ESC-related proteins in gliomas and identify Nanog as one of the key players in determining clinical outcome of human astrocytomas.
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| 2. |
- Elsir, Tamador, et al.
(författare)
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Transcription factor PROX1 : its role in development and cancer.
- 2012
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Ingår i: Cancer Metastasis Review. - : Springer Science and Business Media LLC. - 0167-7659 .- 1573-7233. ; 31:3-4, s. 793-805
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Forskningsöversikt (refereegranskat)abstract
- The homeobox gene PROX1 is critical for organ development during embryogenesis. The Drosophila homologue, known as prospero has been shown to act as a tumor suppressor by controlling asymmetric cell division of neuroblasts. Likewise, alterations in PROX1 expression and function are associated with a number of human cancers including hematological malignancies, carcinomas of the pancreas, liver and the biliary system, sporadic breast cancer, Kaposiform hemangioendothelioma, colon cancer, and brain tumors. PROX1 is involved in cancer development and progression and has been ascribed both tumor suppressive and oncogenic properties in a variety of different cancer types. However, the exact mechanisms through which PROX1 regulates proliferation, migration, and invasion of cancer cells are by large unknown. This review provides an update on the role of PROX1 in organ development and on its emerging functions in cancer, with special emphasis on the central nervous system and glial brain tumors.
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| 3. |
- Elsir, Tamador
(författare)
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Transcription factors PROX1 and p53 in cancer development
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The majority of malignant brain tumors in adults are astrocytic gliomas. These are classified into four malignancy grades according to the World Health Organization (WHO) criteria, including grade I pilocytic astrocytoma, grade II astrocytoma, grade III anaplastic astrocytoma and grade IV glioblastoma. Understanding the underlying molecular defects of these tumors gives us the possibility to design new effective therapies. PROX1 is a transcription factor that has an important role in the developmental process of various organs during embryogenesis, including the central nervous system. In paper I we examined a group of 56 paraffin embedded astrocytic brain tumors for their expression of PROX1. We found that the number of PROX1+ cells was correlated to high tumor grade. We concluded that PROX1 maybe used as a diagnostic tool distinguishing between grade III, IV tumors and grade II astrocytomas. This finding led us to investigate PROX1 s prognostic and predictive value in grade II tumors, because these tumors have a highly unpredictable course of progression to a more malignant grade, which hinders the clinicians choice of treatment. In paper II we studied the expression levels of PROX1 in 128 grade II astrocytic brain tumors and found that it is a highly dependable, predictive factor for short term survival in patients with astrocytic gliomas but not for oligodendrogliomas. We propose that in the future PROX1 maybe used in the clinical routine as a biomarker to help in prediction of prognosis for astrocytic brain tumors. In order to understand why PROX1 is up regulated in these tumors, we determined its expression in different established glioma cell lines, to serve as a tool for the functional studies of the protein (paper III). A hallmark of glioblastoma is mutations in the p53 tumor suppressor gene. p53 is also frequently mutated in other tumors including those from lung, breast and skin. In paper IV we used a mouse skin model, p53QS-val135/QS-val135 (p53QS), to examine the importance of p53 transcriptional regulatory function in tumor suppression. This model contains a double mutationin the N-terminus of p53 abrogating the transactivation domain and a modification at amino acid 135 partially affecting DNA binding. Ras oncogene-induced senescence was lost in both p53QS and p53-/- keratinocytes. Likewise, p53QS, similar to p53-/-, cooperated with v-rasHa to enhance malignant conversion. The tumors arising in p53QS keratinocytes displayed strong nuclear p53 expression, thus the p53QS-val135 allele was maintained during tumor formation. While p53-/- keratinocytes displayed diminished response to TGF-beta, p53QS and p53wt keratinocytes responded equivalently, indicating that the requirement of p53 for maximizing TGF-beta-mediated growth regulation is independent of its transactivation domain and that TGF-beta-mediated growth regulation is not required for p53 mediated tumor suppression in the skin.
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| 4. |
- Langenkamp, Elise, et al.
(författare)
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Elevated Expression of the C-Type Lectin CD93 in the Glioblastoma Vasculature Regulates Cytoskeletal Rearrangements That Enhance Vessel Function and Reduce Host Survival
- 2015
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 75:21, s. 4504-4516
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma is an aggressive brain tumor characterized by an abnormal blood vasculature that is hyperpermeable. Here, we report a novel role for CD93 in regulating angiogenesis in this setting by modulating cell-cell and cell-matrix adhesion of endothelial cells. Tissue microarray analysis demonstrated that vascular expression of CD93 was correlated with poor survival in a clinical cohort of patients with high-grade astrocytic glioma. Similarly, intracranial growth in the GL261 mouse model of glioma was delayed significantly in CD93(-/-) hosts, resulting in improved survival compared with wild-type mice. This effect was associated with increased vascular permeability and decreased vascular perfusion of tumors, indicating reduced vessel functionality in the absence of CD93. RNAi-mediated attenuation of CD93 in endothelial cells diminished VEGF-induced tube formation in a three-dimensional collagen gel. CD93 was required for efficient endothelial cell migration and proper cell polarization in vitro. Further, in endothelial cells where CD93 was attenuated, decreased cell spreading led to a severe reduction in cell adhesion, a lack of proper cell contacts, a loss of VE-cadherin, and aberrant actin stress fiber formation. Our results identify CD93 as a key regulator of glioma angiogenesis and vascular function, acting via cytoskeletal rearrangements required for cell-cell and cell-matrix adhesion.
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| 5. |
- Roodakker, Kenney R., et al.
(författare)
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PROX1 is a novel pathway-specific prognostic biomarker for high-grade astrocytomas; results from independent glioblastoma cohorts stratified by age and IDH mutation status
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:45, s. 72431-72442
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Tidskriftsartikel (refereegranskat)abstract
- PROX1 is a transcription factor with an essential role in embryonic development and determination of cell fate. In addition, PROX1 has been ascribed suppressive as well as oncogenic roles in several human cancers, including brain tumors. In this study we explored the correlation between PROX1 expression and patient survival in high-grade astrocytomas. For this purpose, we analyzed protein expression in tissue microarrays of tumor samples stratified by patient age and IDH mutation status. We initially screened 86 unselected high-grade astrocytomas, followed by 174 IDH1-R132H1 immunonegative glioblastomas derived from patients aged 60 years and older enrolled in the Nordic phase III trial of elderly patients with newly diagnosed glioblastoma. Representing the younger population of glioblastomas, we studied 80 IDH-wildtype glioblastomas from patients aged 18-60 years. There was no correlation between PROX1 protein and survival for patients with primary glioblastomas included in these cohorts. In contrast, high expression of PROX1 protein predicted shorter survival in the group of patients with IDH-mutant anaplastic astrocytomas and secondary glioblastomas. The prognostic impact of PROX1 in IDH-mutant 1p19q non-codeleted high-grade astrocytomas, as well as the negative findings in primary glioblastomas, was corroborated by gene expression data extracted from the Cancer Genome Atlas. We conclude that PROX1 is a new prognostic biomarker for 1p19q non-codeleted high-grade astrocytomas that have progressed from pre-existing lowgrade tumors and harbor IDH mutations.
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| 6. |
- Smits, Anja, et al.
(författare)
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GABA-A Channel Subunit Expression in Human Glioma Correlates with Tumor Histology and Clinical Outcome
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:5, s. e37041-
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Tidskriftsartikel (refereegranskat)abstract
- GABA (γ-aminobutyric acid) is the main inhibitory neurotransmitter in the CNS and is present in high concentrations in presynaptic terminals of neuronal cells. More recently, GABA has been ascribed a more widespread role in the control of cell proliferation during development where low concentrations of extrasynaptic GABA induce a tonic activation of GABA receptors. The GABA-A receptor consists of a ligand-gated chloride channel, formed by five subunits that are selected from 19 different subunit isoforms. The functional and pharmacological properties of the GABA-A channels are dictated by their subunit composition. Here we used qRT-PCR to compare mRNA levels of all 19 GABA-A channel subunits in samples of human glioma (n = 29) and peri-tumoral tissue (n = 5). All subunits except the ρ1 and ρ3 subunit were consistently detected. Lowest mRNA levels were found in glioblastoma compared to gliomas of lower malignancy, except for the θ subunit. The expression and cellular distribution of the α1, γ1, ρ2 and θ subunit proteins was investigated by immunohistochemistry on tissue microarrays containing 87 gliomas grade II. We found a strong co-expression of ρ2 and θ subunits in both astrocytomas (r = 0.86, p<0.0001) and oligodendroglial tumors (r = 0.66, p<0.0001). Kaplan-Meier analysis and Cox proportional hazards modeling to estimate the impact of GABA-A channel subunit expression on survival identified the ρ2 subunit (p = 0.043) but not the θ subunit (p = 0.64) as an independent predictor of improved survival in astrocytomas, together with established prognostic factors. Our data give support for the presence of distinct GABA-A channel subtypes in gliomas and provide the first link between specific composition of the A-channel and patient survival.
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| 7. |
- Sooman, Linda, et al.
(författare)
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FGF2 as a potential prognostic biomarker for proneural glioma patients
- 2015
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Ingår i: Acta Oncologica. - : Informa Healthcare. - 0284-186X .- 1651-226X. ; 54:3, s. 385-394
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The survival of high-grade glioma patients is poor and the treatment of these patients can cause severe side effects. This fosters the necessity to identify prognostic biomarkers, in order to optimize treatment and diminish unnecessary suffering of patients. The aim of this study was to identify prognostic biomarkers for high-grade glioma patients. METHODS: Eleven proteins were selected for analysis due to their suggested importance for survival of patients with other types of cancers and due to a high variation in protein levels between glioma patients (according to the Human Protein Atlas, www.proteinatlas.org). Protein expression patterns of these 11 proteins were analyzed by immunohistochemistry in tumor samples from 97 high-grade glioma patients. The prognostic values of the proteins were analyzed with univariate and multivariate Cox regression analyses for the high-grade glioma patients, including subgroup analyses of histological subtypes and immunohistochemically defined molecular subtypes. RESULTS: The proteins with the most significant (univariate and multivariate p<0.05) correlations were analyzed further with cross-validated Kaplan-Meier analyses for the possibility of predicting survival based on the protein expression pattern of the corresponding candidate. Random Forest classification with variable subset selection was used to analyze if a protein signature consisting of any combination of the 11 proteins could predict survival for the high-grade glioma patients and the subgroup with glioblastoma patients. The proteins which correlated most significantly (univariate and multivariate p<0.05) to survival in the Cox regression analyses were Myc for all high-grade gliomas and FGF2, CA9 and CD44 for the subgroup of proneural gliomas, with FGF2 having a strong negative predictive value for survival. No prognostic signature of the proteins could be found. CONCLUSION: FGF2 is a potential prognostic biomarker for proneural glioma patients, and warrants further investigation.
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