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Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGFβ2 in vascular abnormalization
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. (Dimberg)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. (Dimberg)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. (Dimberg)
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2012 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 228, no 3, 378-390 p.Article in journal (Refereed) Published
Abstract [en]

Glioblastoma are aggressive astrocytic brain tumours characterized by microvascular proliferation and an abnormal vasculature, giving rise to brain oedema and increased patient morbidity. Here, we have characterized the transcriptome of tumour-associated blood vessels and describe a gene signature clearly associated with pleomorphic, pathologically altered vessels in human glioblastoma (grade IV glioma). We identified 95 genes differentially expressed in glioblastoma vessels, while no significant differences in gene expression were detected between vessels in non-malignant brain and grade II glioma. Differential vascular expression of ANGPT2, CD93, ESM1, ELTD1, FILIP1L and TENC1 in human glioblastoma was validated by immunohistochemistry, using a tissue microarray. Through qPCR analysis of gene induction in primary endothelial cells, we provide evidence that increased VEGF-A and TGFβ2 signalling in the tumour microenvironment is sufficient to invoke many of the changes in gene expression noted in glioblastoma vessels. Notably, we found an enrichment of Smad target genes within the distinct gene signature of glioblastoma vessels and a significant increase of Smad signalling complexes in the vasculature of human glioblastoma in situ. This indicates a key role of TGFβ signalling in regulating vascular phenotype and suggests that, in addition to VEGF-A, TGFβ2 may represent a new target for vascular normalization therapy.

Place, publisher, year, edition, pages
2012. Vol. 228, no 3, 378-390 p.
Keyword [en]
angiogenesis, brain tumour, growth factor, laser microdissection, microarray, tumour endothelial marker, vasculature
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-184941DOI: 10.1002/path.4072ISI: 000309916000012OAI: oai:DiVA.org:uu-184941DiVA: diva2:570421
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2012-11-19 Created: 2012-11-15 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Molecular Regulation of Vascular Abnormalization and Its Role in Glioma
Open this publication in new window or tab >>Molecular Regulation of Vascular Abnormalization and Its Role in Glioma
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Glioblastoma, grade IV glioma, is the one of the deadliest cancers, with a median survival of only 12-15 months despite aggressive treatment including surgery, chemotherapy and radiation. One hallmark of glioblastoma is the morphological and functional abnormalization of tumor blood vessels. The molecular mechanisms involved in this process and their functional and pathological implications are not yet fully understood. Indentification of molecular mechanisms that underlie vascular abnormalization in GBM is necessary to develop efficient treatment regimens for normalizing vascular function.

By analyzing the RNA-content of laser microdissected vessels from human biobank specimens using affymetrix microarray analysis, we found that the abnormal glioblastoma vessels have a distinct gene expression signature. We found 95 genes which were differentially expressed in grade IV glioma vessels as compared to vessels in low grade tumors and control brain. 78 of which were up-regulated while 17 were down-regulated. Many of these genes are regulated by VEGFA or TGFβ signaling. In addition, we show a significant increase in Smad signaling complexes in the vasculature of human glioblastoma in situ, suggesting that TGFβ signaling may play important role in vessel abnormalization.

CD93 is a single-pass transmembrane glycoprotein, which we found to be up-regulated in high grade glioma. Vascular expression of CD93 correlates to tumor grade in human glioma. Moreover, high grade glioma patients with high CD93 expression in the vasculature are associate with poor prognosis. We found that knocking down CD93 in endothelial cells with siRNA clearly impaired endothelial cell adhesion, migration and tube formation due to defects in cytoskeletal rearrangement. In addition, tumor growth was severely delayed in the CD93-/- mice.

Pleiotrophin, a multi-functional heparin-binding growth factor, promotes glioma growth in several ways. Here, we identify pleiotrophin as a driver of vascular abnormalization in glioma. We found that high pleiotrophin expression correlates with poor survival of patients with astrocytomas. Pleiotrophin overexpression in orthotopic GL261 gliomas increases microvessel density, enhances tumour growth and decreases survival. Vessels in pleiotrophin-expressing gliomas are poorly perfused and display a high degree of abnormality, coinciding with elevated levels of vascular endothelial growth factor (VEGF) deposited in direct proximity to the vasculature. In addition to its role in vessel abnormalization, pleiotrophin enhanced PDGF-B-induced gliomagenesis. Taken together, our results indicate that PTN has an important role in glioma initiation and establishment of the characteristic abnormal tumor vasculature in glioblastoma, identifying PTN as a potential target for therapy.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1103
Keyword
glioma, vasculature, pleiotrophin, PTN, CD93, angiogenesis, GL261, RCAS
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-248713 (URN)978-91-554-9239-7 (ISBN)
Public defence
2015-05-30, Fåhraeussalen, Rudbecklaboratoriet, Uppsala, 09:00 (English)
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Available from: 2015-05-08 Created: 2015-04-07 Last updated: 2015-07-07

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Mellberg, SofieLangenkamp, EliseZhang, LeiZieba, AgataHuang, HuaEdqvist, Per-HenrikLarsson, ErikSöderberg, OlaGeorgii-Hemming, PatrikAlafuzoff, IrinaDimberg, Anna

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Mellberg, SofieLangenkamp, EliseZhang, LeiZieba, AgataHuang, HuaEdqvist, Per-HenrikLarsson, ErikSöderberg, OlaGeorgii-Hemming, PatrikAlafuzoff, IrinaDimberg, Anna
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Department of Immunology, Genetics and PathologyCancer and Vascular BiologyMolecular and Morphological PathologyMolecular toolsMedical Genetics
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