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Zhang, Lei
Publications (10 of 10) Show all publications
Zhang, L., He, L., Lugano, R., Roodakker, K. R., Bergqvist, M., Smits, A. & Dimberg, A. (2018). IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas. Neuro-Oncology, 20(11), 1505-1516
Open this publication in new window or tab >>IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas
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2018 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 11, p. 1505-1516Article in journal (Refereed) Published
Abstract [en]

Background: Vascular gene expression patterns in lower-grade gliomas (LGGs; diffuse World Health Organization [WHO] grades II–III gliomas) have not been thoroughly investigated. The aim of this study was to molecularly characterize LGG vessels and determine if tumor isocitrate dehydrogenase (IDH) mutation status affects vascular phenotype.

Methods: Gene expression was analyzed using an in-house dataset derived from microdissected vessels and total tumor samples from human glioma in combination with expression data from 289 LGG samples available in the database of The Cancer Genome Atlas. Vascular protein expression was examined by immunohistochemistry in human brain tumor tissue microarrays (TMAs) representing WHO grades II–IV gliomas and nonmalignant brain samples. Regulation of gene expression was examined in primary endothelial cells in vitro.

Results: Gene expression analysis of WHO grade II glioma indicated an intermediate stage of vascular abnormality, less severe than that of glioblastoma vessels but distinct from normal vessels. Enhanced expression of laminin subunit alpha 4 (LAMA4) and angiopoietin 2 (ANGPT2) in WHO grade II glioma was confirmed by staining of human TMAs. IDH wild-type LGGs displayed a specific angiogenic gene expression signature, including upregulation of ANGPT2 and serpin family H (SERPINH1), connected to enhanced endothelial cell migration and matrix remodeling. Transcription factor analysis indicated increased transforming growth factor beta (TGFβ) and hypoxia signaling in IDH wild-type LGGs. A subset of genes specifically induced in IDH wild-type LGG vessels was upregulated by stimulation of endothelial cells with TGFβ2, vascular endothelial growth factor, or cobalt chloride in vitro.

Conclusion: IDH wild-type LGG vessels are molecularly distinct from the vasculature of IDH-mutated LGGs. TGFβ and hypoxia-related signaling pathways may be potential targets for anti-angiogenic therapy of IDH wild-type LGG.

Keywords
angiogenesis, ANGPT2, glioma, IDH, tumor vessel
National Category
Basic Medicine Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-352016 (URN)10.1093/neuonc/noy088 (DOI)000448665500010 ()29846705 (PubMedID)
Funder
Swedish Cancer Society, CAN 2015/1216; CAN 2014/832; CAN 2017/502Swedish Childhood Cancer Foundation, PR2015-0133; NCP2015-0075Swedish Research Council, 2016-02495
Available from: 2018-05-31 Created: 2018-05-31 Last updated: 2019-01-08Bibliographically approved
Ramachandran, M., Yu, D., Dyczynski, M., Baskaran, S., Zhang, L., Lulla, A., . . . Essand, M. (2017). Safe and effective treatment of experimental neuroblastoma and glioblastoma using systemically administered triple microRNA-detargeted oncolytic Semliki Forest virus. Clinical Cancer Research, 23(6), 1519-1530
Open this publication in new window or tab >>Safe and effective treatment of experimental neuroblastoma and glioblastoma using systemically administered triple microRNA-detargeted oncolytic Semliki Forest virus
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2017 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, no 6, p. 1519-1530Article in journal (Refereed) Published
Abstract [en]

PURPOSE:

Glioblastoma multiforme (GBM) and high-risk neuroblastoma are cancers with poor outcome. Immunotherapy in the form of neurotropic oncolytic viruses is a promising therapeutic strategy for these malignancies. Here we evaluate the oncolytic potential of the neurovirulent and partly interferon (IFN)-β-resistant Semliki Forest virus (SFV)-4 in GBMs and neuroblastomas. To reduce neurovirulence we constructed SFV4miRT, which is attenuated in normal CNS cells through insertion of microRNA target sequences for miR124, miR125, miR134 Experimental Design:Oncolytic activity of SFV4miRT was examined in mouse neuroblastoma and GBM cell lines and in patient-derived human glioblastoma cell cultures (HGCC). In vivo neurovirulence and therapeutic efficacy was evaluated in two syngeneic orthotopic glioma models (CT-2A, GL261) and syngeneic subcutaneous neuroblastoma model (NXS2). The role of IFN-β in inhibiting therapeutic efficacy was investigated.

RESULTS:

The introduction of microRNA target sequences reduced neurovirulence of SFV4 in terms of attenuated replication in mouse CNS cells and ability to cause encephalitis when administered intravenously. A single intravenous injection of SFV4miRT prolonged survival and cured 4 of 8 mice (50%) with NXS2 and 3 of 11 mice (27%) with CT-2A, but not for GL261 tumor bearing mice. In vivo therapeutic efficacy in different tumor models inversely correlated to secretion of IFN-β by respective cells upon SFV4 infection in vitro Similarly, killing efficacy of HGCC lines inversely correlated to IFN-β response and interferon-α⁄β receptor (IFNAR)-1 expression.

CONCLUSIONS:

SFV4miRT has reduced neurovirulence, while retaining its oncolytic potential. SFV4miRT is an excellent candidate for treatment of GBMs and neuroblastomas with low IFN-β secretion.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2017
Keywords
Semliki Forest virus, Glioblastoma, Neuroblastoma, Oncolytic virus immunotherapy, Type-I antiviral response
National Category
Other Basic Medicine
Research subject
Oncology; Biology with specialization in Molecular Biotechnology
Identifiers
urn:nbn:se:uu:diva-303633 (URN)10.1158/1078-0432.CCR-16-0925 (DOI)000397344800018 ()27637889 (PubMedID)
Funder
Swedish Research Council, K2013-22191-01-3Swedish Cancer Society, CAN2013/373Swedish Childhood Cancer Foundation, PROJ12/082
Available from: 2016-09-21 Created: 2016-09-21 Last updated: 2018-01-10Bibliographically approved
Zhang, L., Laaniste, L., Jiang, Y., Alafuzoff, I., Uhrbom, L. & Dimberg, A. (2016). Pleiotrophin enhances PDGFB-induced gliomagenesis through increased proliferation of neural progenitor cells. OncoTarget, 7(49), 80382-80390
Open this publication in new window or tab >>Pleiotrophin enhances PDGFB-induced gliomagenesis through increased proliferation of neural progenitor cells
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 49, p. 80382-80390Article in journal (Refereed) Published
Abstract [en]

Pleiotrophin (PTN) augments tumor growth by increasing proliferation of tumor cells and promoting vascular abnormalization, but its role in early gliomagenesis has not been evaluated. Through analysis of publically available datasets, we demonstrate that increased PTN mRNA expression is associated with amplification of chromosome 7, identified as one of the earliest steps in glioblastoma development. To elucidate the role of PTN in tumor initiation we employed the RCAS/tv-a model that allows glioma induction by RCAS-virus mediated expression of oncogenes in neural progenitor cells. Intracranial injection of RCAS-PTN did not induce glioma formation when administrated alone, but significantly enhanced RCAS-platelet derived growth factor (PDGF) B-induced gliomagenesis. PTN co-treatment augmented PDGFBinduced Akt activation in neural progenitor cells in vitro, and enhanced neural sphere size associated with increased proliferation. Our data indicates that PTN expression is associated with chromosome 7 gain, and that PTN enhances PDGFB-induced gliomagenesis by stimulating proliferation of neural progenitor cells.

Keywords
glioma, pleiotrophin, gliomagenesis, tumor initiation, chromosome 7
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-313533 (URN)10.18632/oncotarget.12983 (DOI)000389877500027 ()
Funder
Swedish Cancer Society, CAN 2011/862 CAN 2014/832 CAN 2015/1216Swedish Childhood Cancer Foundation, PR2013-0107 PR2015-0133 NCp2015-0075Swedish Research Council, 2013-3797
Available from: 2017-02-02 Created: 2017-01-20 Last updated: 2017-11-29Bibliographically approved
Langenkamp, E., Zhang, L., Lugano, R., Huang, H., Elhassan, T. E., Georganaki, M., . . . Dimberg, A. (2015). Elevated Expression of the C-Type Lectin CD93 in the Glioblastoma Vasculature Regulates Cytoskeletal Rearrangements That Enhance Vessel Function and Reduce Host Survival. Cancer Research, 75(21), 4504-4516
Open this publication in new window or tab >>Elevated Expression of the C-Type Lectin CD93 in the Glioblastoma Vasculature Regulates Cytoskeletal Rearrangements That Enhance Vessel Function and Reduce Host Survival
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2015 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 21, p. 4504-4516Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-269008 (URN)10.1158/0008-5472.CAN-14-3636 (DOI)000365602200009 ()26363010 (PubMedID)
Funder
Swedish Cancer Society, CAN 2011/862Swedish Childhood Cancer Foundation, PR2013-0107, PROJ11/083Swedish Research Council, 2013-3797, 2008-2853
Available from: 2015-12-11 Created: 2015-12-11 Last updated: 2017-12-01Bibliographically approved
Zhang, L. (2015). Molecular Regulation of Vascular Abnormalization and Its Role in Glioma. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
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. p. 61
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1103
Keywords
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)
Opponent
Supervisors
Available from: 2015-05-08 Created: 2015-04-07 Last updated: 2015-07-07
Cedervall, J., Zhang, Y., Huang, H., Zhang, L., Femel, J., Dimberg, A. & Olsson, A.-K. (2015). Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals. Cancer Research, 75(13), 2653-2662
Open this publication in new window or tab >>Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals
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2015 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 13, p. 2653-2662Article in journal (Refereed) Published
Abstract [en]

Cancer produces a variety of collateral effects in patients beyond the malignancy itself, including threats to distal organ functions. However, the basis for such effects, associated with either primary or metastatic tumors, are generally poorly understood. In this study, we show how heart and kidney vascular function is impaired by neutrophils that accumulate in those tissues as a result of tumor formation in two different transgenic mouse models of cancer (RIP1-Tag2 model of insulinoma and MMTV-PyMT model of breast cancer). Neutrophil depletion by systemic administration of an anti-Gr1 antibody improved vascular perfusion and prevented vascular leakage in kidney vessels. We also observed the accumulation of platelet-neutrophil complexes, a signature of neutrophil extracellular traps (NET), in the kidneys of tumor-bearing mice that were completely absent from healthy nontumor-bearing littermates. NET accumulation in the vasculature was associated with upregulation of the proinflammatory adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the proinflammatory cytokines IL1 beta, IL6, and the chemokine CXCL1. Administering DNase I to dissolve NETs, which have a high DNA content, restored perfusion in the kidney and heart to levels seen in nontumor-bearing mice, and also prevented vessel leakage in the blood vasculature of these organs. Taken together, our findings strongly suggest that NETs mediate the negative collateral effects of tumors on distal organs, acting to impair vascular function, and to heighten inflammation at these sites.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-259098 (URN)10.1158/0008-5472.CAN-14-3299 (DOI)000357334700008 ()26071254 (PubMedID)
Funder
Swedish Cancer Society, 11 0653Swedish Research Council, 2010-6903-75363-44, 2012-77PK-22157-01-2
Available from: 2015-07-28 Created: 2015-07-27 Last updated: 2017-12-04Bibliographically approved
Zhang, L., Kundu, S., Feenstra, T., Li, X., Jin, C., Laaniste, L., . . . Dimberg, A. (2015). Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas.. Science Signaling, 8(406)
Open this publication in new window or tab >>Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas.
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2015 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 8, no 406Article in journal (Refereed) Published
Abstract [en]

Glioblastomas are aggressive astrocytomas characterized by endothelial cell proliferation and abnormal vasculature, which can cause brain edema and increase patient morbidity. We identified the heparin-binding cytokine pleiotrophin as a driver of vascular abnormalization in glioma. Pleiotrophin abundance was greater in high-grade human astrocytomas and correlated with poor survival. Anaplastic lymphoma kinase (ALK), which is a receptor that is activated by pleiotrophin, was present in mural cells associated with abnormal vessels. Orthotopically implanted gliomas formed from GL261 cells that were engineered to produce pleiotrophin showed increased microvessel density and enhanced tumor growth compared with gliomas formed from control GL261 cells. The survival of mice with pleiotrophin-producing gliomas was shorter than that of mice with gliomas that did not produce pleiotrophin. Vessels in pleiotrophin-producing gliomas were poorly perfused and abnormal, a phenotype that was associated with increased deposition of vascular endothelial growth factor (VEGF) in direct proximity to the vasculature. The growth of pleiotrophin-producing GL261 gliomas was inhibited by treatment with the ALK inhibitor crizotinib, the ALK inhibitor ceritinib, or the VEGF receptor inhibitor cediranib, whereas control GL261 tumors did not respond to either inhibitor. Our findings link pleiotrophin abundance in gliomas with survival in humans and mice, and show that pleiotrophin promotes glioma progression through increased VEGF deposition and vascular abnormalization.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-269009 (URN)10.1126/scisignal.aaa1690 (DOI)000366412800003 ()26645582 (PubMedID)
Funder
Swedish Cancer Society, CAN 2011/862Swedish Childhood Cancer Foundation, PR2013-0107 PROJ11/083Swedish Research Council, 2013-3797 2008-2853
Available from: 2015-12-11 Created: 2015-12-11 Last updated: 2018-05-18Bibliographically approved
Femel, J., Huijbers, E. J. M., Saupe, F., Cedervall, J., Zhang, L., Dimberg, A. & Hellman, L. (2014). Progression of metastatic breast cancer can be attenuated by therapeutic vaccination against the tumor vascular marker ED-A. Angiogenesis, 17(3), 769-769
Open this publication in new window or tab >>Progression of metastatic breast cancer can be attenuated by therapeutic vaccination against the tumor vascular marker ED-A
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2014 (English)In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 17, no 3, p. 769-769Article in journal, Meeting abstract (Other academic) Published
National Category
Microbiology in the medical area Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-229603 (URN)000338213400175 ()
Available from: 2014-08-12 Created: 2014-08-12 Last updated: 2018-01-11Bibliographically approved
Femel, J., Huijbers, E. J., Saupe, F., Cedervall, J., Zhang, L., Roswall, P., . . . Olsson, A.-K. (2014). Therapeutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer.. OncoTarget, 5(23), 12418-12427
Open this publication in new window or tab >>Therapeutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer.
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2014 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, no 23, p. 12418-12427Article in journal (Refereed) Published
Abstract [en]

Therapeutic vaccination targeting self-molecules is an attractive alternative to monoclonal antibody-based therapies for cancer and various inflammatory diseases. However, development of cancer vaccines targeting self-molecules has proven difficult. One complicating factor is that tumor cells have developed strategies to escape recognition by the immune system. Antigens specifically expressed by the tumor vasculature can therefore provide alternative targets. The alternatively spliced extra domain-A and B (ED-A and ED-B) of fibronectin are expressed during vasculogenesis in the embryo, but essentially undetectable under normal conditions in the adult. However, these domains are re-expressed during tumor angiogenesis and matrix remodeling, which renders them highly interesting for targeted cancer therapies. Using the MMTV-PyMT transgenic model of metastatic mammary carcinoma, we show that tumor burden can be significantly decreased by immunization against ED-A in a therapeutic setting. Furthermore, we found that in mice carrying anti-ED-A antibodies the number of metastases was reduced. ED-A immunization increased infiltration of macrophages and compromised tumor blood vessel function. These findings implicate an attack of the tumor vasculature by the immune system, through a polyclonal antibody response. We conclude that tumor vascular antigens are promising candidates for development of therapeutic vaccines targeting growth of primary tumors as well as disseminated disease.

Keywords
ED-A, immunization, tumor vasculature, therapeutic, cancer vaccine
National Category
Cancer and Oncology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-229544 (URN)000348037700049 ()25360764 (PubMedID)
Available from: 2014-08-11 Created: 2014-08-11 Last updated: 2018-02-28Bibliographically approved
Dieterich, L. C., Mellberg, S., Langenkamp, E., Zhang, L., Zieba, A., Salomäki, H., . . . Dimberg, A. (2012). Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGFβ2 in vascular abnormalization. Journal of Pathology, 228(3), 378-390
Open this publication in new window or tab >>Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGFβ2 in vascular abnormalization
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2012 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 228, no 3, p. 378-390Article 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.

Keywords
angiogenesis, brain tumour, growth factor, laser microdissection, microarray, tumour endothelial marker, vasculature
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-184941 (URN)10.1002/path.4072 (DOI)000309916000012 ()
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2012-11-19 Created: 2012-11-15 Last updated: 2017-12-07Bibliographically approved
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