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Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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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.

Place, publisher, year, edition, pages
2015. Vol. 8, no 406
National Category
Basic Medicine
Identifiers
URN: urn:nbn:se:uu:diva-269009DOI: 10.1126/scisignal.aaa1690ISI: 000366412800003PubMedID: 26645582OAI: oai:DiVA.org:uu-269009DiVA: diva2:881946
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

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Zhang, LeiKundu, SoumiJin, ChuanEl Hassan, Tamador Elsir AbuOhlin, K ElisabetYu, DiOlsson, Anna-KarinPontén, FredrikMagnusson, Peetra UForsberg, Karin NilssonEssand, MagnusSmits, AnjaDimberg, Anna

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Zhang, LeiKundu, SoumiJin, ChuanEl Hassan, Tamador Elsir AbuOhlin, K ElisabetYu, DiOlsson, Anna-KarinPontén, FredrikMagnusson, Peetra UForsberg, Karin NilssonEssand, MagnusSmits, AnjaDimberg, Anna
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Vascular BiologyScience for Life Laboratory, SciLifeLabNeuro-OncologyDepartment of Immunology, Genetics and PathologyClinical ImmunologyNeurologyDepartment of Medical Biochemistry and MicrobiologyMolecular and Morphological Pathology
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