title: Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas.
abstract: 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.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, The Rudbeck Laboratory, 75185 Uppsala, Sweden.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, The Rudbeck Laboratory, 75185 Uppsala, Sweden.
authors.forename: Soumi
authors.initials: S
authors.lastname: Kundu
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, The Rudbeck Laboratory, 75185 Uppsala, Sweden.
authors.forename: Tjerk
authors.initials: T
authors.lastname: Feenstra
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, The Rudbeck Laboratory, 75185 Uppsala, Sweden.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, The Rudbeck Laboratory, 75185 Uppsala, Sweden.
authors.forename: Chuan
authors.initials: C
authors.lastname: Jin
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, The Rudbeck Laboratory, 75185 Uppsala, Sweden.
authors.forename: Liisi
authors.initials: L
authors.lastname: Laaniste
authors.affiliation: Department of Neuroscience, Neurology, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Tamador Elsir Abu
authors.initials: TE
authors.lastname: El Hassan
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, The Rudbeck Laboratory, 75185 Uppsala, Sweden.
authors.forename: K Elisabet
authors.initials: KE
authors.lastname: Ohlin
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, The Rudbeck Laboratory, 75185 Uppsala, Sweden.
authors.forename: Di
authors.initials: D
authors.lastname: Yu
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, The Rudbeck Laboratory, 75185 Uppsala, Sweden.
authors.forename: Tommie
authors.initials: T
authors.lastname: Olofsson
authors.affiliation: Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Box 582, SE-75123 Uppsala, Sweden.
authors.forename: Anna-Karin
authors.initials: AK
authors.lastname: Olsson
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, The Rudbeck Laboratory, 75185 Uppsala, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pontén
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, The Rudbeck Laboratory, 75185 Uppsala, Sweden.
authors.forename: Peetra U
authors.initials: PU
authors.lastname: Magnusson
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, The Rudbeck Laboratory, 75185 Uppsala, Sweden.
authors.forename: Karin Forsberg
authors.initials: KF
authors.lastname: Nilsson
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, The Rudbeck Laboratory, 75185 Uppsala, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Essand
authors.affiliation: Department of Neuroscience, Neurology, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Anja
authors.initials: A
authors.lastname: Smits
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, The Rudbeck Laboratory, 75185 Uppsala, Sweden.
authors.forename: Lothar C
authors.initials: LC
authors.lastname: Dieterich
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, The Rudbeck Laboratory, 75185 Uppsala, Sweden. anna.dimberg@igp.uu.se.
authors.forename: Anna
authors.initials: A
authors.lastname: Dimberg
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D009363:Neoplasm Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C066845:pleiotrophin; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases