title: VEGF-dependent induction of CD62E on endothelial cells mediates glioma tropism of adult haematopoietic progenitor cells.
abstract: Haematopoietic progenitor cells (HPC) are attracted by experimental gliomas in vivo. This attraction is further enhanced by irradiation or hypoxic preconditioning of the glioma cells. Adhesive interactions might be critical to the preferential accumulation of HPC within the glioma tissue. Here, we studied the interactions of HPC with endothelial cells. Exposure of human cerebral endothelial cells (SV-HCEC), human microvascular endothelial cells (HMEC) and brain tumour endothelial cells derived from human glioblastomas (BTEC) to supernatants of glioma cells and primary glioma cells (SN-G) induced the expression of E-selectin (CD62E). CD62E expression was further enhanced when the glioma cells had been exposed to irradiation or hypoxia prior to the collection of supernatants, as well as by irradiation or exposure to hypoxia of the endothelial cells. Vascular cell adhesion molecule 1 (VCAM-1) was constitutively expressed on SV-HCEC, HMEC and BTEC, but was not modulated by SN-G, irradiation or hypoxia. Transendothelial HPC migration was enhanced after CD62E induction in vitro. Neutralizing antibodies to CD62E strongly reduced the homing of lin(-)Sca-1(+)c-kit(+) cells to orthotopic SMA-560 gliomas in vivo. Tissue microarray sampling normal brain tissue and astrocytomas of WHO grades II-IV revealed a selective expression of CD62E on endothelial cells of tumour vessels. SN-G-induced CD62E expression on endothelial cells in vitro required transforming growth factor (TGF)-beta signalling in glioma cells and vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGF-R2) signalling in endothelial cells. Further, we observed a nuclear factor kappa B-dependent activation of the CD62E promoter peaking at 12 h after VEGF-R2 activation by glioma-derived VEGF. Taken together, we identify glioma cell-induced CD62E expression on endothelial cells as one mediator of the glioma tropism of HPC.
authors.affiliation: Department of General Neurology, Laboratory of Molecular Neurooncology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. ghazaleh.tabatabai@uni-tuebingen.de
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Tabatabai
authors.forename: Caroline
authors.initials: C
authors.lastname: Herrmann
authors.forename: Gabriele
authors.initials: G
authors.lastname: von Kürthy
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Stefan
authors.initials: S
authors.lastname: Grau
authors.forename: Brigitte
authors.initials: B
authors.lastname: Frank
authors.forename: Robert
authors.initials: R
authors.lastname: Möhle
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001323:Autoantibodies / Q000494:pharmacology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002464:Cell Migration Inhibition; D002465:Cell Movement; D018920:Coculture Techniques; D019040:E-Selectin / Q000276:immunology / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D015870:Gene Expression; D005910:Glioma / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D019040:E-Selectin; D016328:NF-kappa B; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2