title: Minor contribution of bone marrow-derived endothelial progenitors to the vascularization of murine gliomas.
abstract: Until recently, it was generally accepted that the vascularization of solid tumors occurred exclusively through the sprouting and co-option from pre-existing blood vessels. Growing evidence now suggests that bone marrow-derived endothelial progenitor cells (EP) circulate in the blood and may play an important role in the formation of new blood vessels in certain tumors. Whether endothelial progenitors participate in the vascularization of brain tumors has not yet been evaluated. In this study, we examined the contribution of EP to tumor angiogenesis in a murine glioma tumor model. Donor bone marrow cells obtained from transgenic mice constitutively expressing beta-galactosidase or GFP either ubiquitously or transcriptionally regulated by an endothelial specific promotor Tie-2 were injected into lethally irradiated adult mice. After bone marrow reconstitution by donor cells, mice were implanted with syngeneic GL261 murine glioma cells. Morphological and confocal 3-dimensional analysis showed that the majority of the engrafted donor marrow cells were expressing hematopoietic and/or microglia markers, but did not appreciably contribute to the tumor vasculature. Implantation of glioma cells genetically engineered to overexpress VEGF produced highly vascularized tumors. However, the number of endothelial progenitors incorporated in the tumor vasculature did not increase. These data strongly suggest that neovascularization in the brain might fundamentally be regulated by the sprouting of pre-existing vessels and implicate that circulating endothelial progenitors do not play a significant role in this process.
authors.affiliation: Department of Neurosurgery, Freiburg University Medical School, Germany. Machein@NZ.ukl.uni-freiburg.de
authors.forename: Márcia Regina
authors.initials: MR
authors.lastname: Machein
authors.forename: Sabine
authors.initials: S
authors.lastname: Renninger
authors.forename: Elisete
authors.initials: E
authors.lastname: de Lima-Hahn
authors.forename: Karl H
authors.initials: KH
authors.lastname: Plate
mesh_terms: D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D015152:Blotting, Northern; D001853:Bone Marrow / Q000502:physiology; D039481:CD11b Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D000071063:Endoglin; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005910:Glioma / Q000378:metabolism / Q000503:physiopathology* / Q000662:veterinary; D006026:Glycoside Hydrolases / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D007150:Immunohistochemistry; D007239:Infections; D007763:Lac Operon; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D018613:Microscopy, Confocal; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D039481:CD11b Antigen; C064206:ENG protein, human; D000071063:Endoglin; D005904:Glial Fibrillary Acidic Protein; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C036763:monocyte-macrophage differentiation antigen; C467480:vascular endothelial growth factor A, mouse; D014841:von Willebrand Factor; D017493:Leukocyte Common Antigens; D006026:Glycoside Hydrolases; C023112:exo-beta-D-galactofuranosidase