title: Flt-1 signaling in macrophages promotes glioma growth in vivo.
abstract: Several lines of evidence indicate that Flt-1, a fms-like tyrosine kinase receptor, which binds to vascular endothelial growth factor (VEGF)-A, VEGF-B, and PlGF, is a positive regulator of angiogenesis in the context of tumor growth and metastasis. However, the molecular basis of its action is still not clear. Besides endothelial cells, Flt-1 is also expressed by other different cell types, including myeloid hematopoeitic cells (monocytes and macrophages). To examine the functions of Flt-1 expressed by bone marrow-derived myeloid cells in supporting tumor growth and angiogenesis, Flt-1 tyrosine kinase-deficient (Flt-1 TK-/-) bone marrow cells were transplanted into lethally irradiated syngeneic recipients. After hematopoietic reconstitution, we orthotopically implanted syngeneic wild-type glioma cells or glioma cells overexpressing either VEGF(164) or PlGF-2. Loss of Flt-1 signaling in bone marrow-derived myeloid cells led to a significant decrease in tumor volume and vascularization in gliomas. VEGF but not PlGF overexpressed by glioma cells restored the tumor growth rate in Flt-1 TK-/- bone marrow chimera. VEGF and PlGF overexpression by tumor cells induced an accumulation of bone marrow-derived myeloid cells into tumor tissue. This infiltration was decreased in tumors grown in Flt-1 TK-/- bone marrow chimeras. When investigating chemokines and growth factors involved in myeloid cell recruitment, we determined elevated SDF-1/CXCL12 levels in VEGF- and PlGF-overexpressing tumors. Collectively, these results suggest that Flt-1 signaling in myeloid cells is essential to amplify the angiogenic response and to promote glioma growth.
authors.affiliation: Tumor Angiogenesis Research Group, Department of Neurosurgery, University of Freiburg, Freiburg, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Kerber
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Reiss
authors.forename: Anke
authors.initials: A
authors.lastname: Wickersheim
authors.forename: Manfred
authors.initials: M
authors.lastname: Jugold
authors.forename: Fabian
authors.initials: F
authors.lastname: Kiessling
authors.forename: Matthias
authors.initials: M
authors.lastname: Heil
authors.forename: Vadim
authors.initials: V
authors.lastname: Tchaikovski
authors.forename: Johannes
authors.initials: J
authors.lastname: Waltenberger
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.forename: Karl H
authors.initials: KH
authors.lastname: Plate
authors.forename: Marcia Regina
authors.initials: MR
authors.lastname: Machein
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000473:pathology; D002199:Capillary Permeability / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D054377:Chemokine CXCL12 / Q000096:biosynthesis; D002678:Chimera / Q000378:metabolism; D005910:Glioma / Q000098:blood supply / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000201:enzymology* / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D008565:Membrane Proteins; C490827:Pigf protein, mouse; D011506:Proteins; D042461:Vascular Endothelial Growth Factor A; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1