Formation of transformed endothelial cells in the absence of VEGFR-2/Flk-1 by Polyoma middle T oncogene.
The middle T antigen of murine Polyomavirus (PymT) rapidly transforms endothelial cells leading to vascular malformations reminiscent of endothelial tumors or hemangiomas. Flk-1, a receptor tyrosine kinase which is activated upon binding of its ligand VEGF, is predominantly expressed in endothelial cells and essential for the formation of blood vessels since absence of Flk-1 prevents the development of mature endothelial cells in mice and in ES-cell differentiation experiments. To investigate the role of Flk-1 in PymT-induced vascular tumor formation, we studied the expression of Flk-1 and VEGF in PymT-transformed endothelial cells (Endothelioma cells, END. cells). The receptor and its ligand were both expressed in END. cells suggesting that a VEGF/Flk-1 autocrine loop might be causally involved in the formation of vascular tumors. To test this hypothesis, ES cells lacking Flk-1 were generated and the transforming potential of PymT was analysed after in vitro differentiation. Flk-1(-/-) END. cell lines were established which are morphologically identical to flk-1(+/+) END. cells and which express several markers characteristic for endothelial cells. This result suggests that PymT functionally replaces the requirement of Flk-1 in expansion and/or survival of endothelial progenitor cells. Therefore, flk-1(-/-) END. cells provide a powerful tool to dissect the downstream signaling pathways of Flk-1.
Mühlner
U
U
Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, Vienna, Austria.
Möhle-Steinlein
U
U
Wizigmann-Voos
S
S
Christofori
G
G
Risau
W
W
Wagner
E F
EF
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000502:physiology*; D002472:Cell Transformation, Viral; D016228:Endothelial Growth Factors / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000473:pathology* / Q000821:virology; D018390:Gene Targeting; D006390:Hemangioendothelioma / Q000473:pathology*; D008222:Lymphokines / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000209:etiology*; D009857:Oncogenes; D011120:Polyomavirus / Q000235:genetics / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency* / Q000502:physiology; D017978:Receptors, Growth Factor / Q000172:deficiency* / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000952:Antigens, Polyomavirus Transforming; D016228:Endothelial Growth Factors; D008222:Lymphokines; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor