Microtumor growth initiates angiogenic sprouting with simultaneous expression of VEGF, VEGF receptor-2, and angiopoietin-2.
Tumors have been thought to initiate as avascular aggregates of malignant cells that only later induce vascularization. Recently, this classic concept of tumor angiogenesis has been challenged by the suggestion that tumor cells grow by co-opting preexisting host vessels and thus initiate as well-vascularized tumors without triggering angiogenesis. To discriminate between these two mechanisms, we have used intravital epifluorescence microscopy and multi-photon laser scanning confocal microscopy to visualize C6 microglioma vascularization and tumor cell behavior. To address the mechanisms underlying tumor initiation, we assessed the expression of VEGF, VEGF receptor-2 (VEGFR-2), and angiopoietin-2 (Ang-2), as well as endothelial cell proliferation. We show that multicellular aggregates (<< 1 mm(3)) initiate vascular growth by angiogenic sprouting via the simultaneous expression of VEGFR-2 and Ang-2 by host and tumor endothelium. Host blood vessels are not co-opted by tumor cells but rather are used as trails for tumor cell invasion of the host tissue. Our data further suggest that the established microvasculature of growing tumors is characterized by a continuous vascular remodeling, putatively mediated by the expression of VEGF and Ang-2. The results of this study suggest a new concept of vascular tumor initiation that may have important implications for the clinical application of antiangiogenic strategies.
Vajkoczy
Peter
P
Department of Neurosurgery, Klinikum Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 103, D-68167 Mannheim, Germany. peter.vajkoczy@nch.ma.uni-heidelberg.de
Farhadi
Mohammad
M
Gaumann
Andreas
A
Heidenreich
Regina
R
Erber
Ralf
R
Wunder
Andreas
A
Tonn
Jörg C
JC
Menger
Michael D
MD
Breier
Georg
G
D042702:Angiopoietin-2; D000818:Animals; D002455:Cell Division; D017690:Cell Transplantation; D002540:Cerebral Cortex; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal / Q000379:methods; D018482:Muscle, Skeletal; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000503:physiopathology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D042702:Angiopoietin-2; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011506:Proteins; 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