J Clin Invest, March 2002, Volume 109, Number 6, 777-785
Copyright ©2002 by the American Society for Clinical Investigation
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Article
Microtumor growth initiates angiogenic sprouting with simultaneous expression of VEGF, VEGF receptor-2, and angiopoietin-2
Peter Vajkoczy1, Mohammad Farhadi1, Andreas Gaumann2, Regina Heidenreich2, Ralf Erber1, Andreas Wunder3, Jörg C. Tonn4, Michael D. Menger5 and Georg Breier2
1 Department of Neurosurgery, Klinikum Mannheim, University of Heidelberg, Mannheim, Germany 2 Department of Molecular Biology, Max-Planck-Institut für Physiologische und Klinische Forschung, Bad Nauheim, Germany 3 Department of Radiochemistry and Radiopharmacology, German Cancer Research Center, Heidelberg, Germany 4 Department of Neurosurgery, Klinikum Grosshadern, Munich, Germany 5 Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany
Address correspondence to: P. Vajkoczy, Department of Neurosurgery, Klinikum Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany. Phone: 49-621-383-2360; Fax: 49-621-383-2004; E-mail: peter.vajkoczy@nch.ma.uni-heidelberg.de.
Received for publication August 30, 2001, and accepted in revised form February 5, 2002.
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 mm3) 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. |
