Microtumor growth initiates angiogenic sprouting with simultaneous expression of VEGF, VEGF receptor-2, and angiopoietin-2
Peter Vajkoczy, … , Michael D. Menger, Georg Breier
Peter Vajkoczy, … , Michael D. Menger, Georg Breier
Published March 15, 2002
Citation Information: J Clin Invest. 2002;109(6):777-785. https://doi.org/10.1172/JCI14105.
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Microtumor growth initiates angiogenic sprouting with simultaneous expression of VEGF, VEGF receptor-2, and angiopoietin-2

Abstract

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.

Authors

Peter Vajkoczy, Mohammad Farhadi, Andreas Gaumann, Regina Heidenreich, Ralf Erber, Andreas Wunder, Jörg C. Tonn, Michael D. Menger, Georg Breier

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Figure 6

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Coordinated upregulation of Ang-2 and VEGFR-2 mediates tumor angiogenesi...
Coordinated upregulation of Ang-2 and VEGFR-2 mediates tumor angiogenesis after intracranial implantation. (a–c) In situ hybridization of 1-week tumors demonstrates that Ang-2 and VEGFR-2 mRNA expression was induced in parallel in tumor and host endothelium (b and c), whereas only low VEGF mRNA levels were present within the tumor (a). (d–f) Sense controls for in situ hybridization. t, tumor mass; p, peritumoral cerebral tissue. (g–i) A strong Ang-2 and VEGFR-2 mRNA expression pattern persisted in 2-week tumors (h and i). VEGF mRNA expression, which was homogeneous at 1 week, became heterogeneous by 2 weeks after implantation (g). (j–m) Serial immunohistochemistry for PECAM (l) and VEGFR-2 (j, k, m) in 1-week (j and l) and 2-week tumors (m) confirms VEGFR-2 expression by endothelial cells of tumor and adjacent host vessels. Square in j indicates area of interest detailed in k. Arrows in k indicate VEGFR-2–positive vessels with perivascular cuff of invading tumor cells. (n and o) Serial immunohistochemistry for PECAM (n) and Ki-67 (o) reveals tumor endothelial cell proliferation. Asterisks indicate identical tumor vessels in serial sections. Arrows indicate Ki-67–positive endothelial cells. Bars represent 100 μm (a–i) and 50 μm (j–o).