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Angiopoietin-2 Overexpression in Morris Hepatoma Results in Increased Tumor Perfusion and Induction of Critical Angiogenesis-Promoting Genes

¹ Department of Anatomy and Cell Biology III, University of Heidelberg, Heidelberg, Germany; ² Clinical Cooperation Unit Nuclear Medicine, DKFZ, Heidelberg, Germany; ³ Department of Nuclear Medicine, University of Heidelberg, Heidelberg, Germany; ⁴ Department of Immunology, University of Rostock, Rostock, Germany; ⁵ Department of Radiopharmaceutical Chemistry, DKFZ, Heidelberg, Germany; and ⁶ Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany

Correspondence: For correspondence or reprints contact: Uwe Haberkorn, MD, Department of Nuclear Medicine, University of Heidelberg, INF 400, Heidelberg, 69120, Germany. E-mail: Uwe_Haberkorn{at}med.uni-heidelberg.de

Monitoring of angiogenesis-relevant approaches with functional imaging and histomorphometric analyses is desirable to evaluate the biologic effects. In this study we wished to examine the complex effects of angiopoietin-2 (Ang-2) gene transfer in a rat hepatoma model. Methods: Using a bicistronic retroviral vector for Ang-2, Morris hepatoma (MH3924A) cell lines with Ang-2 expression were generated (Ang-2-MH3924A). In human umbilical vein endothelial cells (HUVECs) cocultured with Ang-2-MH3924A, the proliferative action with or without growth factors were determined. Furthermore, animal experiments were performed to measure effects on tumor growth and perfusion. Finally, tumors were examined by immunohistochemistry and DNA chip analysis. Results: Ang-2–expressing MH3924A enhanced basic fibroblast growth factor–mediated endothelial cell proliferation. Perfusion, as measured by H₂¹⁵O PET, was increased in genetically modified tumors. Consistent with the increased perfusion, micro- and macrovascularization were increased. However, tumor growth was similar to wild-type MH3924A (WT-MH3924A). Proliferating cell nuclear antigen and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) staining revealed an increased number of positive cells, indicating a compensation of increased proliferation by enhanced apoptosis. DNA chip analysis showed an induction of angiogenesis-promoting genes, including crucial vascular growth factor receptors, as well as genes related to extracellular matrix (ECM), apoptosis, signal transduction, and oxidative stress. Conclusion: Our results suggest that Ang-2 expression increases perfusion or vascularization, especially in interaction with the vascular growth factor system, without affecting tumor growth. Simultaneous, enhanced expression of genes for ECM, apoptosis, and signal transduction indicates Ang-2's versatile role in angiogenesis including its destabilizing function on ECM and endothelium.

Key Words: gene therapy • immunohistochemistry • PET • angiopoietin-2

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