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Transfer of the sFLT-1 Gene in Morris Hepatoma Results in Decreased Growth and Perfusion and Induction of Genes Associated with Stress Response

Departments of ¹ Anatomy and Cell Biology III and ² Nuclear Medicine, University of Heidelberg; ³ Clinical Cooperation Unit Nuclear Medicine and Departments of ⁴ Biophysics and Medical Radiation Physics, and ⁵ Radiopharmaceutical Chemistry, German Cancer Research Center, Heidelberg, Germany; and ⁶ Department of Immunology, University of Rostock, Rostock, Germany

Requests for reprints: Uwe Haberkorn, Department of Nuclear Medicine, University of Heidelberg, Im Neuenheimer Feld 400, Heidelberg, 69120, Germany. Phone: 49-6221-567731; Fax: 49-6221-565473; E-mail: Uwe_Haberkorn{at}med.uni-heidelberg.de.

Purpose: Inhibition of tumor angiogenesis is emerging as a promising target in the treatment of malignancies. Therefore, monitoring of antiangiogenic approaches with functional imaging and histomorphometrical analyses are desirable to evaluate the biological effects caused by this treatment modality.

Experimental Design: Using a bicistronic retroviral vector for transfer of the soluble receptor for the vascular endothelial growth factor (sFLT) hepatoma (MH3924A) cell lines with sFLT expression were generated. In human umbilical vein endothelial cells cultured with conditioned medium of sFLT-expressing hepatoma cells, the inhibitory action of secreted sFLT was determined using a Coulter counter and a thymidine incorporation assay. Furthermore, in vivo experiments were done to measure the effects on tumor growth and perfusion. Finally, the tumors were examined by immunohistochemistry (including computer-assisted morphometry) and DNA chip analysis.

Results: Stable sFLT-expressing hepatoma cells inhibited endothelial cell proliferation in vitro. In vivo, growth and perfusion, as measured by H₂¹⁵O positron emission tomography, were reduced in genetically modified tumors. However, the immunohistochemically quantified microvascularization and macrovascularization, as indicated by CD31- and -actin-positive area, revealed no significant changes, whereas the number of apoptotic cells was increased in sFLT-expressing tumors, although not significantly. DNA chip analysis of tumors with gene transfer showed an increase of genes related to apoptosis, signal transduction, and oxidative stress.

Conclusion: Our results suggest that sFLT expression inhibits tumor growth and perfusion and enhances expression of apoptosis-related genes in this model. Enhanced expression of genes for signal transduction, stress, and metabolism indicates tumor defense reactions.

Key Words: angiogenesis • gene therapy • hepatoma • positron emission tomography • perfusion • gene expression

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