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Angiostatin Overexpression in Morris Hepatoma Results in Decreased Tumor Growth but Increased Perfusion and Vascularization

¹ Department of Anatomy and Cell Biology III, University of Heidelberg, INF 307, Heidelberg, Germany; ² Clinical Cooperation Unit Nuclear Medicine, DKFZ and University of Heidelberg, INF 280, Heidelberg, Germany; ³ Department of Nuclear Medicine, University of Heidelberg, INF 400, Heidelberg, Germany; ⁴ Department of Immunology, University of Rostock, Rostock, Germany; ⁵ Department of Biophysics and Medical Radiation Physics, DKFZ, INF 280, Heidelberg, Germany; ⁶ Department of Internal Medicine III, INF 410, University of Heidelberg, Germany; and ⁷ Department of Radiopharmaceutical Chemistry, German Cancer Research Centre, Heidelberg, Germany

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

Growth of malignant tumors is dependent on sufficient blood supply. Thus, inhibition of tumor angiogenesis is emerging as a promising target in the treatment of malignancies. Human angiostatin (hANG) is one of the most potent inhibitors of endothelial cell proliferation, angiogenesis, and tumor growth in vivo. However, its mechanisms operating in vivo are not well understood. Methods: To obtain more information about functional changes in the angiogenic process, we established Morris hepatoma (MH3924A) cell lines expressing hANG (hANG-MH3924A). The effects of hANG expression on proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs) were measured in coculture experiments in vitro. To evaluate changes in tumor perfusion and blood volume, H₂¹⁵O and ⁶⁸Ga-DOTA-albumin (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) were used for PET studies in vivo. Additionally, immunohistologic quantification of vascularization, apoptosis, and proliferation as well as gene array analyses were performed. Results: Our in vitro experiments demonstrate reduced proliferation and increased apoptosis in HUVECs when being cocultured with hANG-MH3924A. In support, tumor growth of hANG-MH3924A is diminished by 95% in vivo. However, tumor perfusion and blood volume are increased in hANG-MH3924A corresponding to an increased microvessel density. Furthermore, hANG-transfected tumors show changes in expression of genes related to apoptosis, stress, signal transduction, and metabolism. Conclusion: hANG expression leads to inhibition of tumor growth, increased apoptosis, and changes in the expression of multiple genes involved in stress reactions, signal transduction, and apoptosis, which indicates a multifactorial reaction of tumors. An enhanced microvessel density is seen as part of these reactions and is associated with increased perfusion as measured by PET.

Key Words: angiogenesis • gene therapy • PET • angiostatin • perfusion

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