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Troponin I Overexpression Inhibits Tumor Growth, Perfusion, and Vascularization of Morris Hepatoma

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 Biophysics and Medical Radiation Physics, DKFZ, INF 280, Heidelberg, Germany; ⁵ Department of Immunology, University of Rostock, Rostock, Germany; and ⁶ Department of Radiopharmaceutical Chemistry, DKFZ, INF 280, 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

Antiangiogenic gene transfer inhibiting growth of new blood vessels is a promising approach in cancer therapy. Human troponin I (TnI) efficiently inhibits endothelial cell proliferation, migration, as well as angiogenesis and tumor growth in vivo. However, little is known about its effects on perfusion and tumor biology. Methods: Stable Morris hepatoma (MH3924A) cells overexpressing human TnI (TnI-MH3924A) were cocultured with human umbilical vein endothelial cells (HUVECs) followed by measurements of endothelial apoptosis and proliferation. Furthermore, tumor growth and perfusion were determined using H₂¹⁵O and ⁶⁸Ga-DOTA-albumin (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) PET as well as functional MRI. Additionally, histologic measurements of vascularization, apoptosis, proliferation, and gene array analyses were performed. Results: Apoptosis of HUVECs was increased and proliferation was decreased after coculture with TnI-MH3924A cells. TnI-MH3924A tumors showed a significant inhibition of growth (90%) and a decreased perfusion (25%), whereas blood volume remained unchanged. MRI investigations demonstrated a significant decrease of the rate constant k_ep. Immunohistochemical analyses showed decreased microvessel density and proliferation and significant induction of apoptosis. Furthermore, TnI-expressing hepatomas demonstrated changes in the expression of genes related to angiogenesis, apoptosis, signal transduction, or stress. Conclusion: TnI regulates tumor growth by modulating vascularization including apoptosis induction and decrease of proliferation. In addition, changes in expression of genes associated with angiogenesis, apoptosis, signal transduction, or stress were found. The upregulation of angiogenesis and stress-related genes indicates a cross-talk of different mechanisms as part of the tumor's reaction to TnI. Because the decrease of vascularization led to lower perfusion values as measured by PET and MRI, these noninvasive methods are promising tools for the monitoring of antiangiogenic gene therapy.

Key Words: angiogenesis • troponin I • gene therapy • PET • perfusion

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