Neoangiogenese in einem in vitro und in vivo Tumormodell des Phäochromozytoms

Pheochromocytomas are rare, regularly strong vascularized neoplasias of the adrenal medulla, which are malignant in approximately 10%. Due to their rarity little is well-known over their tumor biology. A special problem exists in the demarcation of the malignant illness, which is characterizable so far only by the condition of metastasis already occurred. In these cases the therapy possibilities are extremely limited, so that an urgent need of new therapies exists. Angiogenesis is an essential process in the context of tumor progression and metastasis. The strongest activator of the angiogenesis is the Vascular Endothelial Growth Factor (VEGF). In recent time many examples for the use of angiogenesis- inhibitors for anti-tumor therapy are in the literature, with which among others also neutralizing anti-bodies against VEGF were applied. Against this background this work examined VEGF Expression and the extent of angiogenesis in experimental pheochromocytoma (PC12-cells) and operation specimens from clearly characterized human tumors as a function of the dignity. With the question of negotiability of new therapies it was examined in vitro (PC12-cells) whether through tumor cells induced and VEGF mediated angiogenesis can be proven and finally examined the effect of neutralizing anti-bodies against VEGF as an anti-tumor strategy in an experimental model in vivo. 1. For the first time it could be proven that PC12-cells produce and secrete the angiogenic factor VEGF quantitatively in vitro. Its biological activity has been demonstrated by the proliferation of human endothelial cells (HUVEC). This answer could be prevented by neutralizing anti-VEGF anti-bodies. 2. In experimental PC12-tumors the extent of tumor vascularization correlated with the necrosis rate and VEGF Expression, so that it could be assumed that PC12-cells initiated the development of new blood vessels in vivo through VEGF. 3. The VEGF-obtained angiogenic cascade was tracked in human pheochromocytoma. Besides significant differences concerning VEGF expression and microvessel density between benign and malignant tumors could be proven. 4. The therapy of experimental PC-12 tumors with neutralizing VEGF anti-bodies resulted in significantly lower VEGF expression, microvessel density, mitosis respectively tumor volumes in the case of treated vs. untreated tumors. After these results for the first time the perspective of an adjuvant, anti-angiogenic therapy opens for unresectable or metastasised, malignant pheochromocytoma by means of neutralizing anti-bodies against the vessel growth factor VEGF. The effectiveness in principle of such innovative therapies was already documented clinically in other tumor systems (among others colorectal carcinoma and breast carcinoma).