MDM-2 ONCOPROTEIN OVEREXPRESSION, P53 GENE MUTATION, AND VEGF UP-REGULATION IN ANGIOSARCOMAS

The endothelium is one of the largest cellular compartments of the hum an body and has a high proliferative potential. However, angiosarcomas are among the rarest malignancies. Despite this interesting contradic tion, data on growth and angiogenesis control mechanisms of angiosarco mas are scarce. In this study of 19 angiosarcomas and 10 benign vascul ar control lesions we investigated the sequence and expression of the p53 tumor suppressor gene and the expression of the mdm-2 proto-oncoge ne, which is a negative regulator of p53 activity and of the vascular endothelial growth factor (VEGF), whose expression, among other factor s, is regulated by the p53/MDM-2 pathway. Ten sarcomas (53%) exhibited clear nuclear p53 protein accumulation. Two of these cases revealed m utations in the sequence-specific DNA binding domain of the p53 gene. Thirteen angiosarcomas (68%) showed an increased amount of MDM-2 prote in. Elevated expression of p53 and MDM-2 protein correlated with incre ased VEGF expression, which was found in nearly 80% of the angiosarcom a cases. Negative or clearly lower immunostaining was obtained in case s from the benign control collective. Only one case of a juvenile hema ngioma reached the cutoff value of p53 positivity coincidentally with high VEGF expression, Our data suggest that the p53/MDM-2 pathway is i mpaired in about two-thirds (14/19) of the angiosarcomas, This may be a key event in the pathogenesis of human angiosarcomas, The increased VEGF expression observed supports this hypothesis.