Increased vascular endothelial growth factor in tumor cells and increased production of the receptor for urokinase plasminogen activator in endothelial cells are associated with lymph node metastasis in human breast cancer

Breast cancer tissue from patients with or without lymph node metastasis wa s examined by light immunohistochemistry for vascular endothelial cell grow th factor, urokinase plasminogen activator, urokinase plasminogen activator receptor, the platelet endothelial adhesion molecule CD31, von Willebrand factor, and a-smooth muscle actin. The plasminogen activator receptor and C D31 were also examined by immunoelectron microscopy. Staining for vascular endothelial cell growth factor was increased in tumor cells from patients w ith lymph node metastasis compared with patients with localized disease, an d the density of microvessels and endothelial cells in close proximity to t umor cells was higher in the former group of patients. This was paralleled with an increased staining for the receptor for urokinase plasminogen activ ator in endothelial cells adjacent to the vascular endothelial cell growth factor positive tumor cells in six of seven patients with lymph node spread . Ultrastructurally the urokinase plasminogen activator receptor was locali zed in large cytoplasmatic vacuoles and at the leading edge of endothelial cells. It has been shown in vitro that vascular endothelial cell growth fac tor upregulated the urokinase plasminogen activator receptor on migrating e ndothelial cells thus facilitating angiogenesis, and the present findings s uggest that this mechanism occurs in human breast cancer in association wit h lymph node metastasis.