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 was examined by light immunohistochemistry for vascular endothelial cell growth 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 CD31 were also examined by immunoelectron microscopy. Staining for vascular endothelial cell growth factor was increased in tumor cells from patients with lymph node metastasis compared with patients with localized disease, and the density of microvessels and endothelial cells in close proximity to tumor cells was higher in the former group of patients. This was paralleled with an increased staining for the receptor for urokinase plasminogen activator 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 localized in large cytoplasmatic vacuoles and at the leading edge of endothelial cells. It has been shown in vitro that vascular endothelial cell growth factor upregulated the urokinase plasminogen activator receptor on migrating endothelial cells thus facilitating angiogenesis, and the present findings suggest that this mechanism occurs in human breast cancer in association with lymph node metastasis.