Expression of Vascular Endothelial Growth Factor (VEGF) Associated with Its Receptor (VEGFR) in Relation to Tissue Factor (TF) in Human Breast Cancer Tissue.

New blood vessel formation is an important process in tumor growth and dissemination. The relationship between vessel density and survival of patients was documented in breast cancer patients. Vascular endothelial growth factor (VEGF) is of paramount importance in new blood vessel development. VEGF exerts its biological function through binding to specific receptors (VEGFR-1/Flt-1 and VEGFR-2/KDR/Flk-1). Recent studies revealed that tissue factor (TF), apart from being the main procoagulant in cancer patients, is endowed with biological activities that do not relate to its hemostatic function. There exists a large body of evidence that TF is one of the key regulators of angiogenesis. In vitro experiments demonstrated that TF stimulates the synthesis of VEGF in different cell types. The purpose of the study was to assess the expression of VEGF and VEGF coupled to its receptor in relation to the expression of TF. Studies were performed on breast cancer fragments and metastatic axillary lymph node tissues obtained during surgical treatment of previously untreated patients. The tissues were fixed according to AMeX method and embedded in paraffin. Immunohistochemical staining procedures according to the ABC method and Envision Double Staining System (DAKO) were employed using polyclonal antibodies directed to TF and VEGF and a novel monoclonal antibody that binds to VEGF only when it is associated with its receptor - VEGFR. In breast cancer and lymph node tissues the co-localization of TF and VEGF in cancer cells was observed. Of particular interest was the co-expression of TF and VEGF in association with its receptor - VEGFR in cancer cells and endothelial cells of small blood vessels. Furthermore, VEGF coupled to its receptor was localized in dendritic cells in metastatic lymph nodes, which may indicate its influence on the host immune response system. The observed co-localization of TF and VEGF (including VEGF in association with VEGFR) suggests a functional interrelationship that exists between TF and VEGF in breast cancer in vivo.