VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer

Recently, monoclonal antibodies against the human vascular endothelial grow th factor receptor VEGFR-3 were shown to provide a specific antigenic marke r for lymphatic endothelium in various normal tissues, In this study we hav e investigated, the expression of VEGFR-3 and its ligand VEGF-C in normal b reast tissue and in breast tumors by immunohistochemistry. VEGFR-3 was weak ly expressed in capillaries of normal breast tissue and in fibroadenomas. I n intraductal breast carcinomas, VEGFR-3 was prominent in the "necklace" ve ssels adjacent to the basal lamina of the tumor-filled ducts. VEGF receptor 1 and 2 as well as blood vessel endothelial and basal lamina markers were colocalized with VEGFR-3 in many of these vessels. Antibodies against smoot h muscle alpha-actin gave a weak staining of the necklace vessels, suggesti ng that they were incompletely covered by pericytes/smooth muscle cells. A highly elevated number of VEGFR-3 positive vessels was found in invasive br east cancer in comparison with histologically normal breast tissue (P < 0.0 001, the Mann-Whitney test). VEGF-C was located in the cytoplasm of intradu ctal and invasive cancer cells. The results demonstrate that the expression of VEGFR-3 becomes up-regulated in the endothelium of angiogenic blood ves sels in breast cancer. The results also suggest that VEGF-C secreted by the intraductal carcinoma cells acts predominantly as an angiogenic growth fac tor for blood vessels, although this paracrine signaling network between th e cancer cells and the endothelium may also be involved in modifying the pe rmeabilities of both blood and lymphatic vessels and metastasis formation.