Induction of vascular endothelial growth factor receptor-3 expression on tumor microvasculature as a new progression marker in human cutaneous melanoma

Abstract

The anatomical relation between a malignant tumor and its vascular and lymphatic bed is an important factor influencing metastasis. Lack of specific markers for the lymphatic endothelium has long hampered a reliable detection of lymphatics. Here, we demonstrate that lymphatic endothelium can reliably be identified in a panel of different normal tissues and of benign and malignant tumors. Application of the previously described PAL-E/CD31 double staining protocol differentiates between blood capillaries and veins on one hand and lymphatic vessels on the other. Blood vessel marker CD34, absent from lymphatics, was used additionally to classify arteries. We found that the lymphatic vascular endothelial growth factor receptor-3 (VEGFR-3, also known as Flt-4) was present on both lymphatic and blood vessels in 76 of 113 malignant tumors [adenocarcinoma of kidney (n = 3), colon (n = 3) and liver (n = 3), breast (n = 9) and squamous cell carcinoma (n = 5), primary (n = 81), and metastatic (n = 9) melanoma]. No evident signs of tumor-induced lymphangiogenesis were observed. Evaluation of a series of 110 melanocytic skin lesions indicated that VEGFR-3 expression is confined to the lymphatic vasculature in benign lesions. However, its expression emerges on the blood neovasculature in malignant lesions as soon as metastatic potential develops. We conclude that induction of VEGFR-3 expression on tumor blood vessels may be a general phenomenon that would make VEGFR-3 a marker for tumor endothelium. In addition, we propose VEGFR-3 expression as a new microvascular progression marker in cutaneous melanoma.