Taina A. Partanen

ABSTRACT Recently, vascular endothelial growth factor receptor 3 (VEGFR‐3) has been shown to provide a specific marker for lymphatic endothelia in certain human tissues. In this study, we have investigated the expression of VEGFR‐3 and its ligands VEGF‐C and VEGF‐D in fetal and adult tissues. VEGFR‐3 was consistently detected in the endothelium of lymphatic vessels such as the thoracic duct, but fenestrated capillaries of several organs including the bone marrow, splenic and hepatic sinusoids, kidney glomeruli and endocrine glands also expressed this receptor. VEGF‐C and VEGF‐D, which bind both VEGFR‐2 and VEGFR‐3 were expressed in vascular smooth muscle cells. In addition, intense cytoplasmic staining for VEGF‐C was observed in neuroendocrine cells such as the α cells of the islets of Langerhans, prolactin secreting cells of the anterior pituitary, adrenal medullary cells, and dispersed neuroendocrine cells of the gastrointestinal tract. VEGF‐D was observed in the innermost zone of the adrenal cortex and in certain dispersed neuroendocrine cells. These results suggest that VEGF‐C and VEGF‐D have a paracrine function and perhaps a role in peptide release from secretory granules of certain neuroendocrine cells to surrounding capillaries.—Partanen, T. A., Arola, J., Saaristo, A., Jussila, L., Ora, A., Miettinen, M., Stacker, S. A., Achen, M. G., Alitalo, K. VEGF‐C and VEGF‐D expression in neuroendocrine cells and their receptor, VEGFR‐3, in fenestrated blood vessels in human tissues. FASEB J. 14, 2087–2096 (2000)

Lymphatic vessels have been difficult to study in detail in normal and tumor tissues because of the lack of molecular markers. Here, monoclonal antibodies against the extracellular domain of the vascular endothelial growth factor-C receptor that we have named VEGFR-3 were found to specifically stain endothelial cells of lymphatic vessels and vessels around tumors such as lymphoma and in situ breast carcinoma. Interestingly, the spindle cells of several cutaneous nodular AIDS-associated Kaposi's sarcomas and the endothelium around the nodules were also VEGFR-3 positive. The first specific molecular marker for the lymphatic endothelium should provide a useful tool for the analysis of lymphatic vessels in malignant tumors and their metastases and the cellular origin and differentiation of Kaposi's sarcomas.

BACKGROUND: Among the molecules important to angiogenesis and lymphangiogenesis is vascular endothelial growth factor receptor 3 (VEGFR-3), a member of the receptor tyrosine kinases of endothelial cells. This receptor is expressed consistently in normal lymphatics, lymphangiomas, and in Kaposi sarcoma, but data regarding other vascular tumors are scant. METHODS: In this study the authors immunohistochemically examined VEGFR-3 expression in 82 benign, 31 borderline, and 72 malignant vascular tumors using a monoclonal antibody to VEGFR-3, heat-induced epitope retrieval, and an avidin-biotin-peroxidase detection system. RESULTS: Although normal mesenchymal tissues showed VEGFR-3 only in the lymphatics, benign and malignant vascular tumors and neovascularization of nonendothelial tumors showed widespread VEGFR-3 distribution. All lymphangiomas and Kaposi sarcomas showed consistent VEGFR-3 reactivity. Among the hemangiomas, spindle cell hemangiomas and 80% of capillary (including all lobular capillary hemangiomas) were positive whereas the endothelium of cavernous, venous, and epitheloid hemangiomas were positive in a minority of cases (20%, 27%, and 33%, respectively). Among the borderline lesions, Kaposiform hemangioendotheliomas were intensely positive whereas epithelioid hemangioendotheliomas were positive in 11 of 29 cases (38%). Angiosarcomas showed VEGRF-3 reactivity in the majority of cases (48 of 60 cases; 80%). The nonepithelioid variants more often were positive (40 of 45 cases; 89%) than the epithelioid variants, of which 8 of 15 (53%) showed positive tumor cells. Nonvascular tumors (including perivascular tumors, other sarcomas, melanomas, carcinomas, and large cell lymphomas) consistently were negative whereas tumor neovascularization commonly was VEGFR-3 positive. CONCLUSIONS: The results of the current study show that although VEGFR-3 shows specificity toward lymphatics in normal tissues, this receptor is distributed extensively in benign and malignant vascular tumors and therefore can be considered a novel marker in the assessment of endothelial cell differentiation of vascular neoplasms.