Vascular endothelial growth factor-D is a key molecule that enhances lymphatic metastasis of soft tissue sarcomas

• Published in: Experimental cell research 2012-04, Vol.318 (7), p.800-808
• Main Authors: Yanagawa, Takashi, Shinozaki, Tetsuya, Watanabe, Hideomi, Saito, Kenichi, Raz, Avraham, Takagishi, Kenji
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Aged; ANIMAL TISSUES; Cancer; CATTLE; Cell Movement - drug effects; Cellular biology; CHEMOTHERAPY; Female; FIBROBLASTS; FIBROSARCOMAS; GROWTH FACTORS; Humans; Immunohistochemistry; Lymph node; Lymph Node Excision; LYMPH NODES; Lymphatic endothelial cells; Lymphatic Metastasis; Lymphatic system; Male; METASTASES; Metastasis; Middle Aged; Motility; PEROXIDASES; RADIOTHERAPY; RECEPTORS; Sarcoma - metabolism; Sarcoma - pathology; Tumor Cells, Cultured; Vascular endothelial growth factor; Vascular Endothelial Growth Factor C - biosynthesis; Vascular Endothelial Growth Factor D - biosynthesis; VEGF-C; VEGF-D
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2012.01.024

Studies on lymph node metastasis of soft tissue sarcomas are insufficient because of its rarity. In this study, we examined the expressions of vascular endothelial growth factor (VEGF)-C and VEGF-D in soft tissue sarcomas metastasized to lymph nodes. In addition, the effects of the two molecules on the barrier function of a lymphatic endothelial cell monolayer against sarcoma cells were analyzed. We examined 7 patients who had soft tissue sarcomas with lymph node metastases and who had undergone neither chemotherapy nor radiotherapy before lymphadenectomy. Immunohistochemistry revealed that 2 of 7 sarcomas that metastasized to lymph nodes expressed VEGF-C both in primary and metastatic lesions. On the other hand, VEGF-D expression was detected in 4 of 7 primary and 7 of 7 metastatic lesions, respectively. Interestingly, 3 cases that showed no VEGF-D expression at primary sites expressed VEGF-D in metastatic lesions. Recombinant VEGF-C at 10−8 and VEGF-D at 10−7and 10−8g/ml significantly increased the random motility of lymphatic endothelial cells compared with controls. VEGF-D significantly increased the migration of sarcoma cells through lymphatic endothelial monolayers. The fact that VEGF-D induced the migration of fibrosarcomas through the lymphatic endothelial monolayer is the probable reason for the strong relationship between VEGF-D expression and lymph node metastasis in soft tissue sarcomas. The important propensities of this molecule for the increase of lymph node metastases are not only lymphangiogenesis but also down-regulation of the barrier function of lymphatic endothelial monolayers, which facilitates sarcoma cells entering the lymphatic circulation.