FLT4 antagonist can function as an effective blocker in metastasis of melanoma cells by suppression of lymphangiogenesis

Background \u0026 Aim Background \u0026 Aim Tumor recurrence is a serious concern in the treatment of melanoma. Treatment failures, including relapse, are prompted by metastasis. Malignant melanoma has a cutaneous origin, but it is easily found in visceral organs, such as lung, after metastasis. Like angiogenesis, tumor-induced lymphangiogenesis is also regarded as an important cause of relapse. VEGF-C/FLT4 axis plays a pivotal role in lymphangiogenesis. Especially, distant metastasis is strongly involved in FLT4 activation and it is emerging that importance of lymphatic vessels as a potential therapeutic target for anti-metastatic therapy. Thus, we investigated whether suppression of lymphatic vessel by inhibition of FLT4 phosphorylation can decrease melanoma metastasis in animal model. Methods, Results \u0026 Conclusion Methods To this end, B16-F10 cells with or without FLT4 antagonist was intravenously injected to engraft tumor, then tissues was isolated at 3 weeks post cell transplantation. To confirm roles of FLT4 antagonist in tumor metastasis, real-time PCR and immunohistochemistry were performed using tumor bearing mice. Results \u0026 Conclusion Gross examination and melan A cells in lung was clearly showed that significant reduction of metastatic progress was detected by FLT4 antagonist. (in modules diameter, 4.27-fold; in number of tumor modules, 6.01-fold). In tumor regions, maker genes for lymphatic endothelial cells were significantly increased, compared to that of wild mice. Immunohistochemistry of lung tissues were revealed that FLT4 antagonist exhibited decreased lymphatic capillaries, compared to that of melanoma-bearing mice (wild \u0026 melanoma, 3.98-fold, melanoma \u0026 FLT4 antagonist, 3.02-fold). Proliferative lymphatic capillaries in the intratumoral region were also suppressed by inhibition of FLT4 molecule. Collectively, we found that tumor clusters gradually increased by growth of lymphatic vessels and decreased by its blocking, suggesting that the importance of FLT4 in tumor metastasis. These data provided a platform for advanced therapeutic strategies by targeting lymphatic vessels as a microenvironmental factor and we will next establish plan for clinic application by using safety materials such as peptide and monoclonal antibodies in targeting FLT4.