title: Blockade of FLT4 suppresses metastasis of melanoma cells by impaired lymphatic vessels.
abstract: The metastatic spread of tumor cells via lymphatic vessels affects the relapse of tumor patients. New lymphatic vessel formation, including lymphangiogenesis, is promoted in the tumor environment. The lymphangiogenic factor VEGF-C can mediate lymphatic vessel formation and induce tumor metastasis by binding with FLT4. In melanoma, metastasis via lymphatics such as lymph nodes is one of the main predictors of poor outcome. Thus, we investigated whether blockade of FLT4 can reduce metastasis via the suppression of lymphatic capillaries. Proliferative lymphatic capillaries in melanoma were estimated by immunohistochemistry using FLT4 antibody after the injection of the FLT4 antagonist MAZ51. The numbers of tumor modules in metastasised lungs were calculated by gross examination and lymphatic related factors were examined by qRT-PCR. MAZ51 injection resulted in the suppression of tumor size and module number and the inhibition of proliferative lymphatic vessels in the intratumoral region in the lung and proliferating melanoma cells in the lung compared to those of untreated groups. Additionally, high FLT4 and TNF-alpha were detected in melanoma-induced tissue, while lymphatic markers such as VEGF-C, FLT4 and Prox-1 were significantly decreased in MAZ51 treated groups, implying that anti-lymphangiogenesis by MAZ51 may provide a potential strategy to prevent tumor metastasis in melanoma and high number of lymphatic capillaries could be used diagnosis for severe metastasis.
authors: Department of Biomedical Laboratory Science, College of Health Sciences, Sangji University, Wonju, 26339, Republic of Korea. Electronic address: leejiyoon@sangji.ac.kr.
authors: Ji Yoon
authors: JY
authors: Lee
authors: Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, 24341, Republic of Korea.
authors: Seok-Ho
authors: SH
authors: Hong
authors: Department of Microbiology, Kyungpook National University School of Medicine, Daegu, 41944, Republic of Korea.
authors: Minsang
authors: M
authors: Shin
authors: Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, 24341, Republic of Korea.
authors: Hye-Ryeon
authors: HR
authors: Heo
authors: Department of Biomedical Laboratory Science, College of Health Sciences, Sangji University, Wonju, 26339, Republic of Korea. Electronic address: jih2094@sangji.ac.kr.
authors: In Ho
authors: IH
authors: Jang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D042583:Lymphangiogenesis / Q000187:drug effects* / Q000235:genetics; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: C441602:3-(4-dimethylamino-naphthalen-1-ylmethylene)-1,3-dihydro-indol-2-one; D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D007211:Indoles; D009281:Naphthalenes; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D042582:Vascular Endothelial Growth Factor C; D000098551:Prospero-Related Homeobox 1 Protein; C467483:vascular endothelial growth factor C, mouse; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: FLT4 antagonist; Melanoma cells; Tumor metastasis