title: Suppression of lymph node and lung metastases of endometrial cancer by muscle-mediated expression of soluble vascular endothelial growth factor receptor-3.
abstract: Lymph node metastasis is the most important prognostic factor of endometrial cancer. However, effective therapy has not been established against lymph node metastasis. In this study, we explored the efficacy of gene therapy targeting lymph node metastasis of endometrial cancer by suppressing the action of vascular endothelial growth factor (VEGF)-C through soluble VEGF receptor-3 (sVEGFR-3) expression. For this purpose, we first conducted a model experiment by introducing sVEGFR-3 cDNA into an endometrial cancer cell line HEC1A and established HEC1A/sVEGFR-3 cell line with high sVEGFR-3 expression. The conditioned medium of HEC1A/sVEGFR-3 cells inhibited lymphatic endothelial cell growth in vitro, and sVEGFR-3 expression in HEC1A cells suppressed in vivo lymph node and lung metastases without inhibiting the growth of a subcutaneously inoculated tumor. To validate the therapeutic efficacy, adeno-associated virus vectors encoding sVEGFR-3 were injected into the skeletal muscle of mice with lymph node metastasis. Lymph node and lung metastases of HEC1A cells were completely suppressed by the muscle-mediated expression of sVEGFR-3 using adeno-associated virus vectors. These results suggest the possibility of gene therapy against lymph node and lung metastases of endometrial cancer by using muscle-mediated expression of sVEGFR-3.
authors.affiliation: Division of Genetics Therapeutics, Center for Molecular Medicine, Shimotsuke, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Takahashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mizukami
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Saga
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takei
authors.forename: Masashi
authors.initials: M
authors.lastname: Urabe
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kume
authors.forename: Shizuo
authors.initials: S
authors.lastname: Machida
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000229:Dependovirus / Q000235:genetics; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008198:Lymph Nodes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008207:Lymphatic Metastasis; D051379:Mice; D008807:Mice, Inbred BALB C; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism*; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
chemical_list: D042582:Vascular Endothelial Growth Factor C; C581309:FLT4 protein, human; D040321:Vascular Endothelial Growth Factor Receptor-3