title: VEGF-D-enhanced lymph node metastasis of ovarian cancer is reversed by vesicular stomatitis virus matrix protein.
abstract: Lymphatic metastasis is a poor prognostic factor in ovarian cancer, which correlates to the majority of cancer deaths. Matrix protein (MP) of vesicular stomatitis virus (VSV) exhibits potent antitumor and antiangiogenic activities through inducing apoptosis and inhibiting angiogenesis. In this study, the antitumor and antimetastatic effects of MP were further investigated. Wild-type SKOV3 (WT-SK) cells were successfully transfected with empty vector pcDNA3.1 plasmid, or pcDNA3.1-VEGF-D recombinant plasmid to construct cell lines named EV-SK, and VEGFD-SK, respectively. Inhibition of VEGFD-SK cell migration and invasion was detected by Transwell and wound healing assay. Then, lymphogenous metastatic model of ovarian cancer was established by injecting VEGFD-SK cells subcutaneously into the left hindlimb claw pad of nude mice. The inducted apoptotic effect of MP on VEGFD-SK cells were assessed by flow analysis and Hoechst-33258 staining, respectively, in vitro. The in vivo antitumor and antiangiogenic activities of MP gene were evaluated with lymphogenous metastatic model of ovarian cancer. Tumor volume and lymphatic metastasis rates were measured. Lymphatic vessels were delineated using Evan's blue and LYVE-1 staining. Expression of VEGF-D and MMP-2 were evaluated by immunostaining. Apoptosis of tumor cells was analyzed by Hoechst-33258 staining. Mice bearing VEGFD-SK tumor cells displayed more rapid tumorigenesis, higher lymphogenous metastatic tendency and increased lymphatic vessel density compared with the mice bearing WT-SK or EV-SK cells. However, VEGF-D-enhanced metastasis was evidently reversed by MP. MP significantly reduced the invasion of VEGFD-SK cells, tumor volume, lymphatic metastasis rates and lymphatic vessel density compared with control groups (P<0.05), accompanied with down-expression of VEGF-D and MMP-2 and increased apoptosis. Our data indicate that MP has strong antitumor and antimetastatic abilities, and it may be a promising therapeutic strategy against the lymphatic metastasis of human ovarian cancer.
authors.affiliation: Department of Gynecology and Obstetrics, Key Laboratory of Obstetric and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Qi
authors.affiliation: Provincial Hospital Affiliated to Shandong University, Jinan, P.R. China.
authors.forename: Licheng
authors.initials: L
authors.lastname: Du
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Xiancheng
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Gynecology and Obstetrics, Key Laboratory of Obstetric and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yi
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Wen
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Gynecology and Obstetrics, Key Laboratory of Obstetric and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D064987:Cell- and Tissue-Based Therapy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000628:therapy; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy* / Q000821:virology; D042643:Vascular Endothelial Growth Factor D / Q000096:biosynthesis / Q000235:genetics*; D054243:Vesicular Stomatitis / Q000235:genetics / Q000473:pathology / Q000821:virology; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics; D014763:Viral Matrix Proteins / Q000008:administration & dosage / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: C094460:M protein, Vesicular stomatitis virus; C579459:VEGFD protein, human; D042643:Vascular Endothelial Growth Factor D; D014763:Viral Matrix Proteins; D020778:Matrix Metalloproteinase 2