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.

A Vesicular Stomatitis Virus‐Inspired DNA Nanocomplex for Ovarian Cancer Therapy

“…In this work, we designed a p VSVMP nanocomplex to express VSVMP for cancer therapy. The VSVMP can inhibit the host gene transcription,9 the nucleocytoplasmic transport of host RNAs and proteins,18 the Akt/protein kinase B signaling,19 and the vascular endothelial growth factor secretion 20. Therefore, this p VSVMP nanocomplex that targets multi‐targets can avoid some potential drawbacks of conventional single‐target gene therapy.…”

Targeting Multiple Signaling Pathways in Cancer: The Rutin Therapeutic Approach

“…VEGF is considered a key factor in angiogenesis and tumor growth promotion. Therapeutic intervention involving the inhibition of VEGF has become an innovative strategy for abrogating tumor metastasis [ 182 ]. Rutin exerts cytotoxic effects against SW480 colon cancer cells in vitro, markedly suppressing tumor growth and diminishing the expression of VEGF in vivo [ 117 ].…”

Oncotargeting by Vesicular Stomatitis Virus (VSV): Advances in Cancer Therapy

“…In this aspect, Zhao’s group has documented that liposome-mediated delivery of plasmid DNA to the nude mice with metastatic ovarian cancer showed desired M expression in target cells. Further, the M expression reversed angiogenesis and tumor metastasis while desired induced apoptosis in the tumor cells [ 29 ].…”

“…Other than directly triggering apoptosis, VSV employs an additional mechanism to cause tumor regression. VSV tends to infect tumor vasculature leading to loss of blood flow to the tumor and subsequent blood-coagulation and massive bystander lysis of neovasculature [ 29 , 30 ]. Infiltrations of peripheral neutrophils to the tumor bed further amplify indirect killing of uninfected tumor cells.…”