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Cell Mol Biol Lett. 2018 Jan 3;23:2. doi: 10.1186/s11658-017-0058-9. eCollection 2018.

VEGF and SEMA4D have synergistic effects on the promotion of angiogenesis in epithelial ovarian cancer.

Chen Y1,2,3, Zhang L1,2,3, Liu WX1, Wang K1.

Author information

1
Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Hexi District, Tianjin, 300060 China.
2
Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060 China.
3
National Clinical Research Centre of Cancer, Tianjin, 300060 China.

Abstract

Background:

Anti-angiogenesis therapy that targets VEGF is one of the important treatment strategies in advanced ovarian cancer. However, depending on the pharmaceutical agent, treatment can have undesirable side effects. SEMA4D has recently gained interest for its role in promoting angiogenesis. Here, we try to further understand the mechanism by which SEMA4D promotes angiogenesis in ovarian cancer.

Methods:

Correlation and western blot assaya were used to detect the relationship between VEGF and SEMA4D in clinical tissues and cells. Vasculogenic mimicry and transwell migration analyses were used to detect the roles of VEGF, SEMA4D and plexin-B1 on vasculogenic mimicry and migration. Vascular density and SEMA4D expression was determined using immunofluorescence staining in clinical tissues of EOC. Western blot was used to detect the expressions of CD31, MMP2 and VE-cadherin. We also analyzed the relationship between VEGF-SEMA4D and malignant tumor prognosis.

Results:

We found that knockdown of VEGF could suppress SEMA4D expression and that the expressions of VEGF and SEMA4D have a positive correlation in EOC cancer tissues. Vasculogenic mimicry and transwell migration analyses showed that SEMA4D and VEGF have a synergistic effect on the promotion of angiogenesis in A2780 and HUVEC cells. Soluble SEMA4D (sSEMA4D) could promote VM and migration in A2780 and HUVEC cells via the SEMA4D/plexin-B1 pathway, but the effect was not noted in stably transfected shR-plexin-B1 cells. In clinical tissues of EOC, the vascular density and SEMA4D/plexin-B1 expression were higher. When VEGF, SEMA4D and plexin-B1 was knocked down, the expression of CD31, MMP2 and VE-cadherin, which are the markers and initiators of angiogenesis and the epithelial-mesenchymal transition (EMT) process were reduced. VEGF and SEMA4D had a positive correlation with the malignant degree of ovarian cancer, and SEMA4D can serve as an independent prognostic factor.

Conclusions:

VEGF and SEMA4D have synergistic effects on the promotion of angiogenesis in epithelial ovarian cancer. Targeting VEGF and the SEMA4D signaling pathway could be important for the therapy for EOC.

KEYWORDS:

Angiogenesis; Epithelial ovarian cancer; SEMA4D; Tumor growth; Vegf

PMID:
29308068
PMCID:
PMC5751932
DOI:
10.1186/s11658-017-0058-9
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Ying Chen and Lei Zhang are from Tianjin Medical University Cancer Institute and Hospital, Tianjin Key Laboratory of Cancer Prevention and Therapy and Tianjin National Clinical Research Centre of Cancer, Wen-xin Liu and Ke Wang are from Tianjin Medical University Cancer Institute and Hospital.Human EOC tissues and adjacent non-cancerous tissues were collected from patients at the Tianjin Medical University Cancer Institute and Hospital. Informed consent was obtained from each patient. The Ethics Committee of Tianjin Medical University granted ethics approval (Code of Ethics: TMUhMEC2015021). All patients were cleared and consented to participate according to the parameters defined in ‘Ethics, consent and permissions’ and rights were given to publish individual patient data by each participant .Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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