Abstract
BackgroundVascular endothelial growth factor (VEGF)-D has been shown to promote lymph node metastasis in several cancers. Although generally overexpressed in ovarian carcinoma, its role in nodal dissemination of this cancer is unclear. To clarify the role of VEGF-D and the underlying molecular mechanisms, we investigated the function of VEGF-D using a mouse xenograft model of ovarian cancer.MethodsHuman ovarian serous adenocarcinoma SKOV3 cells were transfected with VEGF-D recombinant plasmid DNA, or with control vectors. The cells were injected subcutaneously into the footpads of nude mice. Tumor growth was evaluated weekly. Draining lymphatics were observed grossly with Evan’s blue lymphangiography. Tumoral lymphatics were delineated with both Evan’s blue and LYVE-1 immunostaining. Tumor metastases to lymph nodes were evaluated by H&E and CA125/CD40 staining. Expression of VEGF-D in primary tumors and levels of CA125 in involved lymph nodes were examined by immunohistochemistry. Tumor cell apoptosis was analyzed by Hoechst dyeing.ResultsMice bearing VEGF-D overexpressing xenografts showed a significantly higher rate of lymph node metastasis and markedly greater tumor volume compared with the controls. The functional lymphatic vessels were denser and enlarged in marginal and central tumor portions. Additionally, higher CA125 expression was observed in the involved lymph nodes. Mice bearing VEGF-D overexpressing xenografts also exhibited a markedly lower apoptotic index compared with the controls.ConclusionsOur data demonstrate the important role of VEGF-D in promoting lymph node metastasis by increasing tumor lymphangiogenesis, stimulating draining lymphatic vessel formation, and enhancing tumor invasiveness. Our findings show that VEGF-D can be a promising therapeutic target for ovarian cancer.
Highlights
Vascular endothelial growth factor (VEGF)-D has been shown to promote lymph node metastasis in several cancers
Immunohistochemistry showed that mouse xenografts bearing Non-transfected SKOV3 cells (SKOV3)/VEGF-D cells exhibited apparent strong staining of VEGF-D in both the cytoplasm and nuclei of the tumor cells while only weak or negative staining of VEGF-D was observed in mouse xenografts bearing SKOV3 cells or SKOV3/pcDNA cells (Figure 1B to 1G)
Xenografts bearing SKOV3 cells overexpressing VEGF-D grew at an apparent faster pace from week 3 post inoculation compared to xenografts bearing SKOV3 cells or SKOV3 cells transfected with control vectors
Summary
Vascular endothelial growth factor (VEGF)-D has been shown to promote lymph node metastasis in several cancers. The finding of vascular endothelial growth factors (VEGF) mediating lymphangiogenesis and thereby promoting lymphatic metastasis in tumors provides a new therapeutic target. After secretion into the extracellular space, the C– and N-terminal propeptides are cleaved from full length VEGF-D to form mature VEGF-D. This proteolytic processing increases the affinity of VEGF-D for VEGFR-3, a tyrosine kinase receptor that is mainly located on adult lymphatic endothelium and is implicated in lymphangiogenesis [9,10]. A prominent role of VEGF-D in lymph node metastasis is supported by findings from several studies of cancer [12,13,14,15], but not by others [16,17,18]
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