title: VEGF-D-induced draining lymphatic enlargement and tumor lymphangiogenesis promote lymph node metastasis in a xenograft model of ovarian carcinoma.
abstract: BACKGROUND
  Vascular 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.
  
  
  METHODS
  Human 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.
  
  
  RESULTS
  Mice 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.
  
  
  CONCLUSIONS
  Our 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.
authors: Li-Cheng
authors: LC
authors: Du
authors: Xian-Cheng
authors: XC
authors: Chen
authors: Dong
authors: D
authors: Wang
authors: Yan-Jun
authors: YJ
authors: Wen
authors: Chun-Ting
authors: CT
authors: Wang
authors: Xue-Mei
authors: XM
authors: Wang
authors: Bing
authors: B
authors: Kan
authors: Yu-Quan
authors: YQ
authors: Wei
authors: Department of Gynecology and Obstetrics, Second West China Hospital, West China Medical School, Sichuan University, South Renmin Road, Chengdu, China. xia-zhao@126.com.
authors: Xia
authors: X
authors: Zhao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D042583:Lymphangiogenesis / Q000502:physiology*; D008207:Lymphatic Metastasis; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D042643:Vascular Endothelial Growth Factor D / Q000096:biosynthesis*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D042643:Vascular Endothelial Growth Factor D