title: A small molecular agent YL529 inhibits VEGF-D-induced lymphangiogenesis and metastasis in preclinical tumor models in addition to its known antitumor activities.
abstract: BACKGROUND
  The lymph node metastasis is a key early step of the tumor metastatic process. VEGFD-mediated tumor lymphangiogenesis plays a key role, since down-regulation of p-VEGFR-3 could block the lymph node metastasis. YL529 has been reported to possess potent anti-angiogenesis and antitumor activities; however, its roles in tumor-associated lymphangiogenesis and lymphatic metastasis remain unclear.
  
  
  METHODS
  We investigated the effect of YL529 on tumor-associated lymphangiogenesis and lymph node metastasis using in vitro lymph node metastasis models and in vivo subcutaneous tumor models in C57 BL/6 mice.
  
  
  RESULTS
  We found that YL529 inhibited VEGF-D-induced survival, proliferation and tube-formation of Human Lymphatic Endothelial Cells. Furthermore, in established in vitro and in vivo lymph node metastasis models using VEGF-D-LL/2 cells, YL529 significantly inhibited the tumor-associated lymphangiogenesis and metastasis. At molecular level, YL529 down-regulated p-VEGFR-3, p-JNK and Bax while up-regulated Bcl-2.
  
  
  CONCLUSIONS
  YL529 provided the therapeutic benefits by both direct effects on tumor cells and inhibiting lymphangiogenesis and metastasis via the VEGFR-3 signaling pathway, which may have significant direct clinical implications.
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Anhui Medical University, 81#, Mei Shan Road, Hefei, 230032, China. youzhixu08@gmail.com.|State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, 17#, 3rd Section, Ren min South Road, Chengdu, 610041, China. youzhixu08@gmail.com.
authors.forename: Youzhi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Anhui Medical University, 81#, Mei Shan Road, Hefei, 230032, China. eva63136@163.com.|State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, 17#, 3rd Section, Ren min South Road, Chengdu, 610041, China. eva63136@163.com.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Transfusion, the First Affiliated Hospital of Anhui Medical University, 81#, Mei Shan Road, Hefei, 230032, China. 158562771@qq.com.
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, 17#, 3rd Section, Ren min South Road, Chengdu, 610041, China. 251241462@qq.com.|Department of Oncology, The People's Hospital of Guizhou Province, 83#, Zhong Shan East Road, Guiyang, 550004, China. 251241462@qq.com.
authors.forename: Wen
authors.initials: W
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, 17#, 3rd Section, Ren min South Road, Chengdu, 610041, China. 553693616@qq.com.
authors.forename: Chunting
authors.initials: C
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, 17#, 3rd Section, Ren min South Road, Chengdu, 610041, China. 273107786@qq.com.
authors.forename: Manli
authors.initials: M
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, 17#, 3rd Section, Ren min South Road, Chengdu, 610041, China. 395067922@qq.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, 17#, 3rd Section, Ren min South Road, Chengdu, 610041, China. 645328757@qq.com.
authors.forename: Guobo
authors.initials: G
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, 17#, 3rd Section, Ren min South Road, Chengdu, 610041, China. 1134079675@qq.com.
authors.forename: Nana
authors.initials: N
authors.lastname: Meng
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, 17#, 3rd Section, Ren min South Road, Chengdu, 610041, China. dazhisklb@foxmail.com.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, 17#, 3rd Section, Ren min South Road, Chengdu, 610041, China. 1443716876@qq.com.
authors.forename: Lixin
authors.initials: L
authors.lastname: Kan
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, 17#, 3rd Section, Ren min South Road, Chengdu, 610041, China. 245428988@qq.com.
authors.forename: Siying
authors.initials: S
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, 17#, 3rd Section, Ren min South Road, Chengdu, 610041, China. ysy_008@163.com.
authors.forename: Shengyong
authors.initials: S
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, 17#, 3rd Section, Ren min South Road, Chengdu, 610041, China. ylting_cd@163.com.
authors.forename: Luoting
authors.initials: L
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, 17#, 3rd Section, Ren min South Road, Chengdu, 610041, China. zhaoyinglan@scu.edu.cn.
authors.forename: YingLan
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mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001557:Benzenesulfonates / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects*; D008207:Lymphatic Metastasis / Q000517:prevention & control*; D051379:Mice; D010847:Picolines / Q000008:administration & dosage* / Q000494:pharmacology; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; C585837:N-methyl-4-(4-(3-(trifluoromethyl)benzamido)phenoxy)picolinamide4- methylbenzenesulfonate; D010847:Picolines; C579459:VEGFD protein, human; D042643:Vascular Endothelial Growth Factor D