title: Suppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer.
abstract: In gastric cancer, lymph node metastasis is one of the major prognostic factors and forms the basis for surgical removal of local lymph nodes. Recently, several studies have demonstrated that overexpression of lymphangiogenic growth factor VEGF-C or VEGF-D induces tumor lymphangiogenesis and promotes lymphatic metastasis in mouse tumor models. We examined whether these processes could be inhibited in naturally metastatic tumors by blocking of their cognate receptor VEGFR-3 signaling pathway. Using a mouse orthotopic gastric cancer model which has a high frequency of lymph node metastasis, we estimated lymphatic vessels in gastric cancers by immunostaining for VEGFR-3 and other specific lymphatic markers, LYVE-1 and prox-1. Then we systemically administered anti-VEGFR-3 blocking antibodies. This treatment resulted in the inhibition of regional lymph node metastasis and reduction of lymphatic vessel density in the primary tumors. In addition, increased density of LYVE-1-positive lymphatic vessels of primary tumors was closely correlated with lymph node metastasis in human samples of gastric cancer. Antilymphangiogenesis by inhibiting VEGFR-3 signaling could provide a potential strategy for the prevention of lymph node metastasis in gastric cancer.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Shimizu
authors.forename: Hajime
authors.initials: H
authors.lastname: Kubo
authors.forename: Koji
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kawashima
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Ueda
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuo
authors.forename: Masaaki
authors.initials: M
authors.lastname: Awane
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Shimahara
authors.forename: Arimichi
authors.initials: A
authors.lastname: Takabayashi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamaoka
authors.forename: Seiji
authors.initials: S
authors.lastname: Satoh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D045744:Cell Line, Tumor / Q000637:transplantation; D005260:Female; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D007167:Immunotherapy; D042583:Lymphangiogenesis / Q000187:drug effects; D008207:Lymphatic Metastasis / Q000503:physiopathology* / Q000517:prevention & control; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000473:pathology*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D033921:Vesicular Transport Proteins; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D006023:Glycoproteins; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; D040321:Vascular Endothelial Growth Factor Receptor-3; D033921:Vesicular Transport Proteins; C119248:LYVE1 protein, human; C492273:LYVE1 protein, mouse