Effects of VEGFR-3 phosphorylation inhibitor on lymph node metastasis in an orthotopic diffuse-type gastric carcinoma model.
BACKGROUND
Vascular endothelial growth factor receptor-3 (VEGFR-3) signalling mediates lymphangiogenesis and lymphatic invasion; however, the effect of VEGFR-3 inhibition on the lymph node (LN) metastasis remains unclear. The aim of this study is to clarify the benefit of a VEGFR-3 inhibitor Ki23057 for LN metastasis.


METHODS
Ki23057 was administered orally to gastric cancer models created by orthotopic inoculation of diffuse-type gastric cancer cells, OCUM-2MLN. The effects of Ki23057 on lymphatic vessel invasion, lymphatic vessel density, and VEGFR-3 phosphorylation were examined by immunostaining or immunoblotting.


RESULTS
Ki23057 inhibited the autophosphorylation of VEGFR-3, with IC50 values of 4.3 nM in the cell-free kinase assay. Murine gastric cancer models created by the orthotopic inoculation of OCUM-2MLN cells showed the diffusely infiltrating growth and frequently developed LN metastasis. The oral administration of Ki23057 significantly (P<0.01) reduced the size of orthotopic tumours and the number of the metastatic LN in gastric cancer models. The degree of lymphatic invasion and lymphangiogenesis was significantly (P<0.05) lower in the gastric tumours treated by Ki23057. Ki23057 inhibited the phosphorylation of VEGFR-3 of lymphatic endothelial cells in gastric tumours.


CONCLUSIONS
The inhibition of lymphangiogenesis targeting VEGFR-3 phosphorylation is a therapeutic strategy for inhibiting LN metastasis of diffuse-type gastric cancer.
Yashiro
M
M
Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. m9312510@med.osaka-cu.ac.jp
Shinto
O
O
Nakamura
K
K
Tendo
M
M
Matsuoka
T
T
Matsuzaki
T
T
Kaizaki
R
R
Ohira
M
M
Miwa
A
A
Hirakawa
K
K
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects; D008207:Lymphatic Metastasis / Q000517:prevention & control*; D026901:Membrane Transport Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D013274:Stomach Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D042582:Vascular Endothelial Growth Factor C / Q000032:analysis; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D006023:Glycoproteins; D026901:Membrane Transport Proteins; D011804:Quinolines; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3; C515425:Ki23057; C492273:LYVE1 protein, mouse; C467483:vascular endothelial growth factor C, mouse