Enhanced cancer metastasis in mice deficient in vasohibin-1 gene.
Vasohibin-1 (VASH1) is isolated as an endogenous angiogenesis inhibitor produced by the vascular endothelium. We previously reported that tumor growth and tumor angiogenesis were augmented in VASH1 (-/-) mice. Here we examined whether VASH1 plays any role in cancer metastasis. When Lewis lung carcinoma (LLC) cells were inoculated in the footpad to observe spontaneous metastasis, a significant increase in lung metastasis together with inguinal lymph node metastasis was evident in the VASH1 (-/-) mice. Histological analyses revealed that vessels of the footpad tumor in VASH1 (-/-) mice were more immature, having fewer mural cells. However, when LLC cells were injected into a tail vein, the extent of lung metastasis was unchanged between wild-type mice and VASH1 (-/-) mice. When VASH1 in endothelial cells in culture was knocked-down by siRNA, we observed a decrease in the content of ZO-1, a component of tight junctions, which decrease resulted in increased transmigration of cancer cells across the endothelial cell monolayer. These results indicate that endogenous VASH1 tightens the endothelial barrier and makes tumor vessels resistant to cancer metastasis.
Department of Vascular Biology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan ; Department of Advanced Surgical Science and Technology, Tohoku University School of Medicine, Sendai, Japan.
Soichi
S
Ito
Hiroki
H
Miyashita
Yasuhiro
Y
Suzuki
Miho
M
Kobayashi
Susumu
S
Satomi
Yasufumi
Y
Sato
D000818:Animals; D015153:Blotting, Western; D018827:Carcinoma, Lewis Lung / Q000150:complications / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000172:deficiency* / Q000235:genetics*; D002460:Cell Line; D002478:Cells, Cultured; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000150:complications / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018797:Cell Cycle Proteins; C510089:Vash1 protein, mouse