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.
PLoS One. 2013 Sep 16;8(9):e73931. doi: 10.1371/journal.pone.0073931. eCollection 2013.
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.
血管抑制素-1（VASH1）是从血管内皮细胞中分离出来的一种内源性血管生成抑制剂。我们之前的研究报告表明，VASH1（-/-）小鼠的肿瘤生长和肿瘤血管生成增强。在这里，我们研究了 VASH1 是否在癌症转移中发挥作用。当将 Lewis 肺癌（LLC）细胞接种到脚掌以观察自发性转移时，VASH1（-/-）小鼠的肺部转移和腹股沟淋巴结转移明显增加。组织学分析显示，VASH1（-/-）小鼠脚掌肿瘤的血管更不成熟，壁细胞更少。然而，当将 LLC 细胞注入尾静脉时，野生型小鼠和 VASH1（-/-）小鼠之间的肺部转移程度没有变化。当通过 siRNA 敲低培养的内皮细胞中的 VASH1 时，我们观察到紧密连接的组成部分 ZO-1 的含量减少，这导致癌细胞穿过内皮细胞单层的迁移增加。这些结果表明，内源性 VASH1 使内皮屏障收紧，并使肿瘤血管对癌症转移具有抵抗力。
