Abstract
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.
Highlights
Cancer is the leading cause of death worldwide, and most of cancer patients die because of metastasis
With regard to its function, we showed that increased tumor growth and tumor angiogenesis were evident when Lewis lung carcinoma (LCC) cells were inoculated into VASH1 (2/2) mice [12]
We examined the role of endogenous VASH1 in cancer metastasis in relation to the interaction between cancer cells and the vasculature
Summary
Cancer is the leading cause of death worldwide, and most of cancer patients die because of metastasis. The tumor vasculature, a gateway of cancer cells for intravasation, is formed by the process known as angiogenesis, one of the principal hallmarks of cancers [3]. This process of angiogenesis includes the following sequential steps: detachment of surrounding mural cells from pre-existing vessels for the initiation of angiogenesis, extracellular matrix degradation by endothelial proteases, migration of endothelial cells (ECs) at the tip, proliferation of ECs at the stalk, tube formation by ECs, and redistribution and tight association of mural cells to ECs for vascular maturation and stabilization [4]. In addition to its anti-angiogenic activity, our recent analysis further demonstrated that VASH1 increases stress tolerance of ECs and stabilizes blood vessels [10]
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