Division of Molecular Medicine and Genetics, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan.
Microvasc Res. 2010 Jul;80(1):133-41. doi: 10.1016/j.mvr.2010.02.006. Epub 2010 Feb 11.
The spread of malignant cells from a localized tumor is thought to be directly related to the number of microvessels in the tumor. The endothelial cell-selective adhesion molecule (ESAM) is a member of the immunoglobulin superfamily that mediates homophilic interactions between endothelial cells. Previous studies have indicated that ESAM regulates angiogenesis in the primary tumor growth and endothelial permeability. In this study, we aimed to further elucidate the role of ESAM in tumor metastasis through angiogenic processes. ESAM expression was higher in hypervascular metastatic tumor tissues than in normal tissues in human lungs. Cell culture studies found that conditioned medium from B16F10 melanoma cells increased ESAM expression in endothelial cells and promoted endothelial migration and tube formation. The B16F10 medium-induced endothelial migration and tube formation were significantly attenuated when ESAM was downregulated by siRNA transfection. Intravenous injection of B16F10 cells into ESAM+/+ and ESAM-/- mice for comparison of metastatic potential resulted in the number of metastatic lung nodules in ESAM-/- mice being 83% lower than of those in ESAM+/+ mice. The microvascular density in the tumor was also lower in ESAM-/- than in ESAM+/+ mice. These findings indicate that ESAM regulates tumor metastasis through endothelial cell migration and tube formation in metastatic nodules. Inhibition of ESAM may therefore inhibit tumor metastasis by inhibiting the angiogenic processes.
恶性细胞从局部肿瘤扩散被认为与肿瘤中的微血管数量直接相关。内皮细胞选择性粘附分子（ESAM）是免疫球蛋白超家族的成员，介导内皮细胞之间的同型相互作用。先前的研究表明，ESAM 调节原发性肿瘤生长和内皮通透性中的血管生成。在这项研究中，我们旨在通过血管生成过程进一步阐明 ESAM 在肿瘤转移中的作用。人肺中高血管转移性肿瘤组织中的 ESAM 表达高于正常组织。细胞培养研究发现，B16F10 黑色素瘤细胞的条件培养基增加了内皮细胞中的 ESAM 表达，并促进了内皮细胞迁移和管形成。当通过 siRNA 转染下调 ESAM 时，B16F10 培养基诱导的内皮细胞迁移和管形成明显减弱。将 B16F10 细胞静脉注射到 ESAM+/+和 ESAM-/-小鼠中，比较转移潜能，结果显示 ESAM-/-小鼠的肺转移结节数量比 ESAM+/+小鼠低 83%。ESAM-/-小鼠肿瘤中的微血管密度也低于 ESAM+/+小鼠。这些发现表明，ESAM 通过调节转移结节中的内皮细胞迁移和管形成来调节肿瘤转移。因此，抑制 ESAM 可能通过抑制血管生成过程来抑制肿瘤转移。
