Daneker G W, Lund S A, Caughman S W, Staley C A, Wood W C
Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA.
Clin Exp Metastasis. 1996 May;14(3):230-8. doi: 10.1007/BF00053896.
Prostacyclins have long been shown to have anti-metastatic activity. One hypothesis is their modulation of cell adhesion molecule (CAM) expression by target organ endothelial cells. We have postulated that prostacyclin, its analogs, and mechanistic mimics decrease colon carcinoma adhesion to cytokine-stimulated endothelial cells by blocking endothelial expression of the adhesion molecule E-selectin, but not the vascular cell adhesion molecule-1 (VCAM-1). Cultured human microvascular endothelial cells (HDMEC) were pre-incubated with prostacyclin (PGI2), dibutyrl-cAMP (dbcAMP), forskolin (FOR), and/or iso-methylbutylxanthine (IBMX) for 15 min, then co-incubated with the cytokine tumor necrosis factor (TNF) for 4 h. HDMEC surface expression of E-selectin and VCAM-1 was evaluated by flow cytometry and ELISA. Adherence of 51Cr-labeled colon carcinoma cells to HDMEC monolayers was then determined. In parallel assays, HDMECs were incubated with anti-E-selectin and anti-VCAM-1 monoclonal antibody (1:100) prior to the addition of tumor cells. Prostacyclins, its analogs, and mimics significantly reduced E-selectin expression by HDMEC, while the reduction of VCAM-1 expression was much less pronounced. Prostacyclins also significantly decreased colon carcinoma adherence to stimulated HDMECs. The inhibition of E-selectin expression, but not VCAM-1 expression, corresponded to the reduction of tumor cell adherence. Prostacyclin's effects on tumor adhesion were nullified by pre-incubation with E-selectin antibody. The inhibition of colon carcinoma adherence to cytokine-stimulated endothelial cells treated with prostacyclin, its analogs, and mimics appears to result from blocking endothelial E-selectin, but not VCAM-1, expression. These data support the hypothesis that prostacyclins may exert their anti-metastatic effect, in part, by inhibiting CAM-mediated adherence of colon carcinoma to endothelial cells in metastatic target organs.
长期以来，前列环素已被证明具有抗转移活性。一种假说是它们通过靶器官内皮细胞调节细胞粘附分子（CAM）的表达。我们推测，前列环素及其类似物以及机制模拟物可通过阻断粘附分子E-选择素的内皮表达，而非血管细胞粘附分子-1（VCAM-1）的内皮表达，来降低结肠癌细胞对细胞因子刺激的内皮细胞的粘附。将培养的人微血管内皮细胞（HDMEC）与前列环素（PGI2）、二丁酰环磷腺苷（dbcAMP）、福斯可林（FOR）和/或异丁基甲基黄嘌呤（IBMX）预孵育15分钟，然后与细胞因子肿瘤坏死因子（TNF）共孵育4小时。通过流式细胞术和酶联免疫吸附测定法评估HDMEC表面E-选择素和VCAM-1的表达。然后测定51Cr标记的结肠癌细胞对HDMEC单层的粘附。在平行试验中，在添加肿瘤细胞之前，将HDMEC与抗E-选择素和抗VCAM-1单克隆抗体（1:100）孵育。前列环素及其类似物和模拟物显著降低了HDMEC的E-选择素表达，而VCAM-1表达的降低则不太明显。前列环素还显著降低了结肠癌细胞对刺激的HDMEC的粘附。E-选择素表达的抑制而非VCAM-1表达的抑制与肿瘤细胞粘附的减少相对应。用E-选择素抗体预孵育可消除前列环素对肿瘤粘附的影响。前列环素及其类似物和模拟物对细胞因子刺激的内皮细胞处理后结肠癌细胞粘附的抑制作用似乎是由于阻断了内皮E-选择素的表达，而非VCAM-1的表达。这些数据支持了这样一种假说，即前列环素可能部分通过抑制CAM介导的结肠癌细胞在转移靶器官中对内皮细胞的粘附来发挥其抗转移作用。
