The antimetastatic role of thrombomodulin expression in islet cell-derived tumors and its diagnostic value
The antimetastatic role of thrombomodulin expression in islet cell-derived tumors and its diagnostic value
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DOI：
10.1158/1078-0432.ccr-03-0750
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发表时间：
2004-09-15
影响因子：
11.5
通讯作者：
Maruyama, I
中科院分区：
文献类型：
--
作者：
Iino, S;Abeyama, K;Maruyama, I
胰岛细胞瘤是一种起源于朗格汉斯胰岛的内分泌肿瘤，在组织学上难以诊断为良性或恶性。分子标记与临床特征相关，大多数胰岛素瘤通常是良性肿瘤，而其他胰岛细胞肿瘤是恶性的，但尚未确定。在这种情况下，我们新发现内皮抗凝血凝血调节蛋白在正常胰岛细胞和胰岛素瘤中表达，但在其他胰岛成分或非胰岛素瘤胰岛细胞肿瘤中不表达。临床结果显示，胰岛素瘤组15例患者均未出现转移，病灶内无血栓调节蛋白表达，而其他胰岛细胞肿瘤组转移发生率高（82%），血栓调节蛋白表达率低（6%）。为了研究血栓调节蛋白的功能作用，特别是关于胰岛细胞肿瘤的临床特征，我们使用MIN6胰岛素瘤细胞系测试了外源性血栓调节蛋白过表达对细胞粘附性和增殖的影响。在基于细胞的实验中，血栓调节蛋白过表达降低细胞增殖，增强Ca2+非依赖性细胞聚集，可能是通过与神经细胞粘附分子的直接相互作用。综上所述，这些结果提示血栓调节蛋白可能作为胰岛素瘤的抗转移分子。此外，血栓调节蛋白是临床上有用的分子标志物，不仅可用于鉴别β细胞来源的胰岛细胞肿瘤（即胰岛素瘤），而且可用于预测胰岛细胞肿瘤的疾病预后。
Islet cell tumors, endocrine neoplasm arising from pancreatic islets of Langerhans, are histologically difficult to diagnose as benign or malignant. Molecular markers are associated with the clinical characteristics that most of insulinoma are usually benign tumors, whereas other islet cell tumors are malignant but have not been identified. In this context, we newly found that an endothelial anticoagulant thrombomodulin was expressed in the normal islet 0 cells and insulinoma, but not of other islet components or non-insulinoma islet cell tumors. Clinically, all of the subjects (n = 15) of the insulinoma group showed no metastasis together with thrombomodulin expression in the lesions, whereas the other islet cell tumor groups showed a high incidence of metastasis (82%) and a low expression rate of thrombomodulin (6%). To examine the functional role of thrombomodulin, especially regarding the clinical characteristics of islet cell tumors, we tested the effect of exogenous thrombomodulin overexpression on cell adhesiveness and proliferation using MIN6 insulinoma cell line. In cell-based experiments, thrombomodulin overexpression reduced cell proliferation and enhanced Ca2+-independent cell aggregation, possibly through direct interaction with neural cell adhesion molecule. Taken together, these results are suggesting that thrombomodulin may act as antimetastatic molecule of insulinomas. In addition, thrombomodulin is a clinically useful molecular marker not only for identifying beta-cell-origin islet cell tumors (i.e., insulinomas) but also for predicting disease prognosis of islet cell tumors.