S100P regulates the collective invasion of pancreatic cancer cells into the lymphatic endothelial monolayer
S100P regulates the collective invasion of pancreatic cancer cells into the lymphatic endothelial monolayer
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DOI：
10.3892/ijo.2019.4812
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发表时间：
2019-07-01
影响因子：
5.2
通讯作者：
Nakamura, Masafumi
中科院分区：
文献类型：
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作者：
Nakayama, Hiromichi;Ohuchida, Kenoki;Nakamura, Masafumi
淋巴结转移是胰腺癌的独立预后因素。然而，淋巴结定植的机制尚不清楚。作为淋巴转移的一种机制，据报道，对于其他类型的癌症，来自肿瘤细胞的球体会在淋巴管单层内皮细胞中引起圆形化学排斥诱导缺陷（CCID）。在胰腺癌中，这种转移机制尚未阐明。本研究评估了这种新的胰腺癌转移机制的参与，并调查了相关因素。在人类胰腺癌组织中，观察到癌细胞簇穿透原发肿瘤周围的淋巴管壁。然后使用体外共培养系统来分析肿瘤细胞介导的淋巴管破坏的机制。延时显微成像显示，胰腺癌细胞的球体导致单层淋巴管内皮细胞出现圆形缺陷。 CCID 形成能力因细胞系而异。球体的聚集和淋巴管内皮细胞（LEC）的粘附均未表现出与这种现象的显着相关性。添加培养癌细胞的上清液增强了 CCID 的形成。微阵列分析显示，当用培养的癌细胞上清液处理 LEC 时，S100 钙结合蛋白 P (S100P) 的表达显着增加。添加 S100P 拮抗剂显着抑制了 LEC 的迁移和 CCID 的形成。目前的研究结果表明，胰腺癌细胞的球体导致单层淋巴管内皮细胞出现圆形缺陷。胰腺癌中的这些 CCID 部分受 S100P 调节，表明 S100P 可能是抑制淋巴结转移的有希望的靶点。
Lymph node metastasis is an independent prognostic factor in pancreatic cancer. However, the mechanisms of lymph node colonization are unknown. As a mechanism of lymphatic metastasis, it has been reported for other types of cancer that spheroids from tumor cells cause circular chemorepellent-induced defects (CCIDs) in lymphatic endothelial monolayers. In pancreatic cancer, such mechanisms of metastasis have not been elucidated. The present study evaluated the involvement of this new mechanism of metastasis in pancreatic cancer and investigated the associated factors. In human pancreatic cancer tissue, it was observed that clusters of cancer cells penetrated the wall of lymphatic ducts around the primary tumor. An in vitro co-culture system was then used to analyze the mechanisms of tumor cell-mediated disruption of lymphatic vessels. Time-lapse microscopic imaging revealed that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. CCID formation ability differed depending on the cell line. Neither aggregation of spheroids nor adhesion to lymphatic endothelial cells (LECs) exhibited a significant correlation with this phenomenon. The addition of supernatant from cultured cancer cells enhanced CCID formation. Microarray analysis revealed that the expression of S100 calcium binding protein P (S100P) was significantly increased when LECs were treated with supernatant from cultured cancer cells. Addition of a S100P antagonist significantly suppressed the migration of LECs and CCID formation. The present findings demonstrated that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. These CCIDs in pancreatic cancer were partly regulated by S100P, suggesting that S100P may be a promising target to inhibit lymph node metastasis.