Low-molecular-weight hyaluronan (LMW-HA) accelerates lymph node metastasis of melanoma cells by inducing disruption of lymphatic intercellular adhesion
Low-molecular-weight hyaluronan (LMW-HA) accelerates lymph node metastasis of melanoma cells by inducing disruption of lymphatic intercellular adhesion
复制标题
低分子量透明质酸（LMW-HA）通过诱导淋巴细胞间粘附破坏加速黑色素瘤细胞的淋巴结转移
DOI：
10.1080/2162402x.2016.1232235
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Gao, Feng
中科院分区：
文献类型：
--
作者：
Du, Yan;Cao, Manlin;Gao, Feng
内皮完整性缺陷引发肿瘤细胞的淋巴转移。来自血浆和间质液的低分子量透明质酸（LMW-HA）被报道与肿瘤淋巴转移有关。此外，LMW-HA被证明破坏淋巴管内皮的完整性，从而促进肿瘤细胞的淋巴转移。迄今为止，关于LMW-HA如何调节淋巴管内皮细胞粘附连接和影响癌细胞向淋巴管转移的报道很少。本研究的目的是阐明LMW-HA介导肿瘤淋巴转移的新机制。在这里，我们采用黑色素瘤转移模型来研究LMW-HA是否通过破坏淋巴管内皮完整性来促进肿瘤细胞从病灶转移到远处淋巴结。我们的数据表明，LMW-HA显着诱导黑色素瘤细胞转移到淋巴结，并加速体内的腹膜淋巴流。进一步的实验表明，黑素瘤细胞穿过人真皮淋巴内皮细胞（HDLEC）单层的迁移增加伴随着淋巴内皮屏障功能受损和渗透性增加。机制研究表明，VE-钙粘蛋白-β-连环蛋白通路及相关信号参与调节内皮细胞间的相互作用，LMW-HA受体（LYVE-1）抗体可显著抑制淋巴管内皮细胞的破坏。因此，我们的研究结果表明，LMW-HA对淋巴管内皮连续性的破坏性影响，导致促进黑色素瘤淋巴转移，也表明了与VE-钙粘蛋白介导的淋巴细胞间连接相关的细胞信号传导机制。
Endothelial integrity defects initiate lymphatic metastasis of tumor cells. Low-molecular-weight hyaluronan (LMW-HA) derived from plasma and interstitial fluid was reported to be associated with tumor lymphatic metastasis. In addition, LMW-HA was proved to disrupt lymphatic vessel endothelium integrity, thus promoting lymphatic metastasis of tumor cells. Until now, there are few reports on how LMW-HA modulates lymphatic endothelial cells adhesion junctions and affects cancer cells metastasizing into lymph vessels. The aim of our study is to unravel the novel mechanism of LMW-HA in mediating tumor lymphatic metastasis. Here, we employed a melanoma metastasis model to investigate whether LMW-HA facilitates tumor cells transferring from foci to remote lymph nodes by disrupting the lymphatic endothelial integrity. Our data indicate that LMW-HA significantly induces metastasis of melanoma cells to lymph nodes and accelerates interstitial-lymphatic flow in vivo. Further experiments show that increased migration of melanoma cells across human dermal lymphatic endothelial cell (HDLEC) monolayers is accompanied by impaired lymphatic endothelial barrier function and increased permeability. The mechanism study reveals that VE-cadherin-beta-catenin pathway and relevant signals are involved in modulating the interactions between endothelial cells and that a significant inhibition of lymphatic endothelium disruption is observed when antibodies to the LMW-HA receptor (LYVE-1) are present. Thus, our findings demonstrate a disruptive effect of LMW-HA on lymphatic endothelium continuity which leads to a promotion on melanoma lymphatic metastasis and also suggest a cellular signaling mechanism associated with VE-cadherin-mediated lymphatic intercellular junctions.