Chemokine-mediated migration of melanoma cells towards lymphatics - a mechanism contributing to metastasis
Chemokine-mediated migration of melanoma cells towards lymphatics - a mechanism contributing to metastasis
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DOI：
10.1038/sj.onc.1210114
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发表时间：
2007-05-10
期刊：
影响因子：
8
通讯作者：
Bates, D. O.
中科院分区：
文献类型：
--
作者：
Shields, J. D.;Emmett, M. S.;Bates, D. O.
导致黑色素瘤等肿瘤转移到外周毛细淋巴管的机制尚不清楚。非互斥机制是淋巴内皮细胞（LEC）响应肿瘤细胞的趋化和增殖（趋化性-淋巴管生成假说）或LEC可能分泌吸引癌细胞的趋化剂（趋化转移假说）。通过迁移测定，我们发现了支持这两种假设的证据。来自转移性恶性黑色素瘤 (MMM) 细胞系的条件培养基 (CM) 吸引 LEC 迁移，这与淋巴管生成假说一致。相反，来自混合内皮细胞或 LEC（而非血液内皮细胞）的 CM 吸引 MMM 细胞，但不吸引非转移性黑色素瘤细胞，这与趋化性转移假说一致。 MMM 细胞系表达淋巴趋化因子 CCL21 的 CCR7 受体，并且 CCL21 中和抗体在体外阻止 MMM 趋化性。为了测试体内趋化转移，将肿瘤细胞异种移植到裸鼠体内，距离注射的 LEC 库大约 1 厘米。两种不同的 MMM 定向向 LEC 生长，而非转移性黑色素瘤则不然。这些观察结果支持这样的假设：MMM 细胞由于趋化 LEC 分泌（包括 CCL21）而向高 LEC 密度区域生长。这种趋化转移可能有助于转移肿瘤细胞与肿瘤周围淋巴密度之间的密切联系，并促进淋巴侵袭。
The mechanisms that cause tumors such as melanomas to metastasize into peripheral lymphatic capillaries are poorly defined. Non-mutually-exclusive mechanisms are lymphatic endothelial cell ( LEC) chemotaxis and proliferation in response to tumor cells ( chemotaxis-lymphangiogenesis hypothesis) or LECs may secrete chemotactic agents that attract cancer cells ( chemotactic metastasis hypothesis). Using migration assays, we found evidence supporting both hypotheses. Conditioned medium ( CM) from metastatic malignant melanoma ( MMM) cell lines attracted LEC migration, consistent with the lymphangiogenesis hypothesis. Conversely, CM from mixed endothelial cells or LECs, but not blood endothelial cells, attracted MMM cells but not non-metastatic melanoma cells, consistent with the chemotactic metastasis hypothesis. MMM cell lines expressed CCR7 receptors for the lymphatic chemokine CCL21 and CCL21 neutralizing antibodies prevented MMM chemotaxis in vitro. To test for chemotactic metastasis in vivo tumor cells were xenotransplanted into nude mice similar to 1 cm from an injected LEC depot. Two different MMM grew directionally towards the LECs, whereas non-metastatic melanomas did not. These observations support the hypothesis that MMM cells grow towards regions of high LEC density owing to chemotactic LEC secretions, including CCL21. This chemotactic metastasis may contribute to the close association between metastasizing tumor cells and peritumor lymphatic density and promote lymphatic invasion.