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Molecular mechanisms of lymphangiogenesis in cutaneous neoplasms

皮肤肿瘤淋巴管生成的分子机制

基本信息

批准号：
20013032
负责人：
HIRAKAWA Satoshi
金额：
$ 11.52万
依托单位：
Ehime University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2009
项目状态：
已结题

项目摘要

However, the role of nodal lymphangiogenesis in distant metastasis and in the overall survival of cancer patients remains unknown. Therefore, we investigated mechanisms that might facilitate regional and distant LN metastasis in extramammary Paget's disease (EMPD). We retrospectively analyzed the impact of tumor-induced lymphatic vessel activation on the survival of 116 patients, the largest cohort with EMPD studied to date. Nodal lymphangiogenesis was significantly increased in metastatic, compared with tumor-free LNs (P = 0.022). Increased lymphatic invasion within regional LNs was significantly associated with distant metastasis in LN (P = 0.047) and organs (P = 0.003). Thus, invasion within regional LNs is a powerful indicator of systemic tumor spread and reduced patient survival in EMPD (P = 0.0004). Lymphatic vessels associated with tumors expressed stromal cell-derived factor-1 (SDF-1), whereas CXCR4 was expressed on invasive Paget cells undergoing epithelial-mesenchymal transition (EMT)-like process. A431 cells overexpressing Snail expressed increased levels of CXCR4 in the presence of TGF-β1. Haptotactic migration assays confirmed that Snail-induced EMT-like process promotes tumor cell motility via the CXCR4-SDF-1 axis. Sinusoidal lymphatic endothelial cells and macrophages expressed SDF-1 in subcapsular sinuses of lymph nodes before Paget cell arrival. Our findings reveal that EMT-related features likely promote lymphatic metastasis of EMPD by activating the CXCR4-SDF-1 axis.

然而，淋巴结的淋巴管生成在远处转移和癌症患者的总体生存中的作用仍然未知。因此，我们研究了可能促进乳腺外佩吉特病（EMPD）局部和远处淋巴结转移的机制。我们回顾性分析了肿瘤诱导的淋巴管活化对116例EMPD患者生存率的影响，这是迄今为止研究的最大EMPD队列。淋巴结转移的淋巴管生成显著增加，与无瘤淋巴结相比（P = 0.022）。局部淋巴结内淋巴管浸润的增加与淋巴结（P = 0.047）和器官（P = 0.003）的远处转移显著相关。因此，局部淋巴结内的浸润是EMPD患者全身肿瘤扩散和患者生存率降低的有力指标（P = 0.0004）。与肿瘤相关的淋巴管表达基质细胞衍生因子-1（SDF-1），而CXCR 4在经历上皮-间质转化（EMT）样过程的侵袭性佩吉特细胞上表达。在TGF-β1存在下，过表达Snail的A431细胞表达CXCR 4水平增加。趋化迁移实验证实Snail诱导的EMT样过程通过CXCR 4-SDF-1轴促进肿瘤细胞运动。在佩吉特细胞到达淋巴结前，淋巴窦内皮细胞和巨噬细胞在淋巴结被膜下窦表达SDF-1。我们的研究结果表明，EMT相关的功能可能通过激活CXCR 4-SDF-1轴促进EMPD的淋巴转移。