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，淋巴结淋巴管生成在远处转移和癌症患者的总体存活中的作用尚不清楚。因此，我们研究了可能在乳腺外病（EMPD）中占据区域和遥远的LN转移的机制。我们回顾性地分析了肿瘤诱导的淋巴管活化对116例患者的存活的影响，这是迄今为止最大的EMPD队列。与无肿瘤的LN相比，转移性的淋巴结淋巴管生成显着增加（p = 0.022）。区域LN中淋巴侵袭的增加与LN（p = 0.047）和器官（p = 0.003）中的远处转移显着相关。这就是区域LNS内的侵袭是全身性肿瘤扩散和EMPD患者存活率降低的有力指标（p = 0.0004）。与表达基质细胞衍生因子-1（SDF-1）相关的淋巴血管，而CXCR4在经历上皮 - 间质转变（EMT）样过程的浸润性PAGET细胞上表达。在存在TGF-β1的情况下，过表达蜗牛过表达的CXCR4水平升高。 Haptotactic迁移分析证实，蜗牛诱导的类似EMT的过程通过CXCR4-SDF-1轴促进了肿瘤细胞的运动。正弦淋巴内皮细胞和巨噬细胞在PAGET细胞到来之前在淋巴结的亚囊窦中表达SDF-1。我们的发现表明，与EMT相关的特征可能通过激活CXCR4-SDF-1轴来促进EMPD的淋巴转移。