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总体生存中的作用仍不清楚，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。诱导淋巴管激活对 116 名患者生存的影响，这是迄今为止研究的最大的 EMPD 队列与无肿瘤淋巴结相比，转移性淋巴结淋巴管生成显着增加（P =局部淋巴结内淋巴浸润的增加与局部淋巴结内的远处转移（P = 0.047）和器官（P = 0.003）显着相关，因此，局部淋巴结内的浸润是 EMPD 中全身性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 CXCR4 表达。在经历上皮-间质转化 (EMT) 样过程的侵袭性 Paget 细胞上过度表达 Snail，在 TGF-β1 存在的情况下表达增加的 CXCR4 水平，证实 Snail 诱导的 EMT 样过程促进肿瘤细胞运动。通过CXCR4-SDF-1轴，正弦淋巴管内皮细胞和巨噬细胞在被膜下表达SDF-1。我们的研究结果表明，EMT 相关特征可能通过激活 CXCR4-SDF-1 轴促进 EMPD 的淋巴转移。