Molecular mechanisms of lymphangiogenesis in cutaneous neoplasms

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尚不清楚。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。我们回顾性分析了肿瘤诱导的淋巴管激活对116例患者生存的影响，这是迄今为止研究的最大的EMPD队列。与无肿瘤的淋巴结相比，淋巴结淋巴管生成在转移灶中显著增加（P = 0.022）。局部淋巴结浸润增加与淋巴结远处转移（P = 0.047）和器官远处转移（P = 0.003）显著相关。因此，局部淋巴结内的侵袭是EMPD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在侵袭性Paget细胞上进行上皮-间质转化（EMT）样过程表达。过表达Snail的A431细胞在TGF-β1存在时表达CXCR4水平升高。触致迁移实验证实，蜗牛诱导的emt样过程通过CXCR4-SDF-1轴促进肿瘤细胞运动。淋巴窦内皮细胞和巨噬细胞在Paget细胞到达前在淋巴结包膜下窦表达SDF-1。我们的研究结果表明，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。

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.