Nodal Lymphangiogenesis and Metastasis Role of Tumor-Induced Lymphatic Vessel Activation in Extramammary Paget's Disease
Nodal Lymphangiogenesis and Metastasis Role of Tumor-Induced Lymphatic Vessel Activation in Extramammary Paget's Disease
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DOI：
10.2353/ajpath.2009.090420
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发表时间：
2009-11-01
影响因子：
6
通讯作者：
Hashimoto, Koji
中科院分区：
文献类型：
--
作者：
Hirakawa, Satoshi;Detmar, Michael;Hashimoto, Koji
在实验性癌症模型中，淋巴管生成促进远处淋巴结（LN）转移。然而，淋巴结内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。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。与无瘤淋巴结相比，转移性淋巴结的淋巴管生成显著增加（P = 0.022）。局部淋巴结内淋巴管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。在转化生长因子β 1存在下，过表达Snail的A431细胞表达CXCR 4水平增加。触针迁移试验证实，蜗牛诱导的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。(Am J pathol 2009，175：2235-2248; DOI：10.2353/ajpath.2009.090420）
Nodal lymphangiogenesis promotes distant lymph node (LN) metastasis in experimental cancer models. However, the role of nodal lymphangiogenesis hi 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 transforming growth factor-beta 1. 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. (Am J pathol 2009, 175:2235-2248; DOI: 10.2353/ajpath.2009.090420)