Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma
Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma
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DOI：
10.1038/nature13111
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发表时间：
2014-03-06
期刊：
影响因子：
64.8
通讯作者：
Tueting, Thomas
中科院分区：
文献类型：
--
作者：
Bald, Tobias;Quast, Thomas;Tueting, Thomas
间歇性强紫外线（UV）暴露是恶性黑色素瘤发生的一个重要病因因素（1）。紫外线辐射引起黑色素细胞中肿瘤起始DNA突变的能力现已得到证实（2），但紫外线辐射的微环境效应（3，4）如何影响黑色素瘤发病机制尚未完全了解。在这里，我们报告了在基因工程小鼠模型中原发性皮肤黑色素瘤的重复紫外线暴露（5）促进转移进展，与其肿瘤起始效应无关。紫外线照射增强了肿瘤细胞沿着近腔血管表面的扩张，并增加了肺转移的数量。这种效应依赖于中性粒细胞的募集和活化，由高迁移率族蛋白1（HMGB 1）从紫外线损伤的表皮角质形成细胞中释放启动，并由Toll样受体4（TLR 4）驱动。紫外线诱导的嗜酸性炎症反应刺激血管生成，并促进黑色素瘤细胞向内皮细胞迁移的能力，并在其表面上使用选择性运动线索。我们的研究结果不仅揭示了先天免疫系统如何感知表皮角质形成细胞的紫外线照射，而且还表明，所产生的炎症反应催化了相互的黑素瘤-内皮细胞相互作用，导致血管周围浸润，这一现象最初被组织病理学家描述为人类黑素瘤中的血管生成性（6）。向血管性是一种迄今未被充分认识的转移机制（7），它也增加了血管内浸润和血行播散的可能性。与我们的研究结果一致，溃疡性原发性人黑色素瘤伴有大量中性粒细胞和反应性血管生成，经常表现出血管生成倾向和转移的高风险。我们的工作表明，针对炎症诱导的黑色素瘤细胞的表型可塑性及其与内皮细胞的关联代表了特异性干扰转移进展的合理策略。
Intermittent intense ultraviolet (UV) exposure represents an important aetiological factor in the development of malignant melanoma(1). The ability of UV radiation to cause tumour-initiating DNA mutations in melanocytes is now firmly established(2), but how the microenvironmental effects of UV radiation(3,4) influence melanoma pathogenesis is not fully understood. Here we report that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model(5) promotes metastatic progression, independent of its tumour-initiating effects. UV irradiation enhanced the expansion of tumour cells along abluminal blood vessel surfaces and increased the number of lung metastases. This effect depended on the recruitment and activation of neutrophils, initiated by the release of high mobility group box 1 (HMGB1) from UV-damaged epidermal keratinocytes and driven by Toll-like receptor 4 (TLR4). The UV-induced neutrophilic inflammatory response stimulated angiogenesis and promoted the ability of melanoma cells to migrate towards endothelial cells and use selective motility cues on their surfaces. Our results not only reveal how UV irradiation of epidermal keratinocytes is sensed by the innate immune system, but also show that the resulting inflammatory response catalyses reciprocal melanoma-endothelial cell interactions leading to perivascular invasion, a phenomenon originally described as angiotropism in human melanomas by histopathologists(6). Angiotropism represents a hitherto underappreciated mechanism of metastasis(7) that also increases the likelihood of intravasation and haematogenous dissemination. Consistent with our findings, ulcerated primary human melanomas with abundant neutrophils and reactive angiogenesis frequently show angiotropism and a high risk for metastases. Our work indicates that targeting the inflammation-induced phenotypic plasticity of melanoma cells and their association with endothelial cells represent rational strategies to specifically interfere with metastatic progression.