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Nature:德国波恩大学揭示晒伤是如何导致黑色素瘤发生的

2014-03-03 16:42  
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德国波恩大学的研究人员利用现代荧光和电子显微镜方法,发现晒伤不仅直接改变色素细胞的基因组,还间接通过周围组织中的炎症过程促成了黑色素瘤形成。相关文章发表于2014年2月26日的《Nature》杂志上。

由于能够在肺、肝脏或大脑等重要器官中形成转移灶,黑色素瘤尤其危险。紫外线辐射被视作是最重要的引发因子。

根据Robert Koch研究所的预测,2014年德国大约将会有2万人形成恶性黑色素瘤。超过2500名受累患者将因癌症转移至内部器官而死。“严重日照后皮肤的炎症反应促进了黑色素瘤细胞沿着体内血管早期迁移,”研究小组的领导者、伯恩大学医院实验皮肤病学教授Thomas Tüting说。

黑色素瘤细胞沿着血管迁移

为了了解恶性黑色素瘤的形成及早期迁移,研究人员开发出了一些小鼠实验模型使得他们能够调查紫外线辐射后炎症反应的影响。

皮肤病学家Evelyn Gaffa博士说:“我们多次观察到在紫外线辐射小鼠的肺脏中黑色素瘤转移灶增多。”分析黑色素瘤组织切片揭示肿瘤细胞沿着炎症皮肤表面的血管扩散。利用现代荧光和电子显微镜方法,研究人员观察到了黑色素瘤细胞、内血管壁和免疫细胞,尤其是中性粒细胞之间的密切联系。

激活的中性粒细胞为黑色素细胞铺平道路

进一步的实验表明,中性粒细胞在转移过程中发挥重要作用。它们被紫外线损伤表皮角质细胞发出的警报信号所吸引。研究人员利用缺失激活先天免疫防御必需重要分子的特殊小鼠品系阐明了潜在的信号通路。

炎症介质促进黑素细胞运动

波恩大学LIMES研究所研究人员开发了一些新实验方法,调查了黑色素瘤细胞与内血管壁细胞(内皮细胞)之间的相互作用。在此过程中,他们观察到血管表面的黑色素瘤细胞能够尤其有效地迁移。“在炎症环境黑色素瘤细胞的运动性增加,”Waldemar Kolanus教授说。

利用人类黑色素瘤细胞以及现代基因组学方法开展进一步的调查,提供了有关炎症介质如何刺激黑色素瘤细胞迁移的一些新认识。“在胚胎发育过程中色素细胞前体沿着体内血管长距离移动以到达皮肤中他们最终的目的地。在黑色素瘤细胞中炎症错误地重新激活了这些迁移程序,”临床化学和临床药理学研究所Michael H?lzel教授说。

“我们的研究结果或许可以解释,为何有表面溃烂黑色素瘤以及中心粒细胞浸润的患者往往会形成器官转移灶,”Tüting教授说。研究人员希望在未来开发出新的靶向疗法,特异地干扰炎症信号级联反应并抑制黑色素瘤细胞在血管的表面迁移。

原文摘要:

Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma

Tobias Bald, Thomas Quast, Jennifer Landsberg, Meri Rogava, Nicole Glodde, Dorys Lopez-Ramos, Judith Kohlmeyer, Stefanie Riesenberg, Debby van den Boorn-Konijnenberg, Cornelia H?mig-H?lzel, Raphael Reuten, Benjamin Schadow, Heike Weighardt, Daniela Wenzel, Iris Helfrich, Dirk Schadendorf, Wilhelm Bloch, Marco E. Bianchi, Claire Lugassy, Raymond L. Barnhill, Manuel Koch, Bernd K. Fleischmann,Irmgard F?rster, Wolfgang Kastenmüller, Waldemar Kolanus et al.

Intermittent intense ultraviolet (UV) exposure represents an important aetiological factor in the development of malignant melanoma. The ability of UV radiation to cause tumour-initiating DNA mutations in melanocytes is now firmly established, but how the microenvironmental effects of UV radiation influence melanoma pathogenesis is not fully understood. Here we report that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model 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. Angiotropism represents a hitherto underappreciated mechanism of metastasis7that 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.

Figure 1: UV irradiation of skin with DMBA-initiated primary melanomas in HGF-CDK4(R24C) mice selectively promotes angiotropic invasion and lung metastasis.

UV irradiation of skin with DMBA-initiated primary melanomas in HGF-CDK4(R24C) mice selectively promotes angiotropic invasion and lung metastasis.

a, Experimental model. b, Macroscopic appearance (left), mean number (middle) and growth kinetics (right) of DMBA-induced skin melanomas in representative cohorts of 5 UV-exposed and control mice. c, Macroscopic appearance of lung meta…

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