Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
Department of Dermatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim 68167, Germany.
Proc Natl Acad Sci U S A. 2022 Aug 16;119(33):e2122716119. doi: 10.1073/pnas.2122716119. Epub 2022 Aug 12.
The microenvironment of malignant melanomas defines the properties of tumor blood vessels and regulates infiltration and vascular dissemination of immune and cancer cells, respectively. Previous research in other cancer entities suggested the complement system as an essential part of the tumor microenvironment. Here, we confirm activation of the complement system in samples of melanoma patients and murine melanomas. We identified the tumor endothelium as the starting point of the complement cascade. Generation of complement-derived C5a promoted the recruitment of neutrophils. Upon contact with the vascular endothelium, neutrophils were further activated by complement membrane attack complexes (MACs). MAC-activated neutrophils release neutrophil extracellular traps (NETs). Close to the blood vessel wall, NETs opened the endothelial barrier as indicated by an enhanced vascular leakage. This facilitated the entrance of melanoma cells into the circulation and their systemic spread. Depletion of neutrophils or lack of MAC formation in complement component 6 (C6)-deficient animals protected the vascular endothelium and prevented vascular intravasation of melanoma cells. Our data suggest that inhibition of MAC-mediated neutrophil activation is a potent strategy to abolish hematogenous dissemination in melanoma.
恶性黑色素瘤的微环境决定了肿瘤血管的特性，并分别调节免疫细胞和癌细胞的浸润和血管扩散。先前在其他癌症实体中的研究表明，补体系统是肿瘤微环境的重要组成部分。在这里，我们证实了黑色素瘤患者和鼠类黑色素瘤样本中补体系统的激活。我们确定肿瘤内皮细胞是补体级联反应的起点。补体衍生的 C5a 的产生促进了中性粒细胞的募集。中性粒细胞与血管内皮接触后，进一步被补体膜攻击复合物（MAC）激活。MAC 激活的中性粒细胞释放中性粒细胞胞外诱捕网（NETs）。在靠近血管壁的地方，NETs 打开了内皮屏障，表现为血管通透性增强。这促进了黑色素瘤细胞进入循环系统并向全身扩散。中性粒细胞耗竭或补体成分 6（C6）缺陷动物中 MAC 形成的缺乏可保护血管内皮并防止黑色素瘤细胞的血管内渗。我们的数据表明，抑制 MAC 介导的中性粒细胞激活是一种有效的策略，可以消除黑色素瘤中的血行播散。
