期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：33
DOI：10.1073/pnas.2122716119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Cancer cell dissemination is the seed for metastasis and adversely linked to patients’ benefit. Critical for hematogenous dissemination is the entrance of the cancer cell into the circulation, which is regulated by vascular permeability within the primary tumor. Here, we describe pathophysiological communication between endothelial cells, tumor infiltrating neutrophils, and the complement system, with implications for vascular barrier opening and melanoma cell dissemination. Experiments in complement-deficient animals indicate that interference with complement-mediated activation of neutrophils stabilizes blood vessel integrity and abolishes the systemic spread of melanoma cells.
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.
