Neutrophils activated by membrane attack complexes increase the permeability of melanoma blood vessels
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Neutrophils activated by membrane attack complexes increase the permeability of melanoma blood vessels. / Liu, Xiaobo; Wang, Yuanyuan; Bauer, Alexander T; Kirschfink, Michael; Ding, Peipei; Gebhardt, Christoffer; Borsig, Lubor; Tüting, Thomas; Renné, Thomas; Häffner, Karsten; Hu, Weiguo; Schneider, Stefan W; Gorzelanny, Christian.
In: P NATL ACAD SCI USA, Vol. 119, No. 33, e2122716119, 16.08.2022.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Neutrophils activated by membrane attack complexes increase the permeability of melanoma blood vessels
AU - Liu, Xiaobo
AU - Wang, Yuanyuan
AU - Bauer, Alexander T
AU - Kirschfink, Michael
AU - Ding, Peipei
AU - Gebhardt, Christoffer
AU - Borsig, Lubor
AU - Tüting, Thomas
AU - Renné, Thomas
AU - Häffner, Karsten
AU - Hu, Weiguo
AU - Schneider, Stefan W
AU - Gorzelanny, Christian
PY - 2022/8/16
Y1 - 2022/8/16
N2 - 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.
AB - 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.
U2 - 10.1073/pnas.2122716119
DO - 10.1073/pnas.2122716119
M3 - SCORING: Journal article
C2 - 35960843
VL - 119
JO - P NATL ACAD SCI USA
JF - P NATL ACAD SCI USA
SN - 0027-8424
IS - 33
M1 - e2122716119
ER -