Malignant T cells express lymphotoxin α and drive endothelial activation in cutaneous T cell lymphoma.
Lymphotoxin α (LTα) plays a key role in the formation of lymphatic vasculature and secondary lymphoid structures. Cutaneous T cell lymphoma (CTCL) is the most common primary lymphoma of the skin and in advanced stages, malignant T cells spreads through the lymphatic to regional lymph nodes to internal organs and blood. Yet, little is known about the mechanism of the CTCL dissemination. Here, we show that CTCL cells express LTα in situ and that LTα expression is driven by aberrantly activated JAK3/STAT5 pathway. Importantly, via TNF receptor 2, LTα functions as an autocrine factor by stimulating expression of IL-6 in the malignant cells. LTα and IL-6, together with VEGF promote angiogenesis by inducing endothelial cell sprouting and tube formation. Thus, we propose that LTα plays a role in malignant angiogenesis and disease progression in CTCL and may serve as a therapeutic target in this disease.
Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Britt
B
Lauenborg
Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Louise
L
Christensen
Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark.
Ulrik
U
Ralfkiaer
Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Katharina L
KL
Kopp
Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark.
Lars
L
Jønson
Department of Oral Medicine and Pathology, School of Dentistry, University of Copenhagen, Copenhagen, Denmark.
Sally
S
Dabelsteen
Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Charlotte M
CM
Bonefeld
Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Carsten
C
Geisler
Department of Pathology, Roskilde Hospital, Roskilde, Denmark.
Lise Mette R
LM
Gjerdrum
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Qian
Q
Zhang
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Mariusz A
MA
Wasik
Department of Pathology, Copenhagen University Hospital, Copenhagen, Denmark.
Elisabeth
E
Ralfkiaer
Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Niels
N
Ødum
Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Anders
A
Woetmann
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001665:Binding Sites / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism; D008207:Lymphatic Metastasis / Q000473:pathology; D016410:Lymphoma, T-Cell, Cutaneous / Q000473:pathology*; D008233:Lymphotoxin-alpha / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000473:pathology*; D013601:T-Lymphocytes / Q000473:pathology; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D004268:DNA-Binding Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D008233:Lymphotoxin-alpha; D016328:NF-kappa B; D034741:RNA, Small Interfering; D047889:Receptors, Tumor Necrosis Factor, Type II; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D025521:Tumor Suppressor Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C507933:JAK3 protein, human; D053616:Janus Kinase 3
CTCL; LTA; angiogenesis