Malignant T cells express lymphotoxin α and drive endothelial activation in cutaneous T cell lymphoma

• Published in: Oncotarget 2015-06, Vol.6 (17), p.15235-15249
• Main Authors: Lauenborg, Britt, Christensen, Louise, Ralfkiaer, Ulrik, Kopp, Katharina L, Jønson, Lars, Dabelsteen, Sally, Bonefeld, Charlotte M, Geisler, Carsten, Gjerdrum, Lise Mette R, Zhang, Qian, Wasik, Mariusz A, Ralfkiaer, Elisabeth, Ødum, Niels, Woetmann, Anders
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Binding Sites - genetics; DNA-Binding Proteins - metabolism; Endothelial Cells - metabolism; Female; Human Umbilical Vein Endothelial Cells; Humans; Interleukin-6 - metabolism; Janus Kinase 3 - genetics; Janus Kinase 3 - metabolism; Lymphatic Metastasis - pathology; Lymphoma, T-Cell, Cutaneous - pathology; Lymphotoxin-alpha - metabolism; Male; Middle Aged; Neovascularization, Pathologic - pathology; NF-kappa B - metabolism; Promoter Regions, Genetic - genetics; Receptors, Tumor Necrosis Factor, Type II - metabolism; Research Paper; RNA Interference; RNA, Small Interfering; Skin Neoplasms - pathology; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - metabolism; T-Lymphocytes - pathology; Tumor Cells, Cultured; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.3837

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.