恶性T细胞表达淋巴毒素α并驱动皮肤T细胞淋巴瘤中的内皮细胞活化。

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

作者信息

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

机构信息

Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.

Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark.

出版信息

Oncotarget. 2015 Jun 20;6(17):15235-49. 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.

淋巴毒素α（LTα）在淋巴管系统和二级淋巴结构的形成中起关键作用。皮肤T细胞淋巴瘤（CTCL）是最常见的原发性皮肤淋巴瘤，在晚期，恶性T细胞通过淋巴管扩散至区域淋巴结、内部器官和血液。然而，关于CTCL扩散的机制知之甚少。在此，我们表明CTCL细胞原位表达LTα，且LTα的表达由异常激活的JAK3/STAT5通路驱动。重要的是，通过肿瘤坏死因子受体2，LTα通过刺激恶性细胞中白细胞介素-6的表达而作为自分泌因子发挥作用。LTα和白细胞介素-6与血管内皮生长因子（VEGF）一起，通过诱导内皮细胞芽生和管腔形成来促进血管生成。因此，我们提出LTα在CTCL的恶性血管生成和疾病进展中起作用，并可能成为该疾病的治疗靶点。