Abstract
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.
Highlights
Cutaneous T cell lymphomas (CTCLs) are a group of lymphoproliferative disorders characterized by a clonal expansion of T cells primarily in the skin
Malignant T cell lines from CTCL patients displayed a constitutive synthesis of Lymphotoxin α (LTα) as judged from the high concentrations (> 5 ng/ml) of the cytokine found in culture supernatants (Figure 1C)
We provide evidence that LTα and TNFR2 are expressed in malignant T cell lines and lymphocytes with malignant cell morphology in situ in skin lesions suggesting that LTα plays a role in the pathogenesis of CTCL
Summary
Cutaneous T cell lymphomas (CTCLs) are a group of lymphoproliferative disorders characterized by a clonal expansion of T cells primarily in the skin. Mycosis fungoides (MF) is the most common type of CTCL and accounts for about 50% of all patients with cutaneous lymphomas [1]. Classical MF progresses through three stages - the patch stage, the plaque stage and the tumor stage. The clinical course of MF is usually indolent and the patch and plaque stages are associated with good prognosis. Abnormalities in cytokine production [6,7,8,9,10], a cytokine-independent constitutive activation of the Janus kinases (JAKs)/ Signal transducer and activator of transcription (STAT) pathway [11,12,13] and aberrant regulation of nuclear factor κB (NFκB) [14,15,16,17] are known to play a key role in the pathogenesis of CTCL
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