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Molecular Targets for Therapy

Jak3- and JNK-dependent vascular endothelial growth factor expression in cutaneous T-cell lymphoma

Leukemia volume 20, pages 1759–1766 (2006)Cite this article

Abstract

Biopsies from patients with cutaneous T-cell lymphoma (CTCL) exhibit stage-dependent increase in angiogenesis. However, the molecular mechanisms responsible for the increased angiogenesis are unknown. Here we show that malignant CTCL T cells spontaneously produce the potent angiogenic protein, vascular endothelial growth factor (VEGF). Dermal infiltrates of CTCL lesions show frequent and intense staining with anti-VEGF antibody, indicating a steady, high production of VEGF in vivo. Moreover, the VEGF production is associated with constitutive activity of Janus kinase 3 (Jak3) and the c-Jun N-terminal kinases (JNKs). Sp600125, an inhibitor of JNK activity and activator protein-1 (AP-1) binding to the VEGF promoter, downregulates the VEGF production without affecting Jak3 activity. Similarly, inhibitors of Jak3 inhibit the VEGF production without affecting JNK activity. Downregulation of Stat3 with small interfering RNA has no effect, whereas curcumin, an inhibitor of both Jak3 and the JNKs, almost completely blocks the VEGF production. In conclusion, we provide evidence of VEGF production in CTCL, which is promoted by aberrant activation of Jak3 and the JNKs. Inhibition of VEGF-inducing pathways or neutralization of VEGF itself could represent novel therapeutic modalities in CTCL.

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Acknowledgements

This work was supported in part by The Danish Research Councils, The Danish Cancer Society, The Novo Nordic Foundation, Fabrikant Vilhelm Pedersen og Hustrus Mindelegat, Dansk Kræftsforsknings Fond, scholarship from the The Danish Cancer Society (T Krejsgaard), the Deutsche Forschungsgemeinschaft (KFO124) (JC Becker) and Købmand i Odense Johann og Hanne Weimann f. Seedroffs Legat (T Labuda). We express our appreciation to Claudia Siedel for her excellent technical assistance and to Eva-Bettina Bröcker for critical discussions during the evaluation of the immunohistochemistry slides. We also thank K Kaltoft for providing us with the MyLa cell lines.

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Authors and Affiliations

  1. Department of Immunology, Institute of Molecular Biology and Physiology, University of Copenhagen, Copenhagen, Denmark

    T Krejsgaard, A Woetmann, P Lovato, T Labuda, K W Eriksen & N Ødum

  2. Department of Immunology, Institute of Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark

    T Krejsgaard, A Woetmann, P Lovato, T Labuda, K W Eriksen & N Ødum

  3. Department of Dermatology, Julius-Maximilians-University, Würzburg, Germany

    C S Vetter-Kauczok & J C Becker

  4. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Q Zhang

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Krejsgaard, T., Vetter-Kauczok, C., Woetmann, A. et al. Jak3- and JNK-dependent vascular endothelial growth factor expression in cutaneous T-cell lymphoma. Leukemia 20, 1759–1766 (2006). https://doi.org/10.1038/sj.leu.2404350

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