RESUMEN
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.
Asunto(s)
Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Linfoma de Células T/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Neoplasias Cutáneas/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Línea Celular Tumoral , Curcumina/farmacología , Inhibidores Enzimáticos/farmacología , Regulación Neoplásica de la Expresión Génica , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Janus Quinasa 3 , Linfoma de Células T/fisiopatología , Linfoma de Células T/terapia , Neovascularización Patológica/metabolismo , Neovascularización Patológica/fisiopatología , Neovascularización Patológica/terapia , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/genética , ARN Mensajero/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Neoplasias Cutáneas/fisiopatología , Neoplasias Cutáneas/terapia , Factor de Transcripción Sp1/genética , Factor de Transcripción Sp1/metabolismo , Factor de Transcripción Sp3/genética , Factor de Transcripción Sp3/metabolismo , Factor de Transcripción AP-1/genética , Factor de Transcripción AP-1/metabolismo , Factor de Transcripción AP-2/genética , Factor de Transcripción AP-2/metabolismo , Transfección , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Cutaneous T-cell lymphoma (CTCL) is the term for diseases characterized by primary accumulation of malignant T cells in the skin. Patients with the two predominant clinical forms of CTCL called mycosis fungoides (MF) and Sézary syndrome (SS) characteristically develop severe immunodeficiency during disease progression and consequently patients with advanced disease frequently die of infections and not from the tumor burden. For decades, it has been suspected that the malignant T cells actively drive the evolving immunodeficiency to avoid antitumor immunity, yet, the underlying mechanisms remain unclear. The identification of a subset of highly immunosuppressive regulatory T cells (Tregs) triggered a variety of studies investigating if MF and SS are malignant proliferations of Tregs but seemingly discordant findings have been reported. Here, we review the literature to clarify the role of Tregs in MF and SS and discuss the potential mechanisms driving the immunodeficiency.
Asunto(s)
Micosis Fungoide/inmunología , Síndrome de Sézary/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígenos CD4/metabolismo , Factores de Transcripción Forkhead/metabolismo , Humanos , Inmunidad Celular , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Micosis Fungoide/metabolismo , Síndrome de Sézary/metabolismo , Linfocitos T Reguladores/metabolismoAsunto(s)
Enfermedades en Gemelos/epidemiología , Enfermedades en Gemelos/genética , Predisposición Genética a la Enfermedad , Linfoma Cutáneo de Células T/epidemiología , Linfoma Cutáneo de Células T/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios de Cohortes , Dinamarca , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sistema de Registros , GemelosAsunto(s)
Células Endoteliales/inmunología , Interleucina-17/inmunología , Linfoma Cutáneo de Células T/inmunología , Proteínas de Neoplasias/inmunología , Neoplasias Cutáneas/inmunología , Linfocitos T/inmunología , Técnicas de Cocultivo , Células Endoteliales/patología , Humanos , Linfoma Cutáneo de Células T/patología , Neoplasias Cutáneas/patología , Linfocitos T/patologíaRESUMEN
Cancer often originates from a site of persistent inflammation, and the mechanisms turning chronic inflammation into a driving force of carcinogenesis are intensely investigated. Cyclooxygenase-2 (COX-2) is an inducible key modulator of inflammation that carries out the rate-limiting step in prostaglandin synthesis. Aberrant COX-2 expression and prostaglandin E(2) (PGE(2)) production have been implicated in tumorigenesis. In this study we show that COX-2 is ectopically expressed in malignant T-cell lines from patients with cutaneous T-cell lymphoma (CTCL) as well as in situ in lymphocytic cells in 21 out of 22 patients suffering from mycosis fungoides (MF) in plaque or tumor stage. COX-2 is not expressed in lymphocytes of 11 patients with patch-stage MF, whereas sporadic COX-2 staining of stromal cells is observed in the majority of patients. COX-2 expression correlates with a constitutive production of PGE(2) in malignant T cells in vitro. These cells express prostaglandin receptors EP3 and EP4 and the receptor antagonist as well as small interfering RNA (siRNA) directed against COX-2, and specific COX-2 inhibitors strongly reduce their spontaneous proliferation. In conclusion, our data indicate that COX-2 mediated PGE(2) exerts an effect as a tumor growth factor in MF.
Asunto(s)
Ciclooxigenasa 2/metabolismo , Linfoma Cutáneo de Células T/metabolismo , Micosis Fungoide/metabolismo , Prostaglandinas E/farmacología , Neoplasias Cutáneas/metabolismo , Western Blotting , Proliferación Celular , Ciclooxigenasa 2/química , Ciclooxigenasa 2/genética , Inhibidores de la Ciclooxigenasa 2/farmacología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Técnicas para Inmunoenzimas , Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma Cutáneo de Células T/patología , Micosis Fungoide/tratamiento farmacológico , Micosis Fungoide/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/farmacología , Receptores de Prostaglandina E/metabolismo , Subtipo EP3 de Receptores de Prostaglandina E , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Células Tumorales CultivadasAsunto(s)
Regulación Neoplásica de la Expresión Génica , Linfoma Cutáneo de Células T/genética , Familia-src Quinasas/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Dasatinib , Humanos , Linfoma Cutáneo de Células T/patología , Linfoma Cutáneo de Células T/terapia , Ratones , Trasplante de Neoplasias , Neoplasias/metabolismo , Fosforilación , Pirimidinas/administración & dosificación , Tiazoles/administración & dosificaciónRESUMEN
Sézary syndrome (SS) is an aggressive variant of cutaneous T-cell lymphoma. During disease progression, immunodeficiency develops; however, the underlying molecular and cellular mechanisms are not fully understood. Here, we study the regulatory T cell (Treg) function and the expression of FOXP3 in SS. We demonstrate that malignant T cells in 8 of 15 patients stain positive with an anti-FOXP3 antibody. Western blotting analysis shows expression of two low molecular splice forms of FOXP3, but not of wild-type (wt) FOXP3. The malignant T cells produce interleukin-10 and TGF-beta and suppress the growth of non-malignant T cells. The Treg phenotype and the production of suppressive cytokines are driven by aberrant activation of Jak3 independent of the FOXP3 splice forms. In contrast to wt FOXP3, the low molecular splice forms of FOXP3 have no inhibitory effect on nuclear factor-kappaB (NF-kappaB) activity in reporter assays which is in keeping with a constitutive NF-kappaB activity in the malignant T cells. In conclusion, we show that the malignant T cells express low molecular splice forms of FOXP3 and function as Tregs. Furthermore, we provide evidence that FOXP3 splice forms are functionally different from wt FOXP3 and not involved in the execution of the suppressive function. Thus, this is the first description of FOXP3 splice forms in human disease.