Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Más filtros











Base de datos
Intervalo de año de publicación
1.
J Clin Invest ; 126(2): 653-66, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26784544

RESUMEN

Worldwide, B cell non-Hodgkin lymphoma is the most common hematological malignancy and represents a substantial clinical problem. The molecular events that lead to B cell lymphoma are only partially defined. Here, we have provided evidence that deficiency of tetraspanin superfamily member CD37, which is important for B cell function, induces the development of B cell lymphoma. Mice lacking CD37 developed germinal center-derived B cell lymphoma in lymph nodes and spleens with a higher incidence than Bcl2 transgenic mice. We discovered that CD37 interacts with suppressor of cytokine signaling 3 (SOCS3); therefore, absence of CD37 drives tumor development through constitutive activation of the IL-6 signaling pathway. Moreover, animals deficient for both Cd37 and Il6 were fully protected against lymphoma development, confirming the involvement of the IL-6 pathway in driving tumorigenesis. Loss of CD37 on neoplastic cells in patients with diffuse large B cell lymphoma (DLBCL) directly correlated with activation of the IL-6 signaling pathway and with worse progression-free and overall survival. Together, this study identifies CD37 as a tumor suppressor that directly protects against B cell lymphomagenesis and provides a strong rationale for blocking the IL-6 pathway in patients with CD37- B cell malignancies as a possible therapeutic intervention.


Asunto(s)
Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Transformación Celular Neoplásica/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , Tetraspaninas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Antígenos CD/genética , Antígenos de Neoplasias/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Centro Germinal/metabolismo , Centro Germinal/patología , Interleucina-6/genética , Interleucina-6/metabolismo , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Tetraspaninas/genética , Proteínas Supresoras de Tumor/genética
2.
Int J Cancer ; 123(3): 609-15, 2008 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-18498132

RESUMEN

In this study we investigated whether the presence of specific populations of tumor infiltrating lymphocytes (TILs) in diagnostic primary melanoma biopsies are related to outcome in clinically stage II melanoma patients. Moreover, we investigated whether the presence of TILs correlates with expression of MHC class I antigen and MHC class II antigen on tumor cells and/or tumor infiltrating antigen presenting cells. Diagnostic primary melanoma samples of 15 patients with an unfavorable outcome were compared with 20 patients with favorable outcome. Patients were matched for age, gender and Breslow thickness. Biopsies were examined for the presence of granzyme B+, CD8+, CD4+ and CD56+ TILs and for expression of MHC class I antigen and MHC class II antigen on tumor and/or tumor infiltrating cells. A favorable clinical outcome was strongly associated with the presence of GrB+ and CD4+ TILs, with expression of MHC class I antigen on tumor cells and with expression of MHC class II antigen on intratumoral antigen presenting cells. These data strongly support the notion that in melanoma patients the cellular immune response is a major factor in preventing melanoma cell dissemination.


Asunto(s)
Biomarcadores de Tumor/análisis , Antígenos de Histocompatibilidad Clase II/análisis , Antígenos de Histocompatibilidad Clase I/análisis , Activación de Linfocitos , Linfocitos Infiltrantes de Tumor , Melanoma/inmunología , Melanoma/patología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Adulto , Anciano , Anciano de 80 o más Años , Células Presentadoras de Antígenos/inmunología , Biopsia , Antígenos CD4/análisis , Antígeno CD56/análisis , Antígenos CD8/análisis , Femenino , Granzimas/análisis , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Resultado del Tratamiento
3.
Clin Cancer Res ; 11(17): 6400-7, 2005 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-16144945

RESUMEN

PURPOSE: There have been reports of successful treatment of metastatic melanoma patients with active specific immunotherapy (ASI) using irradiated autologous tumor cell vaccination. It is still unknown why some patients respond and others do not. Tumor cells can evade the immune system, for example through interference with antigen presentation by down-regulation of MHC molecules or expressing proteins interfering with cytotoxic lymphocyte-induced apoptosis like the granzyme B antagonist protease inhibitor 9 (PI-9). EXPERIMENTAL DESIGN: PI-9 expression was detected in melanoma cell lines. To investigated if PI-9 is important in the response to ASI, paraffin-embedded tissues from stage III or IV melanoma patients were stained. RESULTS: PI-9 is expressed in melanoma cells and expression in metastasized melanoma cells is, in this group of patients, an adverse prognostic marker with regard to overall and disease-free survival. Moreover, loss of MHC-1 expression frequently occurs during tumor progression but is not associated with poor clinical outcome. Interestingly, melanoma patients with a favorable clinical outcome after ASI therapy usually have high percentages of activated (granzyme B-positive) tumor-infiltrating lymphocytes at time of first diagnosis and low percentages of activated lymphocytes at time of recurrent tumor. CONCLUSIONS: Expression of PI-9 in metastatic melanoma cells is associated with unfavorable clinical outcome whereas MHC-1 down-regulation is not. Although it cannot be proven that PI-9 expression is directly responsible for failure of immunotherapy, these data suggest that expression of PI-9 could be an important immune escape mechanism and that modulation of this inhibitor may enhance the efficacy of immunotherapy.


Asunto(s)
Apoptosis , Vacunas contra el Cáncer/uso terapéutico , Linfocitos Infiltrantes de Tumor/patología , Melanoma/inmunología , Serpinas/metabolismo , Neoplasias Cutáneas/inmunología , Adulto , Anciano , Western Blotting , Supervivencia sin Enfermedad , Femenino , Genes MHC Clase I/fisiología , Granzimas , Humanos , Técnicas para Inmunoenzimas , Inmunoterapia , Activación de Linfocitos , Masculino , Melanoma/secundario , Melanoma/terapia , Persona de Mediana Edad , Estadificación de Neoplasias , Serina Endopeptidasas/química , Neoplasias Cutáneas/secundario , Neoplasias Cutáneas/terapia , Tasa de Supervivencia , Resultado del Tratamiento , Células Tumorales Cultivadas
4.
Blood ; 105(7): 2916-23, 2005 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-15576477

RESUMEN

We used biopsy specimens of primary nodal diffuse large B-cell lymphoma (DLBCL) to investigate whether the inhibition of caspase 8 and/or 9 apoptosis signaling pathways predicts clinical outcome. Expression levels of cellular FLICE inhibitory protein (c-Flip) and numbers of active caspase 3-positive lymphoma cells were used to determine the status of the caspase 8-mediated pathway. Expression levels of Bcl-2 and X-linked inhibitor of apoptosis (XIAP) were used to determine the status of the caspase 9-mediated pathway. Expression of c-Flip, XIAP, Bcl-2, and caspase 3 activity all provided prognostic information. According to these immunohistochemical parameters, inhibition of either or both caspase signaling pathways was detected in all patients. Three groups of patients were identified, one with a caspase 8 inhibition profile, one with caspase 8 and 9 inhibition profiles, and one with a caspase 9 inhibition profile. Caspase 9 inhibition was strongly associated with poor response to chemotherapy and usually with fatal outcome, whereas caspase 8 inhibition was associated with excellent clinical outcome. Thus, our data strongly suggest that inhibition of the caspase 9-mediated pathway, but not the caspase 8-mediated pathway, is a major cause for therapy resistance in patients with nodal DLBCL.


Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Caspasas/metabolismo , Etopósido/administración & dosificación , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Transducción de Señal/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Caspasa 3 , Caspasa 8 , Caspasa 9 , Femenino , Humanos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Linfoma de Células B/metabolismo , Linfoma de Células B/mortalidad , Linfoma de Células B/patología , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Resultado del Tratamiento , Proteína Inhibidora de la Apoptosis Ligada a X
5.
Blood ; 103(7): 2710-7, 2004 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-14670919

RESUMEN

SERPINB6 (PI6) is a member of the intracellular serine protease inhibitors (serpins). Previous studies showed that SERPINB6 is localized mainly in the cytoplasm of endothelial cells, some epithelial cells, monocytes, and neutrophils. In these cells SERPINB6 is thought to prevent cellular damage by scavenging leaking lysosomal proteases. We show here, using novel, well-defined monoclonal antibodies, that SERPINB6 is abundantly expressed by mast cells in all organs and by the human mast cell line HMC-1. Gel filtration experiments revealed that the latter cells contain a high-molecular-weight form of SERPINB6, which consists of sodium dodecyl sulfate (SDS)-stable complexes of this inhibitor with monomeric beta-tryptase. Expression of SERPINB6 by mast cells was compared with those of tryptase and CD117 (c-kit) in biopsies from patients with different forms of mast cell disease. In all cases the lesional mast cells expressed SERPINB6, and, in diffuse cutaneous mastocytosis and mastocytoma, SERPINB6 was expressed by a substantially higher number of mast cells when compared with tryptase. In conclusion, SERPINB6 is abundantly expressed by normal mast cells and by mast cells in mastocytoma lesions. We suggest that in mast cells, SERPINB6 serves to regulate the activity of endogenous beta-tryptase in the cytoplasm.


Asunto(s)
Mastocitos/inmunología , Serina Endopeptidasas/metabolismo , Serpinas/genética , Línea Celular , Clonación Molecular , Citoplasma/enzimología , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunohistoquímica , Mastocitosis/inmunología , Plásmidos , Serpinas/metabolismo , Transfección , Triptasas
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA