RESUMEN
Semaphorins are a large class of secreted or membrane-associated proteins that act as chemotactic cues for cell movement via their transmembrane receptors, plexins. We hypothesized that the function of the semaphorin signaling pathway in the control of cell migration could be harnessed by cancer cells during invasion and metastasis. We now report 13 somatic missense mutations in the cytoplasmic domain of the Plexin-B1 gene. Mutations were found in 89% (8 of 9) of prostate cancer bone metastases, in 41% (7 of 17) of lymph node metastases, and in 46% (41 of 89) of primary cancers. Forty percent of prostate cancers contained the same mutation. Overexpression of the Plexin-B1 protein was found in the majority of primary tumors. The mutations hinder Rac and R-Ras binding and R-RasGAP activity, resulting in an increase in cell motility, invasion, adhesion, and lamellipodia extension. These results identify a key role for Plexin-B1 and the semaphorin signaling pathway it mediates in prostate cancer.
Asunto(s)
Adenocarcinoma/genética , Mutación Missense , Proteínas de Neoplasias/genética , Proteínas del Tejido Nervioso/genética , Neoplasias de la Próstata/genética , Receptores de Superficie Celular/genética , Adenocarcinoma/patología , Adenocarcinoma/secundario , Neoplasias Óseas/genética , Neoplasias Óseas/secundario , Adhesión Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática/genética , Masculino , Invasividad Neoplásica/genética , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/fisiología , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/fisiología , Polimorfismo Conformacional Retorcido-Simple , Neoplasias de la Próstata/patología , Estructura Terciaria de Proteína , Seudópodos/ultraestructura , Receptores de Superficie Celular/biosíntesis , Receptores de Superficie Celular/fisiología , Transducción de Señal , Proteína de Unión al GTP rac1/metabolismo , Proteínas ras/metabolismoRESUMEN
Angioimmunoblastic T-cell lymphoma is an aggressive peripheral T-cell lymphoma whose natural history is not fully understood. Up to 17% of cases can present histologically with hyperplastic germinal centres (pattern I). The accurate recognition of Angioimmunoblastic T-cell lymphoma with pattern I remains a challenge and therefore the aim of this study is to phenotypically and morphologically characterize this variant with the use of the follicular helper T-cell (T(FH)) markers PD1, CXCL-13 and ICOS. Out of the 88 Angioimmunoblastic T-cell lymphoma cases reviewed, 10 showed hyperplastic follicles. Molecular probe methods for the detection of T-cell and B-cell clonality, as well as in-situ hybridization probes for EBV RNA expression, were carried out to leave no question as to the establishment of the diagnosis in each case. Of the 10 cases, all (100%) showed strong positive PD1 staining in perifollicular areas and in neoplastic cells surrounding small veins. CXCL13 and ICOS showed a similar staining pattern. By contrast, CD10 was found to only weakly label the neoplastic T cells, with only 5-10% of the target cell population staining for this marker. EBV was found in 9/10 cases. Clinically, 8/9 cases presented with stage IIIB/IVB and in 2/10 cases consecutive biopsies showed 'progression' from pattern I to classical Angioimmunoblastic T-cell lymphoma. In conclusion we have shown that the T(FH) cells markers PD1, CXCL13 and ICOS are useful adjuncts in the diagnosis of Angioimmunoblastic T-cell lymphoma with hyperplastic germinal centres. PD1 also highlighted the presence of neoplastic cells in the outer zone of lymphoid follicles, suggesting that Angioimmunoblastic T-cell lymphoma (pattern I) may originate from T(FH) cells in this region, in accordance with previous immunological studies. As the majority of cases in our series presented clinically with advanced stage disease, progression from pattern I to classical Angioimmunoblastic T-cell lymphoma may represent histological evolution rather than clinical progression.
Asunto(s)
Centro Germinal/patología , Ganglios Linfáticos/patología , Linfoma de Células T/patología , Linfocitos T Colaboradores-Inductores/patología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Biomarcadores de Tumor/inmunología , Quimiocina CXCL13/metabolismo , Femenino , Centro Germinal/inmunología , Humanos , Inmunohistoquímica , Proteína Coestimuladora de Linfocitos T Inducibles , Linfoma de Células T/inmunología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Receptor de Muerte Celular Programada 1 , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
A cure cannot be assured for all men with clinically localized prostate cancer undergoing radical treatment. Molecular markers would be invaluable if they could improve the prediction of occult metastatic disease. This study was carried out to investigate the expression of BCL-2, Ki-67, p53 and E-cadherin in radical prostatectomy specimens. We sought to assess their ability to predict early biochemical relapse in a specific therapeutic setting. Eighty-two patients comprising 41 case pairs were matched for pathological stage, Gleason grade and preoperative prostate-specific antigen (PSA) concentration. One patient in each pair had biochemical recurrence (defined as PSA >or= 0.2 ng mL(-1) within 2 years of surgery) and the other remained biochemically free of disease (defined as undetectable PSA at least 3 years after surgery). Immunohistochemical analysis was performed to assess marker expression on four replicate tissue microarrays constructed with benign and malignant tissue from each radical prostatectomy specimen. Ki-67, p53 and BCL-2, but not E-cadherin, were significantly upregulated in prostate adenocarcinoma compared with benign prostate tissue (P < 0.01). However, no significant differences in expression of any of the markers were observed when comparing patients who developed early biochemical relapse with patients who had no biochemical recurrence. This study showed that expression of p53, BCL-2 and Ki-67 was upregulated in clinically localized prostate cancer compared with benign prostate tissue, with no alteration in E-cadherin expression. Biomarker upregulation had no prognostic value for biochemical recurrence after radical prostatectomy, even after considering pathological stage, whole tumour Gleason grade and preoperative serum PSA level.
Asunto(s)
Adenocarcinoma/diagnóstico , Cadherinas/metabolismo , Perfilación de la Expresión Génica , Antígeno Ki-67/metabolismo , Neoplasias de la Próstata/diagnóstico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/cirugía , Anciano , Biomarcadores de Tumor/metabolismo , Cadherinas/genética , Estudios de Casos y Controles , Regulación Neoplásica de la Expresión Génica , Humanos , Antígeno Ki-67/genética , Masculino , Persona de Mediana Edad , Pronóstico , Próstata/metabolismo , Próstata/patología , Antígeno Prostático Específico/sangre , Prostatectomía , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/cirugía , Proteínas Proto-Oncogénicas c-bcl-2/genética , Factores de Riesgo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Angioimmunoblastic T-cell lymphoma (AITL) is a systemic disease involving lymph nodes, spleen, and bone marrow. Although the histologic features have been well described, the diagnosis is often challenging, as there are no specific phenotypic or molecular markers available. This study shows that the neoplastic cells of AITL can be identified by aberrant CD10 expression. Archival material from 30 cases of AITL, 10 cases of peripheral T-cell lymphoma unspecified (PTL), and 10 cases of reactive lymphoid hyperplasia were reviewed. Single and double immunostaining for CD3, CD4, CD8, CD20, CD21, CD10, BCL6, Ki67, and LMP-1 in situ hybridization for Epstein-Barr early region and polymerase chain reaction (PCR) for T-cell receptor gamma chain gene and immunoglobulin heavy chain gene were performed. Three overlapping histologic patterns with hyperplastic follicles, depleted follicles, or without follicles were identified in AITL. Of the 30 cases of AITL, 27 contained CD10(+) T cells. No CD10(+) T cells were present in the cases of PTL or reactive hyperplasia. PCR confirmed a monoclonal or oligoclonal T-cell population in 29 of 30 cases of AITL and a monoclonal B-cell population in 6 cases. Analysis of microdissected CD10(+) single cells showed that they belonged to the neoplastic clone. In conclusion CD10 is a phenotypic marker that specifically identifies the tumor cells in 90% of AITL, including the early cases. The presence of these cells distinguishes AITL from other PTLs. This finding provides an objective criterion for accurate and early diagnosis of AITL.