RESUMEN
The incidence of adenocarcinoma is increasing, particularly among females. We sought to assess the role of tobacco consumption in clinical presentation according to sex. In this retrospective study, 848 patients diagnosed between 1997 and 2006 at Grenoble University Hospital (Grenoble, France) were stratified into four groups according to smoking habits. Differences between sexes and two contrasting female profiles emerged. Female current smokers were younger than female never-smokers (median 51 versus 69 yrs; p < 0.001), more often had surgery (62.7% versus 39%; p = 0.01) and had a median (95% CI) estimated survival of 26.2 (18.1-49.2) versus 15.1 (12.8-22.2) months (p = 0.002). Both groups had similar survival when taking treatment into account. Among males, smoking did not influence presentation. Male current smokers were older than female current smokers (median 59 yrs; p < 0.001) and fewer had surgery (48.8%; p = 0.015), although the percentage of stage IIIb-IV disease was similar (53% and 46%; nonsignificant) and they had a poorer estimated survival of 14.3 (13.0-18.5) months (p = 0.0024). Males smoked more than females (median 41 versus 30 pack-yrs; p < 0.001). Quitting smoking delayed age at diagnosis by 11 yrs for females (p = 0.0035) and 8 yrs for males (p < 0.001). Our results support the hypothesis that carcinogenesis differs between males and females, and between female smokers and never-smokers.
Asunto(s)
Adenocarcinoma/epidemiología , Neoplasias Pulmonares/epidemiología , Fumar/epidemiología , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Anciano , Femenino , Francia/epidemiología , Humanos , Incidencia , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Prevalencia , Pronóstico , Estudios Retrospectivos , Factores Sexuales , SobrevidaAsunto(s)
Trasplante de Médula Ósea/métodos , Talasemia/cirugía , Niño , Humanos , Masculino , Trasplante Homólogo/métodosRESUMEN
The European Early Lung Cancer (EUELC) project aims to determine if specific genetic alterations occurring in lung carcinogenesis are detectable in the respiratory epithelium. In order to pursue this objective, nonsmall cell lung cancer (NSCLC) patients with a very high risk of developing progressive lung cancer were recruited from 12 centres in eight European countries: France, Germany, southern Ireland, Italy, the Netherlands, Poland, Spain and the UK. In addition, NSCLC patients were followed up every 6 months for 36 months. A European Bronchial Tissue Bank was set up at the University of Liverpool (Liverpool, UK) to optimise the use of biological specimens. The molecular-pathological investigations were subdivided into specific work packages that were delivered by EUELC Partners. The work packages encompassed mutational analysis, genetic instability, methylation profiling, expression profiling utilising immunohistochemistry and chip-based technologies, as well as in-depth analysis of FHIT and RARbeta genes, the telomerase catalytic subunit hTERT and genotyping of susceptibility genes in specific pathways. The EUELC project engendered a tremendous collaborative effort, and it enabled the EUELC Partners to establish protocols for assessing molecular biomarkers in early lung cancer with the view to using such biomarkers for early diagnosis and as intermediate end-points in future chemopreventive programmes.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Anciano , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Metilación de ADN , Análisis Mutacional de ADN , Epitelio/metabolismo , Europa (Continente) , Femenino , Humanos , Inmunohistoquímica/métodos , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptores de Ácido Retinoico/metabolismo , Telomerasa/metabolismoRESUMEN
Increased vascular calcification is a major cause of cardiovascular events in patients with chronic kidney disease (CKD). It is the result of an active ossification process counteracted by ''bone'' proteins such as osteopontin, alkaline phosphatase, osteoprotegerin, and osteocalcin. Chronic kidney disease - mineral and bone disorder (CKD-MBD) is a systemic disorder of mineral and bone metabolism that occurs in CKD. In addition to abnormalities in the serum calcium and phosphate profile, CKD-MBD is characterized by abnormalities of bone turnover, mineralization, volume and growth as well as vascular calcification. Considering that the presence and extent of vascular calcification in CKD portend a poor prognosis, many efforts have been made to shed light on this complicated phenomenon to prevent vascular calcium deposition and its progression. Indeed, careful control of calcium load, serum phosphate and parathyroid hormone along with the use of calcium-free phosphate binders and vitamin D receptor activators represent a new therapeutic armamentarium to improve quality of life and reduce mortality in CKD.
Asunto(s)
Calcinosis/tratamiento farmacológico , Calcinosis/metabolismo , Enfermedades Renales/complicaciones , Enfermedades Renales/metabolismo , Enfermedades Vasculares/tratamiento farmacológico , Enfermedades Vasculares/metabolismo , Biomarcadores/sangre , Calcinosis/sangre , Calcinosis/patología , Calcio/sangre , Quelantes/uso terapéutico , Enfermedad Crónica , Enfermedad de la Arteria Coronaria/metabolismo , Progresión de la Enfermedad , Quimioterapia Combinada , Medicina Basada en la Evidencia , Humanos , Enfermedades Renales/sangre , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/patología , Hormona Paratiroidea/sangre , Fosfatos/sangre , Guías de Práctica Clínica como Asunto , Pronóstico , Calidad de Vida , Insuficiencia Renal Crónica/metabolismo , Enfermedades Vasculares/sangre , Enfermedades Vasculares/patología , Vitamina D/uso terapéuticoRESUMEN
The transcription factor E2F-1 plays a crucial role in the control of cellular growth. We previously reported its differential pattern of expression in human lung tumors. In this study, we have investigated the relationships linking the status of E2F-1 and a mediator of its proteasomal degradation, the S-phase kinase-associated protein 2 (Skp2) F-box protein. Using immunohistochemistry in a series of 129 lung tumors of all histological types, we demonstrate that Skp2 accumulates preferentially in high-grade neuroendocrine (HGNE) lung carcinomas (86%, P<0.0001), and show that Skp2 overexpression is associated with advanced stages (P<0.0001) and nodal metastasis (P<0.0001) in neuroendocrine (NE) lung tumors. Unexpectedly, we observe that Skp2 and E2F-1 expression directly correlates in NE lung tumors (P<0.0001). Moreover, using cellular models, we identify Skp2 as a new E2F-1 transcriptional target. Furthermore, we also provide evidence that Skp2 interacts physiologically with E2F-1 and stimulates its transcriptional activity toward the cyclin E promoter. Consistently, we demonstrate that cyclin E expression directly correlates with Skp2 (P<0.0001) and E2F-1 (P=0.0001) status in NE lung tumors. Overall, our data provide the first evidence of a direct and functional interconnection between the E2F-1, Skp2 and cyclin E oncoproteins in HGNE lung carcinomas.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Ciclina E/metabolismo , Factor de Transcripción E2F1/metabolismo , Neoplasias Pulmonares/metabolismo , Tumores Neuroendocrinos/metabolismo , Proteínas Oncogénicas/metabolismo , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundario , Ciclina E/genética , Humanos , Immunoblotting , Técnicas para Inmunoenzimas , Inmunoprecipitación , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Metástasis Linfática/patología , Estadificación de Neoplasias , Proteínas Oncogénicas/genética , ARN Interferente Pequeño/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Quinasas Asociadas a Fase-S/genética , Transcripción Genética , Regulación hacia ArribaRESUMEN
Lung carcinoma with a basaloid pattern (BC) is classified as either a basaloid variant of squamous cell carcinoma (SCC) or as variant of large cell carcinoma (LCC) depending on the presence of a squamous component. In a previous study of 37 cases, the present authors showed that BC presented with a shorter median and overall survival. In order to confirm its clinical significance in a larger series, 90 BC, including 46 basaloid variants of LCC and 44 basaloid variants of SCC, were compared with 1,328 other nonsmall cell lung carcinoma (NSCLC) with regard to clinical features and survival. The survival of basaloid variants of LCC and SCC was comparable. Median and overall survival were significantly lower for BC than for NSCLC in stage I-II patients, with a median survival of 29 and 49 months, respectively, and 5-yr survival rates of 27 and 44% for BC and NSCLC. When disease-specific survival was considered, BC had a shorter survival than both NSCLC and SCC. Basaloid pattern confers a poor prognosis in nonsmall cell lung carcinoma, especially in stage I-II patients, suggesting that lung carcinoma with a basaloid pattern is not only a variant of squamous cell carcinoma or large cell carcinoma, but is a unique entity with a significantly poor prognosis.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Neoplasias de Células Escamosas/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/clasificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
BACKGROUND: Patients with a previous history of cancer of the upper respiratory and digestive tracts (URDT) frequently develop a bronchial carcinoma (synchronous or metachronous) that may affect their survival. OBJECTIVE: To determine the prevalence of bronchial carcinoma at an early stage in a population of patients treated for cancer of the URDT. MATERIALS AND METHODS: This was a single centre prospective study (2002-2006). Patients in remission following treatment of cancers of the buccal cavity, pharynx (stages I -II) and larynx (stages I - III), were examined by a spiral CT scan and fibreoptic bronchoscopy (white light and autofluorescence), with biopsies, and cytology of the bronchial aspirate. RESULTS: 60 patients (55 men) were included. Two peripheral bronchial carcinomas were detected by scanning and two more (proximal) by endoscopy. All 4 bronchial tumours were squamous carcinomas (stage IA). Three patients had surgery, the fourth declined intervention. CONCLUSION: Our study confirms the high prevalence (6.7%) of bronchial carcinoma in patients with a past history of cancer of the URDT. It emphasises the complimentary roles of spiral scanning and bronchoscopy in early diagnosis. It is still too early to evaluate the impact of these investigations on the survival of the patients.
Asunto(s)
Carcinoma Broncogénico/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Neoplasias de Cabeza y Cuello , Neoplasias Pulmonares/diagnóstico , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Secundarias/diagnóstico , Adulto , Anciano , Broncoscopía , Carcinoma Broncogénico/cirugía , Carcinoma de Células Escamosas/cirugía , Femenino , Humanos , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Neoplasias Primarias Múltiples/cirugía , Neoplasias Primarias Secundarias/cirugía , Estudios Prospectivos , Tomografía Computarizada EspiralRESUMEN
E2F1 is a transcription factor that plays a well-documented role during S phase progression and apoptosis. We had previously postulated that the low level of E2F1 in primary lung adenocarcinoma contributes to their carcinogenesis. Here, we show that E2F1 triggers apoptosis in various lung adenocarcinoma cell lines by a mechanism involving the specific downregulation of the cellular FLICE-inhibitory protein short, leading to caspase-8 activation at the death-inducing signaling complex. Importantly, we also provide evidence that E2F1 sensitizes tumor as well as primary cells to apoptosis mediated by FAS ligand or tumor necrosis factor-related apoptosis-inducing ligand, and enhances the cytotoxic effect of T lymphocytes against tumor cells. Finally, we describe the specific overexpression of c-FLIP(S) in human lung adenocarcinomas with low level of E2F1. Overall, our data identify E2F1 as a critical determinant of the cellular response to death-receptor-mediated apoptosis, and suggest that its downregulation contributes to the immune escape of lung adenocarcinoma tumor cells.
Asunto(s)
Adenocarcinoma/patología , Apoptosis , Regulación hacia Abajo , Factor de Transcripción E2F1/fisiología , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Pulmonares/patología , Adenocarcinoma/química , Adenocarcinoma/genética , Proteínas Reguladoras de la Apoptosis/farmacología , Western Blotting , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Caspasa 8 , Caspasas/metabolismo , Línea Celular Tumoral , Citotoxicidad Inmunológica , ADN/metabolismo , Factor de Transcripción E2F1/genética , Factor de Transcripción E2F1/farmacología , Activación Enzimática , Proteína Ligando Fas , Técnica del Anticuerpo Fluorescente Indirecta , Regulación Neoplásica de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular/fisiología , Neoplasias Pulmonares/química , Neoplasias Pulmonares/genética , Glicoproteínas de Membrana/farmacología , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T Citotóxicos/inmunología , Ligando Inductor de Apoptosis Relacionado con TNF , Factor de Necrosis Tumoral alfa/farmacología , Factores de Necrosis Tumoral/farmacologíaRESUMEN
INTRODUCTION: The entities of non-solid and part-solid pulmonary nodules on CT scan have been recently described. STATE OF ART: Nonsolid and part-solid pulmonary nodules account for between 2.9 and 19% of all pulmonary nodules detected in high-risk patients included in CT screening series for lung cancer. Radio-pathological correlations have shown that the aetiology could be either benign (chronic pneumonia, atypical adenomatous hyperplasia, localized fibrosis) or malignant (broncholoalveolar cell carcinoma, adenocarcinoma, more rarely metastasis). Part-solid or non-solid nodules are more likely to be malignant than solid ones. The doubling time of non-solid nodules can be longer than part-solid ones and even longer than the doubling time of solid nodules. Patient prognosis is related to the proportion of the ground glass component. PERSPECTIVE: The management of these nodules requires prolonged surveillance of nodules less than 10mm in diameter and surgical excision of nodules greater than 10mm persisting on scans between 1 to 3 months after they have been discovered and anti-inflammatory and anti-infectious therapy has been administered. CONCLUSIONS: Nonsolid and part-solid pulmonary nodules found on CT scan warrant a specific diagnostic workup.
Asunto(s)
Nódulo Pulmonar Solitario/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Algoritmos , Humanos , Pulmón/patología , Neoplasias Pulmonares/patología , Lesiones Precancerosas/diagnóstico por imagen , Prevalencia , Nódulo Pulmonar Solitario/etiología , Nódulo Pulmonar Solitario/terapiaRESUMEN
In 165 women with breast cancer who were candidates for mastectomy because the largest diameter of the tumor was 3 cm or more, we administered primary chemotherapy in the attempt to substitute conservative for mutilating surgery. We then systematically quantitated tumor reduction by clinical, radiologic, and histopathologic evaluations. Five consecutive groups of 33 patients received cyclophosphamide, methotrexate, and fluorouracil (CMF); fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide (FAC); or fluorouracil, epirubicin, and cyclophosphamide (FEC). The regimens for the five groups were as follows: group 1, three cycles of CMF; group 2, four cycles of CMF; group 3, three cycles of FAC; group 4, four cycles of FAC; and group 5, three cycles of FEC. In response to primary chemotherapy, 157 of the 161 assessable patients showed measurable tumor shrinkage; progressive disease was documented in four. Tumor shrinkage to less than 3 cm was documented in 127 (81%) of the 157 women subjected to surgery, thus allowing a breast-saving procedure, rather than modified radical mastectomy, in these 127 women. Histopathologic complete remission was documented in seven patients. Tumor response was unrelated to age, menopausal status, DNA content (ploidy), [3H]thymidine-labeling index, drug combination used, or number of treatment cycles in excess of three. The degree of response was inversely proportional to the initial tumor size, and the frequency of response was greater in receptor-negative tumors. Severe vomiting and hair loss were less frequent with CMF than with anthracycline-containing regimens, and the frequency of severe leukopenia and thrombocytopenia was minimal. Our results challenge the classical indication for primary mastectomy by showing that use of full-dose primary chemotherapy, sequentially combined with conservative surgery and radiation, can offer an effective and safe alternative to women concerned about the preservation of body integrity.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Mastectomía , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Cisplatino/administración & dosificación , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Esquema de Medicación , Epirrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Menopausia , Metotrexato/administración & dosificación , RecurrenciaRESUMEN
In order to validate the use of the nude mouse as a model for studying lung cancers, 21 different lung cancers were xenografted onto nude mice and the tumoral DNA and RNA were analyzed for abnormality in the myc family genes (c-myc, L-myc, and N-myc). Six of 14 small cell lung cancers (SCLC) showed a 4-35-fold amplification for L-myc, 5 of 7 non-SCLC a 3-5-fold amplification for c-myc, and 1 of 14 SCLC an 80-fold amplification for N-myc. Of the 7 SCLC with amplified L- or N-myc oncogenes, 4 were of the small and large histological type, while only 5 of the 21 cases studied were of the small and large type. All xenografted tumors with amplification of one of the myc genes showed overexpression of the related mRNA. Overexpression without amplification of the myc genes was observed for 3 SCLC and 2 non-SCLC. These results indicate that the L-myc gene seems to be associated with the small and large phenotype in SCLC, whereas c-myc seems to be implicated in non-SCLC. Of the 21 lung cancers studied 14 were analyzed for myc family gene activation for serial passages into nude mice. No variation of DNA amplification was observed during long-term growth in nude mice for any of the myc oncogenes. Changes in the level of mRNA expression were observed only for c-myc; a beginning of expression in one SCLC and an increase in expression in one non-SCLC were noted in late passages when compared with early ones. The nude mouse is therefore a valuable model for the study of lung cancers "over a 4-year period at least."
Asunto(s)
Carcinoma de Células Pequeñas/genética , Amplificación de Genes , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Oncogenes/fisiología , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Fenotipo , Factores de Tiempo , Activación TranscripcionalRESUMEN
myc gene family activation (c-myc, L-myc, and N-myc) was examined in 26 human lung carcinomas and in their corresponding xenografts in nude mice. Of the 16 neuroendocrine (NE) carcinomas studied, amplification was observed in 4 with a c-myc probe and in 1 with both L- and N-myc probes. Overexpression was found in 1 of 7 cases studied for c-myc mRNA, in 1 of 7 cases for N-myc, and in 2 of 7 cases for L-myc. Of the 10 non-small cell lung carcinomas studied, only c-myc was amplified in 1 case and overexpressed in 5 of 7 cases. These results suggest that L- and N-myc gene activation are restricted to NE carcinomas. Over-expression of the myc gene without amplification was detected in 36% of cases. During heterotransplantation, there was a 27% change in myc gene abnormality and a 57% increase in myc expression levels, mostly in NE carcinomas (5 of 7; 71%). In a total of 42 xenografted lung carcinomas studied, 45% amplification and 77% overexpression of one of the myc genes were detected with a high prevalence of L-myc overexpression in NE carcinomas (50%) and of c-myc overexpression in non-small cell lung carcinomas (66%). Finally, 19 of 26 (73%) tumors are growing in nude mice with no myc gene amplification and 43% with no myc mRNA overexpression. Thus myc gene activation is not strictly required for heterotransplantation but seems to be a favorable factor in the maintenance and progression of lung carcinomas in vivo.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Genes myc , Neoplasias Pulmonares/genética , Familia de Multigenes , Animales , Northern Blotting , Carcinoma/genética , Carcinoma/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Pequeñas/genética , Carcinoma de Células Pequeñas/patología , ADN de Neoplasias/genética , ADN de Neoplasias/aislamiento & purificación , Reordenamiento Génico , Humanos , Neoplasias Pulmonares/patología , Metástasis Linfática , Ratones , Ratones Desnudos , ARN Neoplásico/genética , ARN Neoplásico/aislamiento & purificación , Activación Transcripcional , Trasplante HeterólogoRESUMEN
The p16IN4/CDKN2/MTS1 gene encodes two structurally different proteins: a cyclin-dependent kinase inhibitor called p16INK4a, which regulates retinoblastoma protein-dependent G1 arrest, and a cell cycle inhibitor designated p19ARF, which arrests cell growth in G1-S and also in G2-M. Whereas inactivation of p16INK4a has been described as a frequent event in lung cancer, the current function of p19ARF is still poorly understood. We have examined the expression of the human p19ARF (hp19ARF) protein in a large series of lung cancers using immunohistochemistry and showed that the protein was more frequently lost in high-grade neuroendocrine (NE) lung tumors (large cell NE carcinoma and small cell lung carcinoma; 51 of 78, 65%) than it was in non-small cell lung cancer (25 of 101, 25%). No deleterious mutation was found in exons 1beta and 2 of hp19ARF in those NE tumors with negative immunoreactivity, and a beta transcript was detected in the majority of them. Concomitant absence of hp19ARF and retinoblastoma proteins was frequently detected in high-grade NE lung tumors, whereas no relationship could be found between the status of hp19ARF and p53 proteins in those tumors. These results are consistent with an alternative growth suppressor function for hp19ARF in NE lung cancer that is distinct from that of p16INK4a. Moreover, the frequent uncoupling between the beta transcript and the hp19ARF protein suggests a novel mechanism of inactivation at the translational level.
Asunto(s)
Carcinoma de Células Pequeñas/química , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Neoplasias Pulmonares/química , Proteínas Nucleares , Proteínas/análisis , Mapeo Cromosómico , Inhibidor p16 de la Quinasa Dependiente de Ciclina/análisis , Exones , Humanos , Inmunohistoquímica , Pulmón/química , Polimorfismo Conformacional Retorcido-Simple , Proteínas/genética , Proteínas Proto-Oncogénicas/fisiología , Proteínas Proto-Oncogénicas c-mdm2 , ARN Mensajero/análisis , Proteína de Retinoblastoma/análisis , Proteína p14ARF Supresora de Tumor , Proteína p53 Supresora de Tumor/análisisRESUMEN
The transcription factor E2F1 is a key component of cell cycle that acts to transactivate genes required for S phase entry. Thus, it plays an important role in cellular proliferation, oncogenesis and differentiation. In order to investigate its potential implication in human lung carcinogenesis, we studied E2F1 protein expression by Western blotting and immunohistochemistry in a series of 58 human lung tumours of all histological types. We showed that E2F1 product was overexpressed in 92% (24/26) of small cell lung carcinoma (SCLC) and in 50% (5/10) of large cell neuroendocrine carcinoma (LCNEC) whereas it was undetectable in 90% (10/11) of adenocarcinoma and 82% (9/11) of squamous carcinoma when compared to corresponding normal lung. No amplification was found but an increase in E2F1 mRNA expression was detected in 75% (18/24) of SCLC overexpressing E2F1 product. In these tumours and in contrast with NSCLC, upregulation of E2F1 product was associated with its nuclear accumulation and with overexpression of several of its target-genes. Moreover, E2F1 overexpression in NE lung tumours was significantly associated with a high KI67 index (P<0.0001) as well as a Bcl-2:Bax ratio >1 (P<0.001). Overall, these results demonstrate a distinct pattern of E2F1 expression in human lung tumours and suggest that its deregulation could be involved in the carcinogenesis of SCLC.
Asunto(s)
Carcinoma de Células Pequeñas/metabolismo , Proteínas Portadoras , Proteínas de Ciclo Celular , Proteínas de Unión al ADN , Neoplasias Pulmonares/metabolismo , Factores de Transcripción/biosíntesis , Carcinoma de Células Pequeñas/química , Carcinoma de Células Pequeñas/patología , Factores de Transcripción E2F , Factor de Transcripción E2F1 , Inmunohistoquímica , Neoplasias Pulmonares/química , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas/análisis , Proteínas Proto-Oncogénicas c-bcl-2/análisis , ARN Mensajero/análisis , Proteína de Retinoblastoma/análisis , Proteína 1 de Unión a Retinoblastoma , Factor de Transcripción DP1 , Factores de Transcripción/genética , Factores de Transcripción/fisiología , Proteína p53 Supresora de Tumor/análisis , Regulación hacia Arriba , Proteína X Asociada a bcl-2RESUMEN
The cyclin-dependent kinase inhibitor p16 (p16INK4A/CDKN2/MTS1) is a potent inhibitor of the cyclin D-dependent phosphorylation of the retinoblastoma gene (Rb) product, the inactivation of which induces loss of Rb-dependent G1 arrest through inappropriate phosphorylation of the Rb protein. To analyse the role of p16INK4A as a tumor suppressor in the genesis of non small cell lung cancers (NSCLC) and correlate loss of p16INK4A protein expression to genetic or epigenetic mechanisms, we have performed a comprehensive study of p16 status in a series of 43 NSCLC. To this end, we have investigated p16INK4A protein expression with immunohistochemistry, deletions of the gene by FISH, and determined the methylation status of exon 1alpha using a PCR-based methylation assay. Finally, possible mutations were studied by SSCP and subsequent sequencing. Twenty one of the 43 (49%) NSCLC studied exhibited an absence of p16INK4A nuclear staining. Of these, three (14%) had frameshift or missense mutations, seven (33%) displayed methylation of exon 1alpha and 10 (48%) displayed homozygous deletions. In total, 95% of the tumors with p16INK4A negative staining carried one of these three alternative genetic or epigenetic alterations. Furthermore, a high degree of chromosome 9 polysomy was found (58%) in those tumors with p16INK4A inactivation. Taken together these results suggest that deregulation of the p16 gene locus is a frequently occurring event in NSCLC through distinct mechanisms including rare point mutations, promotor methylation and frequent homozygous deletions. Furthermore, our data show that immunohistochemistry is a rapid and an accurate technique for screening of p16INK4A gene inactivation events that result in loss of protein expression.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Eliminación de Gen , Genes Supresores de Tumor/genética , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/patología , Cromosomas Humanos Par 9/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Metilación de ADN , Exones/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proteínas de Neoplasias/metabolismoRESUMEN
The INK4a/ARF locus which is frequently inactivated in human tumours encodes two different tumour suppressive proteins, p16(INK4a) and ARF. p16(INK4a) is a major component of the RB pathway. ARF is part of an ARF-mdm2-p53 network that exerts a negative control on hyperproliferative signals emanating from oncogenic stimuli. Among these is the transcription factor E2F1, a final effector of the RB pathway, that induces ARF expression. Recent data suggest that ARF function is not restricted to the p53 pathway. However, ARF target(s) implicated in this p53-independent function remains to be identified. We show that ARF is able to inhibit the proliferation of human cell lines independently of their p53 status. In this context, we demonstrate that ARF interacts physically with E2F1 and inhibits its transcriptional activity. Moreover, we show that mdm2 is required for the modulation of E2F1 activity by ARF. Beside the well-known p53 and mdm2 partners, these results identify E2F1 as a new ARF target. Thus, ARF can be viewed as a dual-acting tumour suppressor protein in both the p53 and RB pathways, further emphasizing its role in tumour surveillance.
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Factores de Ribosilacion-ADP/metabolismo , Factores de Ribosilacion-ADP/farmacología , Proteínas Portadoras , Proteínas de Ciclo Celular , Proteínas de Unión al ADN , Proteínas Nucleares , Factores de Transcripción/metabolismo , Transcripción Genética/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Adenocarcinoma Bronquioloalveolar/genética , Adenocarcinoma Bronquioloalveolar/metabolismo , Western Blotting , División Celular/genética , Cloranfenicol O-Acetiltransferasa/metabolismo , Ensayo de Unidades Formadoras de Colonias , Factores de Transcripción E2F , Factor de Transcripción E2F1 , Exones/fisiología , Eliminación de Gen , Glutatión Transferasa/química , Glutatión Transferasa/metabolismo , Humanos , Luciferasas/metabolismo , Mutagénesis/fisiología , Osteosarcoma/genética , Osteosarcoma/metabolismo , Pruebas de Precipitina , Unión Proteica , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2 , Proteína 1 de Unión a Retinoblastoma , Factor de Transcripción DP1 , Transfección , Proteína p53 Supresora de Tumor/análisisRESUMEN
PURPOSE: Primary chemotherapy was administered to patients with tumors that measured > or = 2.5 cm in largest diameter to decrease the size of the primary tumor and allow for effective local and distant control while avoiding mastectomy. PATIENTS AND METHODS: Two prospective nonrandomized studies were performed that used different regimens of primary chemotherapy followed by breast-sparing surgery in the presence of objective tumor remission. Additional postoperative chemotherapy was given to women at high risk of disease relapse. The median follow-up duration was 65 months. RESULTS: A total of 536 assessable patients were enrolled, and the main characteristics were fairly comparable between the two trials. Following primary chemotherapy, 85% of patients could be subjected to breast-sparing surgery; in 14 patients (3%), surgical specimens failed to show any residual neoplastic cell. In the final multivariate analysis, the histologically assessed extent of axillary node involvement (P < .001), as well as degree of response to primary chemotherapy (P = .034), represented the significant variables able to influence 8-year relapse-free survival. In women subjected to a breast-conserving approach, the cumulative risk of local relapse as first event alone was 6.8% (95% confidence interval, 3.9% to 8.8%). CONCLUSION: Current findings indicate that primary chemotherapy can be safely administered in women with large tumors (>5.0 cm) and can allow breast-sparing surgery in a high fraction of patients (62%). However, to assess effectively the worthiness of this approach on long-term results, properlyconceived large randomized studies with newer and more effective drug regimens are warranted.
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Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Cisplatino/administración & dosificación , Terapia Combinada , Progresión de la Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Metotrexato/administración & dosificación , Persona de Mediana Edad , Estudios Prospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Despite the high response rates resulting from chemotherapy, the majority of small-cell lung cancer (SCLC) patients relapse with chemoresistant tumors. To analyze the phenotypic changes that are precursors of chemoresistant status, and to investigate the role of chemotherapy in these changes, tumor samples from 20 patients, taken before chemotherapy (etoposide, doxorubicin, and cyclophosphamide) and again at the onset of chemoresistance (after at least three courses of chemotherapy), were compared. The histologic changes were minor in 10 of 20 patients, as shown by an increase in cell size; they were major in 10 of 20 patients, with the appearance of mixed composite tumors in which neuroendocrine (NE), epidermoid, and glandular components were mixed. Major changes correlated with a good response to chemotherapy (P = .001). Ultrastructural studies showed an increase in neurosecretory granules and desmosomes, and a high frequency of multidirectional differentiation (45%) when comparison was made with pretherapy samples (10%) (P less than .01). Immunohistochemical (IH) analysis showed an increase in cytokeratin (CK) expression in treated patients, with a different labeling pattern and the expression of higher molecular weight CK. The expression of NE lineage markers (Leu 19, Sy 38, SL 11-14) remained stable, while that of NE differentiation markers (Leu 7, chromogranin) increased in the treated patients. The neuron-specific enolase (NSE) activity remained stable in treated SCLC. Large cells with a more differentiated phenotype and proliferative capacity (as shown by Ki 67 labeling), appeared to be characteristic of treated and secondary chemoresistant SCLC. The acquisition of a more complex phenotype, which correlates with primary response to therapy, implies a drug-induced differentiation in SCLC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Carcinoma de Células Pequeñas/metabolismo , Carcinoma de Células Pequeñas/mortalidad , Carcinoma de Células Pequeñas/patología , Carcinoma de Células Pequeñas/secundario , Diferenciación Celular/efectos de los fármacos , Ciclofosfamida/administración & dosificación , Gránulos Citoplasmáticos/ultraestructura , Desmosomas/ultraestructura , Doxorrubicina/administración & dosificación , Resistencia a Medicamentos , Etopósido/administración & dosificación , Femenino , Humanos , Inmunohistoquímica , Queratinas/análisis , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Peso Molecular , Estadificación de Neoplasias , Fenotipo , Fosfopiruvato Hidratasa/análisis , Tasa de SupervivenciaRESUMEN
A prospective screening program, including CT, autofluorescent bronchoscopy, biopsies and bronchial lavage (BL) collection, was initiated with the specific goal of identifying biomarkers for the early detection of non-small cell lung cancer. We report and discuss the results of p16, DAPK, MGMT, FHIT and APC methylation analysis in the 126 first patients: 77 at high risk of cancer and 49 followed up after primary cancer resection. Positive results were found in 49% of BLs, 53% in current smokers and 43% in former smokers. In presence of peripheral tumours, only 38% of BLs were abnormal versus 73% in presence of central tumours, 50% in presence of preneoplasic lesions and 47% in absence of lesions. FHIT methylation was an early event, observed in one-third of the BLs from patients with or without lesions as well as in tumours. APC methylation was a late event observed in 33% of tumours but rarely in BLs. p16 was methylated in 17% of BLs but in 48% of tumours; DAPK in 15% of BL and 22% of tumours. MGMT methylation was rare. Among patients followed up after cancer surgery, 14 were in remission with normalised BL, whereas three had positive BLs and relapsed with a central tumour. Thus, gene methylation in BL might help to detect central tumours but a CT is crucial for peripheral cancer detection.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Metilación de ADN , Genes Relacionados con las Neoplasias , Neoplasias Pulmonares/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Lavado Broncoalveolar , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Regiones Promotoras Genéticas , Estudios Prospectivos , Sensibilidad y Especificidad , Fumar/efectos adversos , Tomografía Computarizada por Rayos XRESUMEN
Lung cancer results from a stepwise accumulation of genetic and molecular abnormalities with unknown temporal relationships to precursor bronchial lesions. In a search for biomarkers of malignant progression, we analyzed the expression of the tumor suppressor gene Rb and of the proteins regulating its phosphorylation and function in G1 arrest, p16INK4A and cyclin D1, in preinvasive bronchial lesions accompanying cancer in 75 patients, in comparison with similar lesions in 22 patients with no cancer history. Rb was constantly expressed in preinvasive lesions, including carcinoma in situ (CIS). In contrast, p16 expression was lost in moderate dysplasia (12%) and in CIS (30%) in patients with lung cancer. p16 loss occurred exclusively in patients who displayed loss of p16 expression in their related invasive carcinoma. Loss of p16 expression was not seen in nine patients with dysplasia but no cancer progression. Cyclin D1 overexpression was seen in hyperplasia and metaplasia (6%), mild dysplasia (17%), moderate dysplasia (46%), and CIS (38%) in patients with cancer but was lost in 5% of the patients during the process of invasion; it was also observed in patients with no cancer progression (14%). Our results indicate that Rb protein function can be invalidated before invasion through alteration of the Rb phosphorylation pathway, by p16 inhibition, and/or by cyclin D1 overexpression and suggest a role for p16 and cyclin D1 deregulation in progression of preinvasive bronchial lesions to invasive carcinoma.