RESUMEN
OBJECTIVES: The hepatocyte growth factor receptor (Met) is frequently overexpressed in Head and Neck Squamous Cell Carcinoma (HNSCC), correlating positively with high-grade tumors and shortened patient survival. As such, Met may represent an important therapeutic target. The purpose of this study was to explore the role of Met signaling for HNSCC growth and locoregional dissemination. MATERIALS AND METHODS: Using a lentiviral system for RNA interference, we knocked down Met in established HNSCC cell lines that express high levels of the endogenous receptor. The effect of Met silencing on in vitro proliferation, cell survival and migration was examined using western analysis, immunohistochemistry and live cell imaging. In vivo tumor growth, dissemination and mouse survival was assessed using an orthotopic tongue mouse model for HNSCC. RESULTS: We show that Met knockdown (1) impaired activation of downstream MAPK signaling; (2) reduced cell viability and anchorage independent growth; (3) abrogated HGF-induced cell motility on laminin; (4) reduced in vivo tumor growth by increased cell apoptosis; (5) caused reduced incidence of tumor dissemination to regional lymph nodes and (6) increased the survival of nude mice with orthotopic xenografts. CONCLUSION: Met signaling is important for HNSCC growth and locoregional dissemination in vivo and that targeting Met may be an important strategy for therapy.
Asunto(s)
Proteínas Proto-Oncogénicas c-met/metabolismo , Neoplasias de la Lengua/metabolismo , Animales , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Indoles/farmacología , Metástasis Linfática , Ratones , Ratones Desnudos , Neoplasias Experimentales , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-met/efectos de los fármacos , ARN Interferente Pequeño/farmacología , Transducción de Señal/efectos de los fármacos , Sulfonamidas/farmacologíaRESUMEN
Genetic alterations of chromosome 7 are common in human cancer. Furthermore, previous studies have supported the presence of a gene important in a broad range of cancers at 7q22-31.1. There is evidence that supports an oncogenic function for this putative gene, as well as evidence that supports a tumor suppressive role. In this study, we used a cross-species candidate gene approach in combination with physical mapping to identify MPP11 as a candidate for the putative cancer-related activity at 7q22-31.1. We then analyzed primary head and neck squamous cell tumors (HNSCCs) for loss of heterozygosity/allelic imbalance (LOH/AI) at the MPP11 genomic locus. Thirty-eight percent of tumors examined displayed LOH/AI involving the MPP11 genomic locus. Mutation analysis of MPP11 in the latter samples did not identify any inactivating mutations. However, immunohistochemical staining of primary tumor sections and Western blot analysis of HNSCC cell lines revealed a tumor-specific high level of expression of MPP11p. Fluorescence in situ hybridization analysis done on the cell lines identified increased chromosome 7 copy number with a concomitant increase in MPP11 copy number. These results suggest an oncogenic role for MPP11 in HNSCC.
Asunto(s)
Carcinoma de Células Escamosas/genética , Proteínas de Unión al ADN/genética , Neoplasias de Cabeza y Cuello/genética , Proteínas Oncogénicas , Proteínas de Saccharomyces cerevisiae , Alelos , Secuencia de Aminoácidos , Animales , Carcinoma de Células Escamosas/metabolismo , Bovinos , Mapeo Cromosómico , Cromosomas Humanos Par 7 , ADN de Neoplasias/genética , Proteínas de Unión al ADN/biosíntesis , Proteínas Fúngicas/genética , Dosificación de Gen , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Hibridación Fluorescente in Situ , Pérdida de Heterocigocidad , Repeticiones de Microsatélite , Chaperonas Moleculares , Datos de Secuencia Molecular , Proteínas de Unión al ARN , Homología de Secuencia de AminoácidoRESUMEN
BACKGROUND: Esthesioneuroblastoma (ENB) is an uncommon malignant neoplasm of the upper nasal cavity. Therapeutic management approaches for this neoplasm lack uniformity and there is no universally accepted staging system. METHODS: A retrospective review of 27 patients with histologically confirmed ENB managed at The Johns Hopkins Hospital. RESULTS: Eighty-five percent of patients had surgical resection as part of their disease management. Complete surgical resection was achieved in 62% of patients who had a craniofacial resection. Eighty percent of patients with negative surgical margins remain with no evidence of disease, with a median follow-up of 5.6 years. Adjuvant radiation therapy was beneficial to 62% of patients with positive surgical margins. Clinical responses were observed with cisplatin- and etoposide-containing chemotherapy regimens in patients with advanced disease. A revised staging system based on our experience is proposed. CONCLUSIONS: ENB is best managed by craniofacial resection with complete tumor resection. Adjuvant radiation therapy is warranted in patients that remain with positive histologic margins of resection. Chemotherapy with cisplatin- and etoposide-containing regimens may be useful for palliation of advanced disease.
Asunto(s)
Estesioneuroblastoma Olfatorio/terapia , Neoplasias Nasales/terapia , Adolescente , Adulto , Anciano , Antineoplásicos/uso terapéutico , Cisplatino/uso terapéutico , Terapia Combinada , Supervivencia sin Enfermedad , Estesioneuroblastoma Olfatorio/mortalidad , Estesioneuroblastoma Olfatorio/patología , Estesioneuroblastoma Olfatorio/cirugía , Etopósido/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Cavidad Nasal , Estadificación de Neoplasias , Neoplasias Nasales/mortalidad , Neoplasias Nasales/patología , Neoplasias Nasales/cirugía , Radioterapia Adyuvante , Estudios RetrospectivosRESUMEN
We report a case of von Hippel-Lindau disease in a 55-year-old woman who presented with an intracanalicular hemangioblastoma and discuss the otologic manifestations of this disease. A review of the literature revealed no previous reports of this entity originating in the internal acoustic canal.
Asunto(s)
Conducto Auditivo Externo , Neoplasias del Oído/etiología , Hemangioblastoma/etiología , Enfermedad de von Hippel-Lindau/complicaciones , Neoplasias del Oído/cirugía , Femenino , Hemangioblastoma/cirugía , Humanos , Persona de Mediana EdadRESUMEN
The completion of the genome sequence of the budding yeast Saccharomyces cerevisiae marks the dawn of an exciting new era in eukaryotic biology that will bring with it a new understanding of yeast, other model organisms, and human beings. This body of sequence data benefits yeast researchers by obviating the need for piecemeal sequencing of genes, and allows researchers working with other organisms to tap into experimental advantages inherent in the yeast system and learn from functionally characterized yeast gene products which are their proteins of interest. In addition, the yeast post-genome sequence era is serving as a testing ground for powerful new technologies, and proven experimental approaches are being applied for the first time in a comprehensive fashion on a complete eukaryotic gene repertoire.