RESUMEN
Stem cells contribute to regeneration of tissues and organs. Cells with stem cell-like properties have been identified in tumors from a variety of origins, but to our knowledge there are yet no reports on tumor-related stem cells in the human upper respiratory tract. In the present study, we show that a tracheal mucoepidermoid tumor biopsy obtained from a 6 year-old patient contained a subpopulation of cells with morphology, clonogenicity and surface markers that overlapped with bone marrow mesenchymal stromal cells (BM-MSCs). These cells, designated as MEi (mesenchymal stem cell-like mucoepidermoid tumor) cells, could be differentiated towards mesenchymal lineages both with and without induction, and formed spheroids in vitro. The MEi cells shared several multipotent characteristics with BM-MSCs. However, they displayed differences to BM-MSCs in growth kinectics and gene expression profiles relating to cancer pathways and tube development. Despite this, the MEi cells did not possess in vivo tumor-initiating capacity, as proven by the absence of growth in situ after localized injection in immunocompromised mice. Our results provide an initial characterization of benign tracheal cancer-derived niche cells. We believe that this report could be of importance to further understand tracheal cancer initiation and progression as well as therapeutic development.
Asunto(s)
Tumor Mucoepidermoide/patología , Células Madre Neoplásicas/patología , Neoplasias de la Tráquea/patología , Animales , Separación Celular , Niño , Femenino , Perfilación de la Expresión Génica , Genómica , Humanos , Masculino , Células Madre Mesenquimatosas/patología , Ratones , Tumor Mucoepidermoide/diagnóstico , Tumor Mucoepidermoide/genética , Neoplasias de la Tráquea/diagnóstico , Neoplasias de la Tráquea/genéticaRESUMEN
Chimeric oncoproteins created by chromosomal translocations are among the most common genetic mutations associated with tumorigenesis. Malignant mucoepidermoid salivary gland tumors, as well as a growing number of solid epithelial-derived tumors, can arise from a recurrent t (11, 19)(q21;p13.1) translocation that generates an unusual chimeric cAMP response element binding protein (CREB)-regulated transcriptional coactivator 1 (CRTC1)/mastermind-like 2 (MAML2) (C1/M2) oncoprotein comprised of two transcriptional coactivators, the CRTC1 and the NOTCH/RBPJ coactivator MAML2. Accordingly, the C1/M2 oncoprotein induces aberrant expression of CREB and NOTCH target genes. Surprisingly, here we report a gain-of-function activity of the C1/M2 oncoprotein that directs its interactions with myelocytomatosis oncogene (MYC) proteins and the activation of MYC transcription targets, including those involved in cell growth and metabolism, survival, and tumorigenesis. These results were validated in human mucoepidermoid tumor cells that harbor the t (11, 19)(q21;p13.1) translocation and express the C1/M2 oncoprotein. Notably, the C1/M2-MYC interaction is necessary for C1/M2-driven cell transformation, and the C1/M2 transcriptional signature predicts other human malignancies having combined involvement of MYC and CREB. These findings suggest that such gain-of-function properties may also be manifest in other oncoprotein fusions found in human cancer and that agents targeting the C1/M2-MYC interface represent an attractive strategy for the development of effective and safe anticancer therapeutics in tumors harboring the t (11, 19) translocation.
Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Animales , Línea Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 19/genética , Proteínas de Unión al ADN/química , Redes Reguladoras de Genes , Genes myc , Células HEK293 , Humanos , Ratones , Tumor Mucoepidermoide/genética , Tumor Mucoepidermoide/metabolismo , Células 3T3 NIH , Proteínas Nucleares/química , Proteínas de Fusión Oncogénica/química , Dominios y Motivos de Interacción de Proteínas , Ratas , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/metabolismo , Transactivadores , Factores de Transcripción/química , Translocación GenéticaRESUMEN
BACKGROUND: Overexpression of sphingosine kinase-1 (SPHK1) has been demonstrated to be associated with the development and progression in various types of human cancers. The current study was to characterize the expression of SPHK1 in salivary gland carcinomas (SGC) and to investigate the association between SPHK1 expression and progression of SGC. METHODS: The expression of SPHK1 was examined in 2 normal salivary gland tissues, 8 SGC tissues of various clinical stages, and 5 pairs of primary SGC and adjacent salivary gland tissues from the same patient, using real-time PCR and western blot analysis. Furthermore, the SPHK1 protein expression was analyzed in 159 clinicopathologically characterized SGC cases by immunohistochemistry. Statistical analyses were performed to determine the prognostic and diagnostic associations. RESULTS: SPHK1 expression was found to be markedly upregulated in SGC tissues than that in the normal salivary gland tissues and paired adjacent salivary gland tissues, at both mRNA and protein levels. Statistical analysis revealed a significant correlation of SPHK1 expression with the clinical stage (P = 0.005), T classification (P = 0.017), N classification (P = 0.009), M classification (P = 0.002), and pathological differentiation (P = 0.013). Patients with higher SPHK1 expression had shorter overall survival time, whereas patients with lower SPHK1 expression had better survival. Importantly, patients in the group without adjuvant therapy who exhibited high SPHK1 expression had significantly lower overall survival rates compared with those with low SPHK1 expression. Moreover, multivariate analysis suggested that SPHK1 expression might be an independent prognostic indicator for the survival of SGC patients. CONCLUSIONS: Our results suggest that SPHK1 expression is associated with SGC progression, and might represent as a novel and valuable predictor for adjuvant therapy to SGC patients.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Neoplasias de las Glándulas Salivales/metabolismo , Glándulas Salivales/metabolismo , Adenocarcinoma Papilar/genética , Adenocarcinoma Papilar/metabolismo , Adenocarcinoma Papilar/patología , Biomarcadores de Tumor/genética , Western Blotting , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/metabolismo , Carcinoma de Células Acinares/patología , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Adenoide Quístico/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Rayos gamma , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Tumor Mucoepidermoide/genética , Tumor Mucoepidermoide/metabolismo , Tumor Mucoepidermoide/patología , Cuidados Paliativos , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Pronóstico , ARN Mensajero/genética , Radioterapia Adyuvante , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Glándulas Salivales/patología , Tasa de SupervivenciaRESUMEN
BACKGROUND: Alteration of cadherin and catenin expression is associated with loss of differentiation, acquisition of an invasive phenotype, and poor prognosis in many types of cancers. The roles of cadherins and catenins in mucoepidermoid carcinoma (MEC) are not fully understood. METHODS: Based on immunohistochemical studies, the expressions of E-, N-, and P-cadherins and alpha-, beta-, and gamma-catenins in MEC were investigated, and correlations with clinicopathologic parameters were evaluated. RESULTS: These six molecules were strongly expressed in normal ductal epithelium but increased or decreased immunoreactivities of those proteins in MEC were frequently observed, especially for E-cadherin and alpha-catenin. The immunoactivity of beta-catenin showed significant correlation with grade (P = 0.05) and stage (P < 0.0001). beta-Catenin expressions are also correlated with gamma-catenin expression (P = 0.006) according to cross-table analysis. Survival analysis indicated that stage, grade, and beta-catenin expressions had significant correlation with survival. CONCLUSION: Aberrant beta-catenin expression may play an important role in the histologic differentiation and tumor staging of MEC.
