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1.
Biomed Res Int ; 2013: 279505, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23762835

RESUMO

Tumor-associated immune cells often lack immune effector activities, and instead they present protumoral functions. To understand how tumors promote this immunological switch, invasive and noninvasive breast cancer cell (BRC) lines were cocultured with a promonocytic cell line in a Matrigel-based 3D system. We hypothesized that if communication exists between tumor and immune cells, coculturing would result in augmented expression of genes associated with tumor malignancy. Upregulation of proteases MMP1 and MMP9 and inflammatory COX2 genes was found likely in response to soluble factors. Interestingly, changes were more apparent in promonocytes and correlated with the aggressiveness of the BRC line. Increased gene expression was confirmed by collagen degradation assays and immunocytochemistry of prostaglandin 2, a product of COX2 activity. Untransformed MCF-10A cells were then used as a sensor of soluble factors with transformation-like capabilities, finding that acini formed in the presence of supernatants of the highly aggressive BRC/promonocyte cocultures often exhibited total loss of the normal architecture. These data support that tumor cells can modify immune cell gene expression and tumor aggressiveness may importantly reside in this capacity. Modeling interactions in the tumor stroma will allow the identification of genes useful as cancer prognostic markers and therapy targets.


Assuntos
Células Acinares/patologia , Neoplasias da Mama/patologia , Colágeno/metabolismo , Ciclo-Oxigenase 2/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Células Precursoras de Monócitos e Macrófagos/enzimologia , Células Acinares/metabolismo , Neoplasias da Mama/genética , Comunicação Celular/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Técnicas de Cocultura , Dinoprostona/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Matriz Extracelular/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Biológicos , Células Precursoras de Monócitos e Macrófagos/patologia , Invasividade Neoplásica , Fenótipo , Proteólise , Solubilidade , Regulação para Cima
2.
Arch Med Res ; 31(2): 172-81, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10880723

RESUMO

BACKGROUND: The invasive and metastatic potential of malignant cells results from complex interactions of numerous factors not yet fully understood. Genomic alterations such as ras overexpression and nm23-H1 inhibition have been found to be frequently associated with increased invasiveness in various cancers. On the other hand, secretion of different proteinases are necessary for malignant cells to traverse a network of matrix macromolecules, but the relationship between the genomic alterations and the proteolytic phenotype is still unclear. Our aim was to investigate whether the appearance of the proteolytic phenotype had any correlation with the expression of H-ras and nm23-H1 genes in carcinoma of the uterine cervix. METHODS: Twenty-five samples from patients with carcinoma of the uterine cervix at different clinical stages were studied. Cathepsin B1, plasminogen activator, and collagenase activity were assessed in tissue cytosols using specific synthetic oligopeptides as substrates. The expression of H-ras and nm23-H1 was investigated by means of immunohistochemistry and in situ hybridization. RESULTS: Our results showed that cathepsin B1 was the most consistently elevated proteinase, demonstrating a linear correlation with clinical staging. H-ras expression was found elevated in 40% of the cases. Nm23-H1 protein immunoreactivity was positive in 40% of the cases. No correlation was found among H-ras, cathepsin B1 activity, and survival rate. Among cases with high cysteine proteinase activity, a different clinical behavior depending on the expression of Nm23-H1 was observed. The cases with Nm23-H1 protein had a markedly better survival rate than those lacking this protein. In contrast, the absence of Nm23-H1 in association with high cathepsin B1 activity was a clear indicator of a poor prognosis. CONCLUSIONS: These findings suggest a complex interaction between the proteolytic phenotype and the expression of H-ras and nm23-H1 genes in carcinoma of the cervix that influences the clinical behavior of the tumor.


Assuntos
Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Genes ras , Proteínas Monoméricas de Ligação ao GTP/biossíntese , Proteínas de Neoplasias/biossíntese , Núcleosídeo-Difosfato Quinase , Proteínas Proto-Oncogênicas p21(ras)/biossíntese , Fatores de Transcrição/biossíntese , Neoplasias do Colo do Útero/genética , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Catepsina B/análise , Colagenases/análise , Citosol/química , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Hibridização In Situ , Proteínas Monoméricas de Ligação ao GTP/genética , Nucleosídeo NM23 Difosfato Quinases , Invasividade Neoplásica/genética , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , Inibidor 1 de Ativador de Plasminogênio/análise , Fatores de Transcrição/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
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