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1.
J Pathol ; 225(1): 142-50, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21710490

RESUMO

Lymph node metastasis is associated with resistance to conventional therapy and poor survival of patients with oral squamous cell carcinoma (OSCC). Although lymphangiogenesis is well known to be associated with the occurrence of lymph node metastasis in various cancers, the precise mechanisms of lymphangiogenesis in OSCC are largely unknown. IL-6, a potent pro-inflammatory cytokine, has been shown to play active roles in various cancers, including OSCC. This study aimed to investigate the involvement of IL-6 signalling in lymphatic metastasis and to evaluate the efficacy of tocilizumab, a humanized anti-human IL-6 receptor antibody, as an anti-lymphangiogenic agent for OSCC. This investigation confirmed that levels of expression of IL-6 protein and VEGF-C mRNA in OSCC tissues were significantly correlated with lymph node metastasis in patients with OSCC, as assessed by immunohistochemical analysis and real-time quantitative RT-PCR. In vitro studies showed that IL-6 regulated VEGF-C mRNA expression in a human OSCC cell line, SAS cells, through the phosphoinositide 3-kinase-Akt pathway. In addition, treatment with tocilizumab led to markedly reduced VEGF-C mRNA expression and OSCC-related lymphangiogenesis in SAS xenografts. Together, these data suggest that tocilizumab acted as expected: it inhibited lymph node metastasis in OSCC by reducing tumour lymphangiogenesis.


Assuntos
Carcinoma de Células Escamosas/secundário , Interleucina-6/fisiologia , Linfangiogênese/fisiologia , Neoplasias Bucais/fisiopatologia , Fator C de Crescimento do Endotélio Vascular/biossíntese , Idoso , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/fisiopatologia , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfangiogênese/efeitos dos fármacos , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/genética , Fosfatidilinositol 3-Quinases/fisiologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/fisiologia , RNA Mensageiro/genética , RNA Neoplásico/genética , Transdução de Sinais/fisiologia , Células Tumorais Cultivadas , Fator C de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de Xenoenxerto
2.
J Cell Physiol ; 193(1): 55-63, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12209880

RESUMO

Cultivation of human parotid glands in serum-free medium (Ca(2+) concentration, 0.2 mM) with growth supplements resulted in isolation of a homogeneous population of epithelial cells without any mesenchymal cells. The isolated cells showed an undifferentiated phenotype with scant cytoplasmic organelles, and low levels of alpha-amylase expression. The cells remained viable and undifferentiated for up to 24 passages when subcultured at 80% confluence in 0.2 mM Ca(2+) medium with a 1:3 split ratios. There was little cell-cell contact. A Ca(2+) switch from 0.2 to 1 mM induced cell-cell contact with translocation of desmosomal proteins from the cytoplasm to the cell membrane, and sequential differentiation of serous acinar cells with a glandular arrangement, well-developed cytoplasmic organelles and an increased level of alpha-amylase expression. These morphological changes and desmosome assembly were blocked by treatment with non-specific PKC inhibitor. Moreover, the addition of PKC activator, tetradecanoylphorbol 13-acetate (TPA), to 0.2 mM Ca(2+) medium caused transient assembly of desmosome-like structure, but did not induce cell-cell contact or morphological differentiation. Cultivation of the cells in 1.5 mM Ca(2+) medium resulted in increased stratification of the cells and reduced alpha-amylase expression. These findings provide the first demonstration that continuous cultivation in 1.0 mM Ca(2+) medium is required for cellular differentiation of salivary gland acinar cells, and maintenance of the differentiated state.


Assuntos
Cálcio/farmacologia , Glândula Parótida/efeitos dos fármacos , Western Blotting , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Meios de Cultura Livres de Soro/farmacologia , Proteínas do Citoesqueleto/metabolismo , Desmoplaquinas , Desmossomos/efeitos dos fármacos , Desmossomos/metabolismo , Relação Dose-Resposta a Droga , Ativadores de Enzimas/farmacologia , Inibidores Enzimáticos/farmacologia , Substâncias de Crescimento/farmacologia , Humanos , Organelas/efeitos dos fármacos , Glândula Parótida/citologia , Proteína Quinase C/efeitos dos fármacos , Proteína Quinase C/metabolismo , alfa-Amilases/metabolismo
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