RESUMO
An association between inflammation and cancer has long been recognized, but the cause and effect relationship linking the two remains unclear. Myc is a pleiotropic transcription factor that is overexpressed in many human cancers and instructs many extracellular aspects of the tumor tissue phenotype, including remodeling of tumor stroma and angiogenesis. Here we show in a beta-cell tumor model that activation of Myc in vivo triggers rapid recruitment of mast cells to the tumor site-a recruitment that is absolutely required for macroscopic tumor expansion. In addition, treatment of established beta-cell tumors with a mast cell inhibitor rapidly triggers hypoxia and cell death of tumor and endothelial cells. Inhibitors of mast cell function may therefore prove therapeutically useful in restraining expansion and survival of pancreatic and other cancers.
Assuntos
Transformação Celular Neoplásica/genética , Mastócitos/metabolismo , Neovascularização Patológica/etiologia , Neoplasias Pancreáticas/irrigação sanguínea , Proteínas Proto-Oncogênicas c-myc/fisiologia , Animais , Células da Medula Óssea/citologia , Células Cultivadas , Quimiocina CCL2/metabolismo , Quimiocina CCL5/metabolismo , Fêmur/citologia , Regulação Neoplásica da Expressão Gênica , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neovascularização Patológica/genética , Neovascularização Patológica/fisiopatologia , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/fisiopatologia , Proteínas Proto-Oncogênicas c-myc/genéticaRESUMO
Serum mast cell tryptase levels are used as a diagnostic criterion and surrogate marker of disease severity in mastocytosis. Approximately 29% of the healthy population lacks alpha tryptase genes; however, it is not known whether lack of alpha tryptase genes leads to variability in tryptase levels or impacts on disease severity in mastocytosis. We have thus analyzed tryptase haplotype in patients with mastocytosis, computing correlations between haplotype and plasma total and mature tryptase levels; and disease category. We found: (1) the distribution of tryptase haplotype in patients with mastocytosis appeared consistent with Hardy-Weinberg equilibrium and the distribution in the general population; (2) the disease severity and plasma tryptase levels were not affected by the number of alpha or beta tryptase alleles in this study; and (3) information about the tryptase haplotype did not provide any prognostic value about the severity of disease. Total and mature tryptase levels positively correlated with disease severity, as well as prothrombin time and partial thromboplastin time, and negatively correlated with the hemoglobin concentration.
