RESUMO
BACKGROUND: Lymphocytes from tumor-bearing animals have been shown to lack antitumor function. The objective of this study was to investigate the status of the signal transducers, Stat1 and Stat3, in T lymphocytes of animals bearing D1-DMBA-3 mammary tumors and to elucidate if any alterations in these signal transducers can be explained by the presence of tumor-derived factors and correlated with the lack of antitumor function in these cells. MATERIALS AND METHODS: T Lymphocytes from spleens of normal and tumor-bearing mice were purified and assayed for the presence of Stat1 and Stat3 by Western blot analysis. RESULTS: It was found that levels of both Stat1 and Stat3 were reduced in T lymphocytes of tumor-bearers not only in their active, phosphorylated form but in total protein levels. CONCLUSION: These findings indicate that during mammary tumor progression, alteration of various transcription factors may contribute to the down-regulation of immune function.
Assuntos
Adenocarcinoma/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Linfócitos T/metabolismo , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/imunologia , Animais , Western Blotting , Carcinógenos/toxicidade , Ensaio de Imunoadsorção Enzimática , Feminino , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/genéticaRESUMO
Expression of the transmembrane isoform of Mucin 1 (MUC1/TM) in an aggressive murine mammary tumor line, DA-3, does not alter tumor development and metastasis, leading to death of the host. However, tumor cells expressing a secreted isoform of MUC1 (MUC1/sec) fail to develop tumors in immunocompetent mice. The rejection of MUC1/sec-expressing tumor cells is immunologically mediated, as, initially, innate cells and, ultimately, T cells are required. After gene array analysis, and confirmation at the protein level, it was discovered that MUC1/sec-expressing tumor cells (DA-3/sec) have a significant reduction in expression of urokinase-type plasminogen activator (uPA) relative to the parental tumor line and tumor cells expressing MUC1/TM. The serine protease uPA has been found to be involved in growth-promoting signaling, angiogenesis, and induction of matrix remodeling leading to metastasis. Although the tumor-promoting Stat3 transcription factor was unaltered in these tumor cells, the tumor-suppressive and IFN-responsive signal transducer and activator of transcription 1 (Stat1) is dramatically up-regulated in DA-3/sec cells. In addition, treatment of various murine and human cell lines with conditioned medium containing MUC1/sec results in up-regulation of Stat1. DA-3/sec tumor cells are also sensitized to the antiproliferative effects of IFN-gamma. Furthermore, transfection of the Stat1 gene into DA-3 tumor cells leads to a down-regulation of uPA and delays tumor progression. Thus, Stat1 up-regulation in DA-3/sec cells seems to play a significant role in the mechanism(s) by which rejection of tumor cells expressing MUC1/sec may be occurring.
