RESUMO
Peritoneum is the most common site for ovarian cancer metastasis. Here we investigate how cancer epigenetics regulates reciprocal tumor-stromal interactions in peritoneal metastasis of ovarian cancer. Firstly, we find that omental stromal fibroblasts enhance colony formation of metastatic ovarian cancer cells, and de novo expression of transforming growth factor-alpha (TGF-α) is induced in stromal fibroblasts co-cultured with ovarian cancer cells. We also observed an over-expression of tumor necrosis factor-alpha (TNF-α) in ovarian cancer cells, which is regulated by promoter DNA hypomethylation as well as chromatin remodeling. Interestingly, this ovarian cancer-derived TNF-α induces TGF-α transcription in stromal fibroblasts through nuclear factor-κB (NF-κB). We further show that TGF-α secreted by stromal fibroblasts in turn promotes peritoneal metastasis of ovarian cancer through epidermal growth factor receptor (EGFR) signaling. Finally, we identify a TNFα-TGFα-EGFR interacting loop between tumor and stromal compartments of human omental metastases. Our results therefore demonstrate cancer epigenetics induces a loop of cancer-stroma-cancer interaction in omental microenvironment that promotes peritoneal metastasis of ovarian cancer cells via TNFα-TGFα-EGFR.
Assuntos
Receptores ErbB/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/metabolismo , Fator de Crescimento Transformador alfa/metabolismo , Microambiente Tumoral , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Idoso , Animais , Comunicação Celular , Linhagem Celular Tumoral , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Metástase Neoplásica , Transplante de Neoplasias , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/secundário , Células Estromais/metabolismo , Células Estromais/patologiaRESUMO
Depression is a common problem for many Hong Kong Chinese elderly, especially those living in nursing homes. This study examines the relationship between fear of falling and depressive symptoms as well as the role of participation in physical activity and fall efficacy in the linkage between the fear of falling and depression. A sample of 100 residents living in nursing homes were interviewed. Using multiple regression models, we found that elderly persons who had greater fear of falling tended to report depressive symptoms more frequently after controlling socio-demographic and physical health status variables. In addition, activity involvement and fall efficacy acted as mediators and moderators in the link between the fear of falling and depression. Policy makers and aged care professional practitioners should find these findings valuable in promoting activity to aid in the prevention of depression amongst the elderly population.