Assuntos
Neoplasias da Mama , Mastectomia , Mama/cirurgia , Neoplasias da Mama/cirurgia , China , Feminino , Humanos , Instrumentos CirúrgicosRESUMO
γδT cells have been reported to exert immunosuppressive functions in multiple solid malignant diseases, but their immunosuppressive functional subpopulation in breast cancer (BC) is still undetermined. Here, we collected 40 paired BC and normal tissue samples from Chinese patients for analysis. First, we showed that γδT1 cells comprise the majority of CD3+ T cells in BC; next, we found that CD73+γδT1 cells were the predominant regulatory T-cell (Treg) population in BC, and that their prevalence in peripheral blood was also related to tumour burden. In addition, CD73+γδT1 cells exert an immunosuppressive effect via adenosine generation. We also found that BC could modulate CD73 expression on γδT cells in a non-contact manner. The microarray analysis and functional experiments indicated that breast tumour cell-derived exosomes (TDEs) could transmit lncRNA SNHG16, which upregulates CD73 expression, to Vδ1 T cells. Regarding the mechanism, SNHG16 served as a ceRNA by sponging miR-16-5p, which led to the derepression of its target gene SMAD5 and resulted in potentiation of the TGF-ß1/SMAD5 pathway to upregulate CD73 expression in Vδ1 T cells. Our results showed that the BC-derived exosomal SNHG16/miR-16-5p/SMAD5-regulatory axis potentiates TGF-ß1/SMAD5 pathway activation, thus inducing CD73 expression in Vδ1 T cells. Our results first identify the significance of CD73+Vδ1 Tregs in BC, and therapy targeting this subpopulation or blocking TDEs might have potential for BC treatment in the future.
Assuntos
5'-Nucleotidase/genética , Neoplasias da Mama/imunologia , Exossomos/imunologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem da Célula/imunologia , Movimento Celular/genética , Proliferação de Células/genética , Intervalo Livre de Doença , Exossomos/genética , Exossomos/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Linfócitos Intraepiteliais/imunologia , Células MCF-7 , Análise em Microsséries , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteína Smad5/genética , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta1/genéticaRESUMO
The dependence of tumor growth on neovascularization has become an important aspect of cancer biology. Tumor angiogenesis is one of the key mechanisms of tumorigenesis, growth and metastasis. The key events involved in this process are endothelial cell proliferation, migration, and vascular formation. Recent studies have revealed the importance of tumor-associated endothelial cells (TECs) in the development and progression of colorectal cancer (CRC), including epithelial proliferation, stem cell maintenance, angiogenesis, and immune remodeling. Decades of research have identified that the molecular basis of tumor angiogenesis includes vascular endothelial growth factors (VEGFs) and their receptor family, which are the main targets of antiangiogenesis therapy. VEGFs and their receptors play key roles in the pathology of angiogenesis, and their overexpression indicates poor prognosis in CRC. This article reviews the characteristics of the tumor vasculature and the role of TECs in different stages of CRC and immune remodeling. We also discuss the biological effects of VEGFs and their receptor family as angiogenesis regulators and emphasize the clinical implications of TECs in clinical treatment.