肿瘤微环境来源的TGF-β1通过诱导树突状细胞FasL的表达促进肺癌的进展及其机制研究

Fas（also known as CD95/Apo-1）is a classic apoptotic signal，almost all tumors express Fas, but activation of Fas signal do not induce tumor apoptosis , instead of promoting the progress of tumor in most cases. Several studies have assessed that the activation of Fas signal do not induce lung cancer cells apoptosis, but recruit myeloid -derived suppressor cells (Myeloid-derived suppressor cells, MDSCs) to mediate tumor progression. Dendritic cells (Dendritic cells, DCs) can stimulate strong anti-tumor immune response, the DC vaccine is effective for treating tumor . Recently TGF-β1 was reported can induce FasL expression of DCs. In addition, the lung tumor microenvironment can detect high levels of TGF-β1. Our previous experiments showed that 3LL murine Lewis lung tumor tissue or cell culture supernatant can induce DCs express considerable FasL and promote their invasion . Therefore , we hypothesized that TGF-β1 in tumor microenvironment can induce FasL expression of DCs to promote tumor progression. This project will clarify the role of DCs promote tumor progression and its relationship with the FasL and TGF-β1 in vivo and vitro . In addition , we will sort FasLhigh DCs or FasLlowDCs from tumor mice and evaluate its effect on the biological behavior of lung cancer cells, thereby providing new ideas for the treatment of lung cancer.

Fas是经典的凋亡信号，几乎所有的肿瘤均表达Fas，但多数肿瘤Fas信号的活化不引起细胞凋亡，却促进其进展，研究显示肺癌细胞Fas信号的活化不诱导细胞凋亡，却通过促进其招募髓系来源的抑制性细胞介导肿瘤进展。树突状细胞（Dendritic cells，DCs）能激发机体强大的抗肿瘤免疫，是治疗肿瘤的有效疫苗。最近有报道指出，TGF-β1能诱导DCs高表达FasL。另外，肺癌肿瘤微环境中能检测到高水平TGF-β1。我们前期实验显示，3LL小鼠肺癌细胞培养或肿瘤组织研磨上清能诱导DCs表达FasL，并促进其体外侵袭。因此，我们推测，肿瘤微环境中的TGF-β1能诱导DCs表达FasL而促进肿瘤进展。本项目将通过体内、外实验明确DCs促肿瘤进展的作用及与FasL和TGF-β1的关系。此外，通过分选肺癌小鼠体内来源的FasL高、低表达的DCs，评价其对肺癌细胞生物学行为的影响，为肺癌的治疗提供新思路。

Fas是经典的凋亡信号，几乎所有的肿瘤均表达Fas，但多数肿瘤Fas信号的活化不引起细胞凋亡，却促进其进展，研究显示肺癌细胞Fas信号的活化不诱导细胞凋亡，却通过促进其招募髓系来源的抑制性细胞介导肿瘤进展。树突状细胞（Dendritic cells，DCs）能激发机体强大的抗肿瘤免疫，是治疗肿瘤的有效疫苗。最近有报道指出，TGF-β1能诱导DCs高表达FasL。另外，肺癌肿瘤微环境中能检测到高水平TGF-β1。我们前期实验显示，3LL小鼠肺癌细胞培养或肿瘤组织研磨上清能诱导DCs表达FasL，并促进其体外侵袭。因此，我们推测，肿瘤微环境中的TGF-β1能诱导DCs表达FasL而促进肿瘤进展。本项目将通过体内、外实验明确DCs促肿瘤进展的作用及与FasL和TGF-β1的关系。此外，通过分选肺癌小鼠体内来源的FasL高、低表达的DCs，评价其对肺癌细胞生物学行为的影响，为肺癌的治疗提供新思路。