Viard-Leveugle Isabelle, Veyrenc Sylvie, French Lars E, Brambilla Christian, Brambilla Elisabeth
Lung Cancer Research Group, INSERM U578, Institut Albert Bonniot, 38706 La Tronche Cedex, France.
J Pathol. 2003 Oct;201(2):268-77. doi: 10.1002/path.1428.
Fas (CD95) and its ligand FasL signal apoptosis and are involved in tissue homeostasis and the elimination of target cells by cytotoxic T cells. Corruption of this signalling pathway in tumour cells, for example by reduced Fas expression or increased FasL expression, can participate in tumour development and immune escape. The present study has analysed Fas/FasL expression and Fas death signalling function in vivo in lung tumour tissues [57 non-small cell lung carcinomas and 64 neuroendocrine lung tumours including small cell lung carcinoma (SCLC)] in comparison with normal lung tissue, and in vitro in neuroendocrine tumour cell lines in comparison with normal human bronchial epithelial cells. The Fas expression score was markedly decreased compared with normal lung tissue in 90% of the 121 lung tumours and was completely lost in 24%. The Fas staining pattern suggested cytoplasmic Fas expression in tumours, whereas membrane expression was observed in normal lung tissue. Loss of Fas at the cell surface was also shown in vitro by FACS analysis of neuroendocrine tumour cell lines and was concomitant with the resistance of tumour cells to FasL-mediated apoptosis according to in vitro cell viability. The lack of cell surface Fas expression in tumour cell lines resulted from the lack of intracellular Fas protein due to impaired Fas gene transcription. The FasL expression score was also decreased in most non-small cell lung carcinomas compared with normal bronchial cells, whereas 91% of SCLCs had higher expression than normal cells. FasL overexpression was related to advanced tumour stage as well as to a Fas/FasL ratio less than 1. It is concluded that a marked decrease in Fas expression may be part of lung tumourigenesis allowing tumour cells to escape from apoptosis. FasL overexpression in the context of Fas down-regulation in SCLC predicts the ability of SCLC cells to induce paracrine killing of Fas-expressing cytotoxic T cells. In lung tumours, Fas restoration may represent a key, although not unique, step in therapeutic strategies to reconstitute the ability of tumour cells to undergo apoptosis.
Fas（CD95）及其配体FasL介导细胞凋亡信号，参与组织稳态维持以及细胞毒性T细胞对靶细胞的清除过程。肿瘤细胞中该信号通路的破坏，如Fas表达降低或FasL表达增加，可参与肿瘤的发生发展及免疫逃逸。本研究分析了肺肿瘤组织[57例非小细胞肺癌和64例神经内分泌肺肿瘤，包括小细胞肺癌（SCLC）]与正常肺组织相比，体内Fas/FasL的表达及Fas死亡信号功能；并分析了神经内分泌肿瘤细胞系与正常人支气管上皮细胞相比，体外Fas/FasL的表达及Fas死亡信号功能。在121例肺肿瘤中，90%的肿瘤组织Fas表达评分与正常肺组织相比显著降低，24%的肿瘤组织Fas表达完全缺失。Fas染色模式显示肿瘤细胞中Fas呈细胞质表达，而正常肺组织中Fas呈膜表达。通过对神经内分泌肿瘤细胞系进行FACS分析，体外实验也显示肿瘤细胞表面Fas缺失，并且根据体外细胞活力检测结果，这与肿瘤细胞对FasL介导的凋亡具有抗性相关。肿瘤细胞系缺乏细胞表面Fas表达是由于Fas基因转录受损导致细胞内Fas蛋白缺乏。与正常支气管细胞相比，大多数非小细胞肺癌组织中FasL表达评分也降低，而91%的SCLC组织FasL表达高于正常细胞。FasL过表达与肿瘤晚期以及Fas/FasL比值小于1有关。研究得出结论，Fas表达显著降低可能是肺肿瘤发生的一部分，使肿瘤细胞能够逃避凋亡。在SCLC中，Fas下调背景下的FasL过表达预示着SCLC细胞具有诱导表达Fas的细胞毒性T细胞发生旁分泌杀伤的能力。在肺肿瘤中，恢复Fas表达可能是重建肿瘤细胞凋亡能力的治疗策略中的关键步骤，尽管不是唯一步骤。
