Wang Wei-Shu, Chen Po-Min, Wang Huann-Sheng, Liang Wen-Yih, Su Yeu
Division of Medical Oncology, Department of Medicine. Division of Colorectal Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China.
Carcinogenesis. 2006 May;27(5):1113-20. doi: 10.1093/carcin/bgi351. Epub 2006 Feb 10.
The ability of tumor cells to resist apoptosis triggered by immune cells results in their escape from immune surveillance of the host. A critical effector of apoptosis is the Fas/Fas ligand (FasL) system that mediates the tumoricidal effects of cytotoxic T cells. Recently, in vitro cleavage of Fas expressed in various tumor cells by matrix metalloproteinase-7 (MMP-7) was demonstrated. In the present study, we first analyzed the influence of this metalloproteinase on Fas signaling in SW480, HCT-15 and HT-29 colorectal carcinoma (CRC) cells by assessing their responses to either an agonistic Fas antibody (CH11) or the FasL-bearing Jurkat cells after they were pretreated with MMP-7. Interestingly, both antibody- and Jurkat cell-induced apoptosis in three different CRC lines were significantly reduced by MMP-7 pretreatment. Additionally, immunohistochemical (IHC) staining was used to examine the expression levels of MMP-7 and Fas in tumor samples of 54 CRC patients. In agreement with our in vitro observation, the expression of MMP-7 in tumor tissues was inversely correlated with those of Fas (P < 0.001; chi2-test). Moreover, shortened survival was found in patients with a higher MMP-7 and a lower Fas expression, respectively, in their tumor tissues (P < 0.0001). Finally, by multivariate analysis, we discovered that MMP-7 (P = 0.001) and Fas levels (P = 0.036) were independent prognostic factors for CRC patients. These results suggest that Fas downregulation and a consequential increased resistance to FasL-triggered apoptosis resulting from upregulated MMP-7 in colorectal cancer cells could be a key mechanism for their escape from the immune surveillance, thereby predicting a poor survival in CRC patients.
肿瘤细胞抵抗免疫细胞触发的凋亡的能力导致它们逃避宿主的免疫监视。凋亡的一个关键效应因子是Fas/Fas配体（FasL）系统，该系统介导细胞毒性T细胞的杀肿瘤作用。最近，已证实基质金属蛋白酶-7（MMP-7）可在体外切割各种肿瘤细胞中表达的Fas。在本研究中，我们首先通过评估SW480、HCT-15和HT-29结肠直肠癌（CRC）细胞在用MMP-7预处理后对激动性Fas抗体（CH11）或携带FasL的Jurkat细胞的反应，来分析这种金属蛋白酶对Fas信号传导的影响。有趣的是，MMP-7预处理显著降低了三种不同CRC细胞系中抗体和Jurkat细胞诱导的凋亡。此外，免疫组织化学（IHC）染色用于检测54例CRC患者肿瘤样本中MMP-7和Fas的表达水平。与我们的体外观察结果一致，肿瘤组织中MMP-7的表达与Fas的表达呈负相关（P < 0.001；卡方检验）。此外，在肿瘤组织中MMP-7较高而Fas表达较低的患者中发现生存期缩短（P < 0.0001）。最后，通过多变量分析，我们发现MMP-7（P = 0.001）和Fas水平（P = 0.036）是CRC患者的独立预后因素。这些结果表明，结肠癌细胞中MMP-7上调导致Fas下调以及对FasL触发的凋亡的相应抗性增加可能是它们逃避免疫监视的关键机制，从而预示CRC患者的生存期较差。
