Bjørge L, Hakulinen J, Wahlström T, Matre R, Meri S
Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Finland.
Int J Cancer. 1997 Jan 6;70(1):14-25. doi: 10.1002/(sici)1097-0215(19970106)70:1<14::aid-ijc3>3.0.co;2-9.
Ovarian cancer has features that makes it well-suited for MAb adjuvant immunotherapy. Several of the MAbs used in clinical trials mediate cancer cell destruction by activation of complement (C). In this study, therefore, we examined the ability of ovarian-tumor cells to resist C attack. We found that the C regulators membrane cofactor protein (MCP, CD46) and protectin (CD59) were strongly expressed in the tumor cells in all 28 benign and malignant tumors examined. Decay-accelerating factor (DAF; CD55) was more heterogeneously expressed, and only 75% of the tumors exhibited a moderate amount of DAF in the tumor cells. In adenoma cells, CD59 and DAF were preferentially located apically, while in adenocarcinoma cells they were expressed also at the basolateral cell surface. The ovarian-carcinoma cell lines SK-OV-3, Caov-3, SW626 and PA-1 expressed both the 58- and the 68-kDa isoforms of MCP. DAF was present as a glycosyl-phosphatidylinositol(GPI)-anchored 70-kDa glycoprotein. The surface-expression level of DAF varied, and correlated with the vulnerability of the cells to C-mediated lysis. CD59 was expressed as a GPI-linked 19- to 25-kDa protein exhibiting multiple glycosylation variants. The surface expression of CD59 correlated with the amount of the main 1.9 + 2.1-kb CD59 mRNA transcripts. Neutralization of CD59 with an anti-CD59 MAb significantly enhanced C-mediated killing of the cell lines. Low expression of C regulators on the PA-1 teratocarcinoma cell line was associated with high sensitivity to C lysis. Thus, the expression of C regulators on malignant ovarian cells may constitute a tumor escape mechanism, and is a critical parameter to be examined when MAb therapy is being considered.
卵巢癌具有一些特性，使其非常适合单克隆抗体辅助免疫治疗。在临床试验中使用的几种单克隆抗体通过激活补体（C）介导癌细胞破坏。因此，在本研究中，我们检测了卵巢肿瘤细胞抵抗补体攻击的能力。我们发现，在所检测的全部28例良性和恶性肿瘤的肿瘤细胞中，补体调节蛋白膜辅因子蛋白（MCP，CD46）和保护素（CD59）均强烈表达。衰变加速因子（DAF；CD55）的表达更具异质性，只有75%的肿瘤在肿瘤细胞中表现出中等量的DAF。在腺癌细胞中，CD59和DAF优先定位于顶端，而在腺癌癌细胞中，它们也在基底外侧细胞表面表达。卵巢癌细胞系SK-OV-3、Caov-3、SW626和PA-1表达MCP的58 kDa和68 kDa两种异构体。DAF以糖基磷脂酰肌醇（GPI）锚定的70 kDa糖蛋白形式存在。DAF的表面表达水平各不相同，且与细胞对补体介导的溶解的易感性相关。CD59表达为GPI连接的19至25 kDa蛋白，表现出多种糖基化变体。CD59的表面表达与主要的1.9 + 2.1 kb CD59 mRNA转录本的量相关。用抗CD59单克隆抗体中和CD59可显著增强补体介导的细胞系杀伤作用。PA-1畸胎癌细胞系上补体调节蛋白的低表达与对补体溶解的高敏感性相关。因此，恶性卵巢细胞上补体调节蛋白的表达可能构成一种肿瘤逃逸机制，并且是在考虑单克隆抗体治疗时需要检测的关键参数。
