Davidson B, Goldberg I, Gotlieb W H, Kopolovic J, Ben-Baruch G, Nesland J M, Berner A, Bryne M, Reich R
Department of Pathology, The Norwegian Radium Hospital, Montebello, Oslo, Norway.
Clin Exp Metastasis. 1999;17(10):799-808. doi: 10.1023/a:1006723011835.
The object of this study was to analyze the potential association between the expression of MMP-2, MMP-9, MT1-MMP and TIMP-2, and disease outcome in advanced-stage ovarian carcinomas. Sections from 70 paraffin-embedded blocks (36 primary ovarian carcinomas and 34 metastatic lesions) from 45 patients diagnosed with advanced stage ovarian carcinomas (FIGO stages III-IV) were studied using mRNA in situ hybridization (ISH) technique. Patients were divided retrospectively in two groups based on disease outcome. Long-term survivors (21 patients) and short-term survivors (24 patients) were defined using a double cut-off of 36 months for disease-free survival (DFS) and 60 months for overall survival (OS). Mean follow-up period for patients that were diagnosed with advanced-stage carcinoma was 70 months. The mean values for DFS and OS were 109 and 125 months for long-term survivors, as compared to 3 and 21 months for short-term survivors, respectively. Intense mRNA signals were detected more frequently in tumor cells of short-term survivors with use of all four probes. Comparable findings were observed in peritumoral stromal cells with ISH for MMP-2, MMP-9 and TIMP-2 mRNA. Notably, primary tumors with intense mRNA signal for TIMP-2 (No = 14) were uniformly associated with a fatal outcome. In univariate analysis of primary tumors, mRNA levels of TIMP-2 in stromal cells (P = 0.0002), as well as for MMP-9 (P = 0.012) and TIMP-2 (P = 0.02) in tumor cells, correlated with poor outcome. In univariate analysis of metastatic lesions, mRNA levels of TIMP-2 in stromal cells (P = 0.031), as well as for MMP-2 (P = 0.027) and MT1-MMP (P = 0.008) in tumor cells, correlated with poor outcome. Interestingly, the presence of MT1-MMP in stromal cells correlated with longer survival (P = 0.025). In a multivariate analysis of ISH results for primary tumors, TIMP-2 levels in stromal cells (P = 0.006) and MMP-9 levels in tumor cells (P = 0.011) retained their predictive value. We conclude that MMP-2, MMP-9, MT1-MMP and TIMP-2 are valid markers of poor survival in advanced-stage ovarian carcinoma.
本研究的目的是分析基质金属蛋白酶-2（MMP-2）、基质金属蛋白酶-9（MMP-9）、膜型基质金属蛋白酶-1（MT1-MMP）和基质金属蛋白酶组织抑制因子-2（TIMP-2）的表达与晚期卵巢癌疾病转归之间的潜在关联。使用mRNA原位杂交（ISH）技术对45例诊断为晚期卵巢癌（国际妇产科联盟（FIGO）分期III-IV期）患者的70个石蜡包埋组织块（36例原发性卵巢癌和34个转移灶）进行研究。根据疾病转归将患者回顾性地分为两组。长期生存者（21例患者）和短期生存者（24例患者）通过无病生存期（DFS）36个月和总生存期（OS）60个月的双重截断值来定义。诊断为晚期癌的患者平均随访期为70个月。长期生存者的DFS和OS平均值分别为109个月和125个月，而短期生存者分别为3个月和21个月。使用所有四种探针时，在短期生存者的肿瘤细胞中更频繁地检测到强烈的mRNA信号。在对MMP-2、MMP-9和TIMP-2 mRNA进行ISH检测时，在肿瘤周围基质细胞中观察到类似的结果。值得注意的是，TIMP-2 mRNA信号强烈的原发性肿瘤（n = 14）均与致命结局相关。在原发性肿瘤的单因素分析中，基质细胞中TIMP-2的mRNA水平（P = 0.0002）以及肿瘤细胞中MMP-9（P = 0.012）和TIMP-2（P = 0.02）的mRNA水平与不良结局相关。在转移灶的单因素分析中，基质细胞中TIMP-2的mRNA水平（P = 0.031）以及肿瘤细胞中MMP-2（P = 0.027）和MT1-MMP（P = 0.008）的mRNA水平与不良结局相关。有趣的是，基质细胞中MT1-MMP的存在与更长的生存期相关（P = 0.025）。在原发性肿瘤ISH结果的多因素分析中，基质细胞中TIMP-2水平（P = 0.006）和肿瘤细胞中MMP-9水平（P = 0.011）保留了其预测价值。我们得出结论，MMP-2、MMP-9、MT1-MMP和TIMP-2是晚期卵巢癌生存不良的有效标志物。
