Ishikawa Shinya, Takenaka Kazumasa, Yanagihara Kazuhiro, Miyahara Ryo, Kawano Yozo, Otake Yosuke, Hasegawa Seiki, Wada Hiromi, Tanaka Fumihiro
Department of Thoracic Surgery, Kyoto University, Faculty of Medicine, Kyoto, Japan.
Clin Cancer Res. 2004 Oct 1;10(19):6579-85. doi: 10.1158/1078-0432.CCR-04-0272.
The purpose is to assess clinical significance of matrix metalloproteinase (MMP)-2 and MMP-9 status, especially MMP-2 status, in stromal cells in non-small-cell lung cancer (NSCLC) because experimental studies have revealed that stromal MMP-2 plays important roles in progression of malignant tumors, but most clinical studies focused on tumoral MMP-2 expression, not stromal MMP-2 expression.
We conducted a retrospective study on MMP-2 and MMP-9 expression as evaluated immunohistochemically in a total of 218 consecutive patients with completely resected pathological stage I-IIIA, NSCLC.
Strong MMP-2 expression in tumor cells and stromal fibroblasts were documented in 54 (24.8%) and 132 (60.6%) patients, respectively. Strong MMP-2 expression in stromal fibroblasts was more frequently seen in squamous cell carcinoma (72.7%) than in adenocarcinoma (54.9%; P = 0.016). Tumors showing strong MMP-2 expression in stromal fibroblasts showed a significantly higher intratumoral microvessel density (IMVD) than weak stromal MMP-2 tumors (mean intratumoral microvessel density, 50.9 versus 32.4, P = 0.003). In addition, postoperative prognosis of strong stromal MMP-2 patients was significantly poorer than that of weak stromal MMP-2 patients (5-year survival rate, 77.5 versus 60.2%, P = 0.032), and the prognostic significance was enhanced in squamous cell carcinoma patients but disappeared in adenocarcinoma patients. Multivariate analyses confirmed that strong stromal MMP-2 expression was a significant factor to predict a poor prognosis in squamous cell carcinoma patients, not in adenocarcinoma patients. In contrast, MMP-2 or MMP-9 status in tumor cells was not a significant prognostic factor.
MMP-2 status in stromal fibroblasts, not in tumor cells, was a significant prognostic factor associated with angiogenesis in NSCLC.
评估基质金属蛋白酶（MMP）-2和MMP-9状态，尤其是MMP-2状态在非小细胞肺癌（NSCLC）基质细胞中的临床意义，因为实验研究表明基质MMP-2在恶性肿瘤进展中起重要作用，但大多数临床研究关注肿瘤MMP-2表达，而非基质MMP-2表达。
我们对218例连续的完全切除的病理I-IIIA期NSCLC患者进行了回顾性研究，通过免疫组织化学评估MMP-2和MMP-9表达。
分别在54例（24.8%）和132例（60.6%）患者中记录到肿瘤细胞和基质成纤维细胞中MMP-2的强表达。基质成纤维细胞中MMP-2的强表达在鳞状细胞癌（72.7%）中比腺癌（54.9%；P = 0.016）中更常见。基质成纤维细胞中MMP-2强表达的肿瘤显示肿瘤内微血管密度（IMVD）显著高于基质MMP-2弱表达的肿瘤（平均肿瘤内微血管密度，50.9对32.4，P = 0.003）。此外，基质MMP-2强表达患者的术后预后明显比基质MMP-2弱表达患者差（5年生存率，77.5%对60.2%，P = 0.032），且在鳞状细胞癌患者中预后意义增强，但在腺癌患者中消失。多因素分析证实，基质MMP-2强表达是预测鳞状细胞癌患者预后不良的重要因素，而非腺癌患者。相反，肿瘤细胞中MMP-2或MMP-9状态不是显著的预后因素。
基质成纤维细胞而非肿瘤细胞中的MMP-2状态是与NSCLC血管生成相关的重要预后因素。
