Cox G, Jones J L, O'Byrne K J
Department of Respiratory Medicine, Glenfield Hospital, Leicester, United Kingdom.
Clin Cancer Res. 2000 Jun;6(6):2349-55.
Matrix metalloproteinase (MMP)-9 is an endopeptidase that digests basement membrane type IV collagen. Enhanced expression has been related to tumor progression both in vitro and in vivo. The control of MMP transcription is complex, but recently, epidermal growth factor receptor (EGFR) expression has been implicated in up-regulation of MMP-9 in tumor cells in vitro. Our objective was to evaluate the relationship between MMP-9 and EGFR expression in non-small cell lung cancer (NSCLC) and to assess the impact of expression on clinicopathological parameters and survival. This is a retrospective study of 169 patients who underwent resection for stage I-IIIa NSCLC with a postoperative survival >60 days. Minimum follow-up was 2 years. Standard avidin-biotin complex immunohistochemistry was performed on 4-microm paraffin-embedded sections from the tumor periphery using monoclonal antibodies to EGFR and MMP-9. MMP-9 was expressed in the tumor cells of 88 of 169 (52%) cases. EGFR expression was found in 94 of 169 (56%) cases [membranous, 55 of 169 (33%); cytoplasmic, 39 of 169 (23%)]. MMP-9 expression was associated with poor outcome in univariate (P = 0.0023) and multivariate (P = 0.027) analysis. Membranous, cytoplasmic, and overall EGFR expression were not associated with outcome (P = 0.13, 0.99, and 0.17, respectively). MMP-9 expression showed a strong correlation with EGFR expression (P < 0.0001) and EGFR membranous expression (P = 0.002) but not with cytoplasmic EGFR expression (P = 0.18). Co-expression of MMP-9 and EGFR (37%) conferred a worse prognosis (P = 0.0001). Subset analysis revealed only MMP-9 and membranous EGFR co-expression (22%) was associated with poor outcome (P = 0.0019). Our results show that a significant proportion of NSCLC tumors co-express MMP-9 and EGFR. The co-expression of these markers confers a poor prognosis. This finding suggests that EGFR signaling pathway may play an important role in the invasive behavior of NSCLC via specific up-regulation of MMP-9.
基质金属蛋白酶（MMP）-9是一种可消化IV型基底膜胶原蛋白的内肽酶。其表达增强与肿瘤在体外和体内的进展均相关。MMP转录的调控较为复杂，但最近有研究表明，表皮生长因子受体（EGFR）的表达与体外肿瘤细胞中MMP-9的上调有关。我们的目的是评估非小细胞肺癌（NSCLC）中MMP-9与EGFR表达之间的关系，并评估其表达对临床病理参数和生存率的影响。这是一项对169例I-IIIa期NSCLC患者进行手术切除且术后生存期>60天的回顾性研究。最短随访时间为2年。使用抗EGFR和MMP-9的单克隆抗体，对肿瘤周边4微米厚的石蜡包埋切片进行标准抗生物素蛋白-生物素复合物免疫组织化学检测。169例患者中有88例（52%）的肿瘤细胞表达MMP-9。169例患者中有94例（56%）检测到EGFR表达[膜性表达，169例中有55例（33%）；细胞质表达，169例中有39例（23%）]。在单因素分析（P = 0.0023）和多因素分析（P = 0.027）中，MMP-9表达与不良预后相关。膜性、细胞质和总体EGFR表达与预后均无相关性（分别为P = 0.13、0.99和0.17）。MMP-9表达与EGFR表达（P < 0.0001）及EGFR膜性表达（P = 0.002）呈强相关，但与细胞质EGFR表达无相关性（P = 0.18）。MMP-9与EGFR共表达（37%）预示着更差的预后（P = 0.0001）。亚组分析显示，只有MMP-9与膜性EGFR共表达（22%）与不良预后相关（P = 0.0019）。我们的研究结果表明，相当一部分NSCLC肿瘤同时表达MMP-9和EGFR。这些标志物的共表达预示着不良预后。这一发现表明，EGFR信号通路可能通过特异性上调MMP-9在NSCLC的侵袭行为中发挥重要作用。
