Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human pancreatic adenocarcinomas: Clinicopathologic and prognostic significance of matrilysin expression
Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human pancreatic adenocarcinomas: Clinicopathologic and prognostic significance of matrilysin expression
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DOI：
10.1200/jco.2001.19.4.1118
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发表时间：
2001-02-15
影响因子：
45.3
通讯作者：
Imai, K
中科院分区：
文献类型：
--
作者：
Yamamoto, H;Itoh, F;Imai, K
目的：基质金属蛋白酶 (MMP5) 与其天然抑制剂、金属蛋白酶组织抑制剂 (TIMP) 之间平衡的破坏与多种癌症的进展有关。本研究的目的是确定特定的 MMP 或 TIMP 在胰腺癌中是否具有临床病理学和预后意义。 患者和方法：使用免疫组织化学，我们分析了 70 例胰腺导管腺癌组织中 MMP-1、MMP-2、MMP-3、MMP-7（基质溶解素）、MMP-9、MT1-MMP、TIMP-1 和 TIMP-2 的表达。结果与临床病理特征和患者的生存率相匹配。还检测了抑制特定MMP对胰腺癌细胞体外侵袭力的影响。结果：在肿瘤细胞或肿瘤基质细胞或两种成分中以不同频率检测到MMP-1、MMP-2、MMP-3、matrilysin、MMP-9、MT1-MMP、TIMP-1和TIMP-2的表达。在MMP中，基质溶素在肿瘤巢中表现出独特的分布；它的表达通常在肿瘤的侵袭性前沿最为明显。在40例（57%）中观察到，在浸润前沿超过30%的癌细胞中有免疫染色信号的切片被判断为matrilysin阳性。 Matrilysin 阳性与 pT、pN 和 pM 类别以及更晚期的病理肿瘤淋巴结转移阶段显着相关。基质溶素阳性癌症患者的总生存时间明显短于基质溶素阴性癌症患者。在多变量分析中，Matrilysin 是总体生存的重要独立预后因素。相反，其他 MMP 或 TIMP 的存在与临床病理特征之间没有相关性，个别 MMP 或 TIMP 的存在与生存也没有相关性。反义基质溶素转染的 CFPAC-1 细胞表达的基质溶素水平降低，并表现出相似的生长潜力，但与新转染的 CFPAC-1 细胞相比，体外侵袭性更小。结论：我们的结果表明，基质溶素可能在胰腺癌的进展中发挥关键作用，从而导致不良预后。由于不同合成的MMP抑制剂对不同类型的MMP5的影响程度不同，因此检测MMP尤其是基质溶素的表达可以作为选择最有效的MMP抑制剂的指标。
purpose: A disruption in the balance between the matrix metalloproteinases (MMP5) and their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs), has been implicated in the progression of many types of cancer. The aim of this study was to determine whether a specific MMP or TIMP has clinicopathologic and prognostic significance in pancreatic carcinoma.Patients and Methods: Using immunohistochemistry, we analyzed 70 pancreatic ductal adenocarcinoma tissues for expression of MMP-1, MMP-2, MMP-3, MMP-7 (matrilysin), MMP-9, MT1-MMP, TIMP-1, and TIMP-2. The results were matched with clinicopatholagic characteristics and patients' survival. The effects of the suppression of a specific MMP on in vitro invasiveness of pancreatic carcinoma cells were also examined.Results: Expression of MMP-1, MMP-2, MMP-3, matrilysin, MMP-9, MT1-MMP, TIMP-1, and TIMP-2 was detected in either tumor cells or tumor stromal cells, or in both components, at varying frequencies. Among MMPs, matrilysin showed a unique distribution in the tumor nests; its expression was usually most pronounced at the invasive front of the tumors. Sections with immunostaining signals in more than 30% of carcinoma cells at the invasive front, which were observed in 40 cases (57%), were judged to be positive for matrilysin. Matrilysin positivity was significantly correlated with pT, pN, and pM categories and with more advanced pathologic tumor-node-metastasis stages. Patients with matrilysin-positive carcinoma had a significantly shorter overall survival time than did those with matrilysin-negative carcinoma. Matrilysin was a significant independent prognostic factor for overall survival in multivariate analysis. In contrast, there was no correlation between the presence of other MMPs or TIMPs and clinicopathologic characteristics, nor was the presence of individual MMPs or TIMPs related to survival. Antisense matrilysin-transfected CFPAC-1 cells expressed reduced levels of matrilysin and demonstrated a similar growth potential but were less invasive in vitro compared with neotransfected CFPAC-1 cells.Conclusion: Our results suggest that matrilysin may play a key role in progression of pancreatic carcinoma and thereby contribute to a poor prognosis. Because different synthetic MMP inhibitors affect different types of MMP5 to ct different degree, examination of the expression of MMPs, especially that of matrilysin, may serve as an indicator for selecting the most effective MMP inhibitor.