Active matrix metalloproteinase 9 expression is associated with primary glioblastoma subtype.
Active matrix metalloproteinase 9 expression is associated with primary glioblastoma subtype.
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发表时间：
2002-09
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通讯作者：
G. Choe;Jun K Park;L. Jouben-Steele;T. Kremen;L. Liau;H. Vinters;T. Cloughesy;P. Mischel
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作者：
G. Choe;Jun K Park;L. Jouben-Steele;T. Kremen;L. Liau;H. Vinters;T. Cloughesy;P. Mischel
目的多形性胶质母细胞瘤是一种侵袭性肿瘤，具有广泛脑侵犯的特点。基质金属蛋白酶-9在这一过程中起着重要作用。根据不同的临床和分子特征，基底膜可分为两个亚型。原发胶质瘤发生于新生状态，常过度表达表皮生长因子受体(EGFR)及其配体非依赖变异体--EGFR变异体III(EGFRvIII)；继发性胶质瘤发生于较低级别的胶质瘤，通常含有p53基因突变。由于EGFR信号在其他类型的癌细胞中促进了MMP9的表达和激活，我们分析了MMP9是否与原发的GBM亚型有关。实验设计对20例GBM患者进行尸检，明胶酶谱检测肿瘤组织和邻近正常脑组织中基质金属蛋白酶的表达。采用免疫组织化学方法检测EGFR、EGFRvIII、P53和活化的丝裂原活化蛋白激酶/细胞外信号调节激酶的表达，并分析其分子表型与基质金属蛋白酶-9表达的关系。结果90%的肿瘤组织中存在潜伏性的基质金属蛋白酶-9，50%的肿瘤组织中存在活性的基质金属蛋白酶-9。正常脑组织中均未检测到基质金属蛋白酶-9(P<；0.001)。更重要的是，原发性基底膜比继发性基底膜更容易含有活性基质金属蛋白酶-9(69%的原发基底膜和14%的继发性基底膜含有活性基质金属基质；P=0.027)。在EGFR过表达/野生型P53染色的肿瘤中，73%的肿瘤组织中有活性的MMP9表达，而在Egfr阴性/异常P53染色的肿瘤中，仅有20%的肿瘤组织中有活性的MMP9表达(P=0.072)。活跃的基质金属蛋白酶-9的表达与EGFRvIII的表达更密切相关，在EGFRvIII免疫阳性的肿瘤中有83%出现，而在EGFRvIII阴性的肿瘤中无一例发生(P=0.0004)。细胞外信号调节激酶的激活也与EGFRⅢ的表达(P<；0.0001)和基质金属蛋白酶-9的激活(P=0.003)密切相关。结论MMP9活化与原发GBM亚型之间存在新的关联，提示原发GBM患者，尤其是那些肿瘤表达EGFRvIII的患者，可能从抗MMPs治疗中受益。
PURPOSE Glioblastoma multiforme (GBM) is an aggressive cancer characterized by extensive brain invasion. Matrix metalloproteinase (MMP)-9 plays a major role in this process. GBMs can be divided into two subtypes based on distinct clinical and molecular features. Primary GBMs arise de novo and frequently overexpress the epidermal growth factor receptor (EGFR) and its ligand-independent variant, EGFR variant III (EGFRvIII); secondary GBMs progress from a lower grade glioma and commonly harbor p53 mutations. Because EGFR signaling promotes MMP-9 expression and activation in other cancer cell types, we analyzed whether MMP-9 was associated with primary GBM subtype. EXPERIMENTAL DESIGN Autopsies were performed on 20 GBM patients, and MMP expression was assessed by gelatin zymography in the tumor and the adjacent normal brain. EGFR, EGFRvIII, p53, and activated mitogen-activated protein kinase/extracellular signal-regulated kinase were assessed by immunohistochemistry, and associations between molecular phenotype and MMP-9 expression were analyzed. RESULTS Latent MMP-9 was detected in 90% of tumors, and active MMP-9 was found in 50% of tumors. MMP-9 was not detected in any of the normal brain samples (P < 0.001). More importantly, primary GBMs were significantly more likely than secondary GBMs to contain active MMP-9 (69% of primary and 14% of secondary GBMs contained active MMP-9; P = 0.027). Active MMP-9 was observed in 73% of EGFR-overexpressing/wild-type p53-staining tumors but in only 20% of EGFR-negative/aberrant p53-staining tumors (P = 0.072). Active MMP-9 expression was even more strongly correlated with EGFRvIII expression, occurring in 83% of the EGFRvIII-immunopositive tumors but in none of the EGFRvIII-negative tumors (P = 0.0004). Extracellular signal-regulated kinase activation was also strongly correlated with EGFRvIII expression (P < 0.0001) and with MMP-9 activation (P = 0.003). CONCLUSIONS These results identify a novel association between MMP-9 activation and primary GBM subtype and suggest that primary GBM patients, especially those whose tumors express EGFRvIII, may benefit from anti-MMP therapy.