Analysis of host- and tumor-derived proteinases using a custom dual species microarray reveals a protective role for stromal matrix metal loproteinase-12 in non-small cell lung cancer
Analysis of host- and tumor-derived proteinases using a custom dual species microarray reveals a protective role for stromal matrix metal loproteinase-12 in non-small cell lung cancer
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DOI：
10.1158/0008-5472.can-05-4279
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发表时间：
2006-08-15
期刊：
影响因子：
11.2
通讯作者：
Matrisian, Lynn M.
中科院分区：
文献类型：
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作者：
Acuff, Heath B.;Sinnamon, Mark;Matrisian, Lynn M.
我们使用了一个定制的Affyellow蛋白酶芯片（Hu/Mu ProtIn芯片），旨在区分人类和小鼠基因，分析蛋白酶和蛋白酶抑制剂在肺癌中的表达。使用原位肺癌模型，我们发现小鼠基质金属蛋白酶（MMP）-12，MMP-13和组织蛋白酶K在肿瘤组织中与正常小鼠肺组织相比表达上调。为了确定使用该模型系统检测到的基质蛋白酶的相关性，我们将结果与使用U133 Plus 2.0 Affyellow微阵列分析的人肺腺癌标本进行了比较。MMP-12、MMP-13和组织蛋白酶K在人肿瘤中的表达与正常肺相比增加，与原位模型中观察到的相似。免疫组化分析证实MMP-12在人肺肿瘤标本间质中表达。为了确定基质MMP-12的生物学相关性，将鼠刘易斯肺癌细胞注射到同系野生型（WT）和MMP-12缺失小鼠的尾静脉中。MMP-12-null和WT小鼠发展了相等数量的肺肿瘤;然而，与WT对照相比，MMP-12-null小鼠中直径达到> 2 mm的肿瘤数量增加了2倍。肿瘤大小的增加与CD 31阳性血管的增加和血管抑素K1-K4种类的循环水平的降低相关。这些结果显示基质MMP-12在肺肿瘤生长中的保护作用。Hu/Mu ProtIn芯片的使用使我们能够区分肿瘤和宿主来源的蛋白酶，并指导进一步分析这些基因在肿瘤进展中的意义。
We used a customized Affymetrix protease microarray (Hu/Mu ProtIn chip) designed to distinguish human and mouse genes to analyze the expression of proteases and protease inhibitors in lung cancer. Using an orthotopic lung cancer model, we showed that murine matrix metalloproteinase (MMP)-12, MMP-13, and cathepsin K were up-regulated in tumor tissue compared with normal mouse lung. To determine the relevance of stromal proteases detected using this model system, we compared the results to an analysis of human lung adenocarcinoma specimens using the U133 Plus 2.0 Affymetrix microarray. MMP-12, MMP-13, and cathepsin K showed an increase in expression in human tumors compared with normal lung similar to that seen in the orthotopic model. Immunohistochemical analysis confirmed MMP-12 expression in the stroma of human lung tumor samples. To determine the biological relevance of stromal MMP-12, murine Lewis lung carcinoma cells were injected into the tail vein of syngeneic wild-type (WT) and MMP-12-null mice. MMP-12-null and WT mice developed equivalent numbers of lung tumors; however, there was a 2-fold increase in the number of tumors that reached > 2 mm in diameter in MMP-12-null mice compared with WT controls. The increase in tumor size correlated with an increase in CD31-positive blood vessels and a decrease in circulating levels of the K1-K4 species of angiostatin. These results show a protective role for stromal MMP-12 in lung tumor growth. The use of the Hu/Mu ProtIn chip allows us to distinguish tumor- and host-derived proteases and guides the further analysis of the significance of these genes in tumor progression.