Clinicopathological analysis of lung adenocarcinomas by EGFR gene mutation and gene expression analysis

肺腺癌的预后极差。本项目的目的是通过基因表达谱和免疫组织化学分析来确定分子靶向药物的候选分子。1肺腺癌中EGFR突变和癌胎儿蛋白GPC3的表达分析：包括我们的报道在内的最近的研究表明，癌胎儿蛋白GPC3在卵黄囊瘤、绒毛膜癌、畸胎瘤、肝细胞癌和肾母细胞瘤的肿瘤细胞中表达。肺组织标本取自东京大学医院病理科2005年和2006年的档案。32例标本可同时进行EGFR突变和GPC3免疫染色分析。32例中有11例检测到EGFR突变(34%)。GPC3阳性8例，包括6例混合型腺癌、1例伴有粘液分泌的实性腺癌、1例高分化腺癌。2例周型GPC3表达和EGFR型…突变检测到更多的离子。基因表达谱显示GPC3在18个肺腺癌细胞系中的一个表达。这些结果表明，GPC3在肺腺癌中的表达广泛提示胎儿型腺癌，GPC3有望成为分子靶向药物的候选药物。2在人肺腺癌中，最近的重要课题是EGFR激酶抑制剂吉非替尼和厄洛替尼的获得性耐药。C-Met是替代EGFR途径的候选信号分子之一。在12个肺腺癌细胞系中，有5个细胞系检测到c-Met的结构性激活。C-Met过表达的机制可能是有或无基因扩增、配体非依赖性和细胞-基质黏附。3肿瘤缺氧与癌细胞的恶性表型和患者预后不良有关。在A549肺腺癌细胞系中，低氧诱导细胞运动，EGFR基因表达水平的EGFR抑制剂AG1478完全抑制低氧对细胞运动的促进作用。较少

Prognosis of lung adenocarcinomas is extremely poor. This project purpose is that the identification of the candidate molecules for molecularly-targeted drug by gene expression profile and immunohistochemical analyses.1 Analyses of EGFR mutation and oncofetal protein GPC3 expression in lung adenocarcinomas: Recent studies including our reports have shown the expression of oncofetal protein GPC3 in neoplastic cells of Yolk sac tumor, choriocarcinoma, teratoma, hepatocellular carcinoma, and Wilm's tumor. Lung tissue specimens were retrieved from the file of the Department of Pathology, Tokyo University Hospital in 2005 and 2006. The 32 samples could be analyzed both with EGFR mutation and GPC3 immunostaining. EGFR mutation was detected in 11 cases of 32 cases (34%). GPC3 was positive in 8 cases, including 6 adenocarcinomas with mixed subtypes, one solid adenocarcinoma with mucin production, and well differentiated fetal adenocarcinoma. In 2 cases, both week GPC3 expression and EGFR mutat … More ion were detected. Gene expression profile revealed the expression of GPC3 in the one of 18 lung adenocarcinomas cell lines. Those results suggested the GPC3 expression in lung adenocarcinomas broadly indicated the fetal type adenocarcinomas and GPC3 is promising candidate for molecularly-targeted drug.2 In human lung adenocarcinomas, recent important topic was the acquired resistance the EGFR kinase inhibitors, gefitinib and erlotinib. One of the candidates for alternative constitutive active signaling molecule is c-met, instead of EGFR pathway. Constitutive activation of c-Met was detected 5 out of 12 lung adenocarcinomas cell lines. The mechanisms c-Met overexpression were that either with or without gene amplification, ligand-independent and depends on cell-matrix adhesion.3 Tumor hypoxia is associated with a malignant phenotype of cancer cells and poor patient prognosis. In the A549 lung adenocarcinomas cell line, hypoxia induced the cell motility and EGFR gene expression level EGFR inhibitor AG1478 completely inhibited the promotion of cell motility induced by hypoxia. Less