Surgical Oncology, Division of Genome Radiobiology and Medicine, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Clin Cancer Res. 2012 Feb 15;18(4):945-55. doi: 10.1158/1078-0432.CCR-11-1946. Epub 2011 Dec 21.
Lung adenocarcinoma often manifests as tumors with mainly lepidic growth. The size of invasive foci determines a diagnosis of in situ, minimally invasive adenocarcinoma, or invasive types and suggests that some adenocarcinomas undergo malignant progression in that order. This study investigates how transcriptional aberrations in adenocarcinoma cells at the early stage define the clinical phenotypes of adenocarcinoma tumors at the advanced stage.
We comprehensively searched for differentially expressed genes between preinvasive and invasive cancer cells in one minimally invasive adenocarcinoma using laser capture microdissection and DNA microarrays. We screened expression of candidate genes in 11 minimally invasive adenocarcinomas by reverse transcriptase PCR and examined their involvement in preinvasive-to-invasive progression by transfection studies. We then immunohistochemically investigated the presence of candidate molecules in 64 samples of advanced adenocarcinoma and statistically analyzed the findings, together with clinicopathologic variables.
The transcription factors Notch2 and Six1 were upregulated in invasive cancer cells in all 11 minimally invasive adenocarcinomas. Exogenous Notch2 transactivated Six1 followed by Smad3, Smad4, and vimentin, and enlarged the nuclei of NCI-H441 lung epithelial cells. Immunochemical staining for the transcription factors was double positive in the invasive, but not in the lepidic growth component of a third of advanced Ads, and the disease-free survival rates were lower in such tumors.
Paired upregulation of Notch2 and Six1 is a transcriptional aberration that contributes to preinvasive-to-invasive adenocarcinoma progression by inducing epithelial-mesenchymal transition and nuclear atypia. This aberration persisted in a considerable subset of advanced adenocarcinoma and conferred a more malignant phenotype on the subset.
肺腺癌常表现为以贴壁生长为主的肿瘤。浸润灶的大小决定了原位癌、微浸润腺癌或浸润性癌的诊断，并提示一些腺癌可能按此顺序发生恶性进展。本研究旨在探讨腺癌早期肿瘤细胞的转录异常如何定义晚期腺癌肿瘤的临床表型。
我们使用激光捕获显微切割和 DNA 微阵列，全面搜索了一个微浸润性腺癌中前浸润性和浸润性癌细胞之间差异表达的基因。我们通过逆转录 PCR 筛选了 11 例微浸润性腺癌中候选基因的表达，并通过转染研究研究了它们在向侵袭性进展中的作用。然后，我们用免疫组织化学方法检测了 64 例晚期腺癌样本中候选分子的存在，并结合临床病理变量进行统计学分析。
在所有 11 例微浸润性腺癌中，转录因子 Notch2 和 Six1 在浸润性癌细胞中上调。外源性 Notch2 转激活 Six1 后，激活 Smad3、Smad4 和波形蛋白，使 NCI-H441 肺上皮细胞的核增大。免疫组化染色显示，三分之一的晚期 Ads 浸润性部分而不是贴壁生长部分的转录因子呈双阳性，这些肿瘤的无病生存率较低。
Notch2 和 Six1 的配对上调是一种转录异常，通过诱导上皮-间充质转化和核异型性，促进了前浸润性向腺癌的进展。这种异常在相当一部分晚期腺癌中持续存在，并赋予该亚组更具恶性表型。
