Research Group Surgical Oncology, Experimental and Clinical Research Center (a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine), Berlin, Germany.
Mod Pathol. 2011 Oct;24(10):1390-403. doi: 10.1038/modpathol.2011.99. Epub 2011 Jun 24.
Gastric adenocarcinomas can be divided into two major histological types, the diffuse and intestinal type (Laurén classification). Since they diverge in many clinical and molecular characteristics, it is widely accepted that they represent distinct disease entities that may benefit from different therapeutic approaches. Gene expression profiling studies have identified numerous genes that are differentially expressed between them. However, none of these studies covered the whole transcriptome and the published gene lists reveal little overlap, raising the need for further, more comprehensive analyses. Here, we present the first transcriptome-wide expression profiling study comparing the two types (diffuse n=19, intestinal n=24), which identified >1000 genes that are differentially expressed. Among them, thrombospondin 4 (THBS4) showed the strongest correlation to histological type, with vast overexpression in the diffuse type. Quantitative real-time PCR validated this strong overexpression and revealed that intestinal tumors generally lack THBS4 expression. Immunohistochemistry demonstrated THBS4 overexpression on the protein level (n=10) and localized THBS4 to the stromal aspect. Its expression was primarily observed within the extracellular matrix surrounding the tumor cells, with the highest intensities found in regions of high tumor cell density and invasion. Intestinal tumors and matched non-neoplastic gastric epithelium and stroma did not feature any relevant THBS4 expression in a preliminary selection of analyzed cases (n=5). Immunohistochemical colocalization and in vitro studies revealed that THBS4 is expressed and secreted by cancer-associated fibroblasts. Furthermore, we show that THBS4 transcription in fibroblasts is stimulated by tumor cells. This study is the first to identify THBS4 as a powerful marker for diffuse-type gastric adenocarcinomas and to provide an initial characterization of its expression in the course of this disease.
胃腺癌可分为两种主要的组织学类型，弥漫型和肠型（Laurén 分类）。由于它们在许多临床和分子特征上存在差异，因此广泛认为它们代表不同的疾病实体，可能受益于不同的治疗方法。基因表达谱研究已经鉴定出许多在它们之间表达差异的基因。然而，这些研究都没有涵盖整个转录组，并且已发表的基因列表显示出很少的重叠，这就需要进一步、更全面的分析。在这里，我们首次进行了全转录组表达谱比较这两种类型（弥漫型 n=19，肠型 n=24）的研究，鉴定出 >1000 个差异表达的基因。其中，血小板反应蛋白 4（THBS4）与组织学类型相关性最强，在弥漫型中表达显著上调。实时定量 PCR 验证了这种强烈的过表达，并显示肠型肿瘤通常缺乏 THBS4 表达。免疫组织化学显示 THBS4 在蛋白水平上的过表达（n=10），并将 THBS4 定位到基质方面。其表达主要在肿瘤细胞周围的细胞外基质中观察到，在肿瘤细胞密度高和侵袭的区域发现最高强度。在初步选择分析的病例（n=5）中，肠型肿瘤和匹配的非肿瘤性胃上皮和基质均未显示任何相关的 THBS4 表达。免疫组织化学共定位和体外研究表明，THBS4 由癌相关成纤维细胞表达和分泌。此外，我们表明肿瘤细胞刺激成纤维细胞中 THBS4 的转录。这项研究首次将 THBS4 鉴定为弥漫型胃腺癌的有力标志物，并初步描述了其在该疾病过程中的表达情况。
