Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN 55905, USA.
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
Gynecol Oncol. 2019 Feb;152(2):368-374. doi: 10.1016/j.ygyno.2018.11.014. Epub 2018 Nov 15.
Mesenchymal (MES) subtype of high-grade serous ovarian cancer (HGSOC) is associated with worse outcomes including survival and resectability compared with other molecular subtypes. Molecular subtypes have historically been derived from 'tumor', consisting of both cancer and stromal cells. We sought to determine the origins of multiple MES subtype gene signatures in HGSOC.
Fifteen patients with MES subtype of HGSOC diagnosed between 2010 and 2013 were identified. Formalin-fixed paraffin-embedded (FFPE) blocks from primary surgery were sectioned for immunohistochemistry (IHC) staining of relevant proteins. Eight genes (ACTA2, COL5A1, COL11A1, FAP, POSTN, VCAN, ZEB1 and p-SMAD2) were selected for IHC staining based on their differential expression in MES vs. non-MES subtypes of HGSOC. Slides were scored for intensity and localization and simple statistics were used to compare expression results in cancer vs. stroma and between primary and metastatic sites.
COL5A1, VCAN, FAP, and ZEB1 proteins were almost exclusively expressed by stroma as opposed to cancer cells. In addition, stromal expression was dominant for ACTA2, COL11A1, POSTN and p-SMAD2. In general there were minimal differences in expression of proteins between primary and metastatic sites, exceptions being COL5A1 (reduced in metastases) and COL11A1 (increased in metastases). Nuclear p-SMAD2 expression was more common in metastatic stroma.
The existing molecular classification of HGSOC MES subtype reflects a significant stromal contribution, suggesting an important role in HGSOC behavior and thus stroma may be a relevant therapeutic target. Specific patterns of expression indicate that collagens and TGF-β signaling are involved in the metastatic process.
与其他分子亚型相比，间充质（MES）型高级别浆液性卵巢癌（HGSOC）的预后包括生存和可切除性更差。分子亚型传统上来源于“肿瘤”，包含癌细胞和基质细胞。我们试图确定 HGSOC 中多个 MES 亚型基因特征的起源。
鉴定了 2010 年至 2013 年间诊断为 MES 型 HGSOC 的 15 名患者。对原发手术的福尔马林固定石蜡包埋（FFPE）块进行免疫组织化学（IHC）染色，以检测相关蛋白。根据 MES 与 HGSOC 的非 MES 亚型之间的差异表达，选择了 8 个基因（ACTA2、COL5A1、COL11A1、FAP、POSTN、VCAN、ZEB1 和 p-SMAD2）进行 IHC 染色。根据强度和定位对幻灯片进行评分，并使用简单统计比较癌症与基质之间以及原发与转移部位之间的表达结果。
COL5A1、VCAN、FAP 和 ZEB1 蛋白几乎仅由基质表达，而不是癌细胞。此外，ACTA2、COL11A1、POSTN 和 p-SMAD2 的基质表达更为突出。一般来说，原发与转移部位之间的蛋白表达差异不大，COL5A1（转移部位减少）和 COL11A1（转移部位增加）除外。核 p-SMAD2 表达在转移性基质中更为常见。
现有的 HGSOC MES 亚型分子分类反映了基质的重要贡献，这表明基质在 HGSOC 行为中起重要作用，因此基质可能是一个相关的治疗靶点。特定的表达模式表明，胶原蛋白和 TGF-β 信号参与了转移过程。
