Susman Sergiu, Barnoud Raphaelle, Bibeau Frederique, Borrini Francesco, Pocard Marc, Tomuleasa Ciprian, Sabourin Jean-Cristophe
Department of Digestive Oncology, Gustave Roussy Institute of Oncology, Villejuif, France;Department of Morphological Sciences, University of Medicine and Pharmacy, Cuj-Napoca, Romania.
Department of Pathology, Hôpital de la Croix Rouge, Lyon, France.
J Gastrointestin Liver Dis. 2015 Mar;24(1):77-83. doi: 10.15403/jgld.2014.1121.sus.
Despite some recent advances, gastric cancer remains an important cause of death at world level. This indicates an absence of therapeutic options, stemming from the limited understanding of the molecular mechanisms involved in carcinogenesis. Nearly fifty years ago Lauren classified gastric cancers, according to the morphological aspect, as intestinal or diffuse. The phenotype of the cells indicates the presence of different molecular mechanisms, which can be approached in the light of recent data and identified with the help of current techniques. The best described are the germline/somatic mutations or the hypermethylations of the E-cadherin 1 CDH1 gene promotor.
We analyzed 195 gastric tumors,120 intestinal and 75 diffuse type, using immunohistochemistry (tissue microarray TMA method) for pStat3Tyr705, E-cadherin, α-catenin and β-catenin; 985 spots of gastric tumors, distributed on 4 TMA blocks were analyzed. For pStat3Tyr705 we took the nuclear staining into account and for the adhesion molecules, membrane staining.
In our study, in the diffuse type gastric cancer, pStat3Tyr705 nuclear expression was statistically significantly increased (p=0.003). Also we observed a decreased expression of the adhesion molecules in the same type of gastric cancer (E-cadherin p<0.0001, α-catenin p<0.0001, β-catenin p<0.0001), suggesting that epithelial-to-mesenchymal transition (EMT) may be involved not only in gastric carcinogenesis, but also in resistance to treatment.
The Stat3 role has been recently highlighted in carcinogenesis of the diffuse type of gastric cancer. We found that the morphological features of the diffuse type also suggest the involvement of EMT in this type of gastric cancer. Therefore, targeting the key molecules involved in this process may interfere with EMT process in the diffuse type of gastric cancer.
尽管近年来取得了一些进展，但胃癌仍是全球范围内重要的死亡原因。这表明由于对致癌分子机制的了解有限，缺乏有效的治疗选择。近五十年前，劳伦根据形态学特征将胃癌分为肠型或弥漫型。细胞表型表明存在不同的分子机制，根据最新数据可以对这些机制进行研究，并借助当前技术加以识别。其中研究得最为透彻的是种系/体细胞突变或E-钙黏蛋白1（CDH1）基因启动子的高甲基化。
我们采用免疫组织化学方法（组织芯片TMA法），对195例胃肿瘤进行分析，其中肠型120例，弥漫型75例，检测磷酸化信号转导及转录激活因子3（pStat3Tyr705）、E-钙黏蛋白、α-连环蛋白和β-连环蛋白；共分析了分布在4个TMA芯片上的985个胃肿瘤样本点。对于pStat3Tyr705，我们考虑细胞核染色情况，对于黏附分子，则考虑细胞膜染色情况。
在我们的研究中，弥漫型胃癌中pStat3Tyr705的细胞核表达在统计学上显著增加（p = 0.003）。我们还观察到同一类型胃癌中黏附分子的表达降低（E-钙黏蛋白p < 0.0001，α-连环蛋白p < 0.0001，β-连环蛋白p < 0.0001），这表明上皮-间质转化（EMT）可能不仅参与胃癌的发生，还与治疗耐药有关。
信号转导及转录激活因子3（Stat3）在弥漫型胃癌发生中的作用最近受到关注。我们发现弥漫型的形态学特征也提示EMT参与了此类胃癌。因此，针对这一过程中涉及的关键分子可能会干扰弥漫型胃癌中的EMT过程。
