The Lauren Classification Highlights the Role of Epithelial-to-Mesenchymal Transition in Gastric Carcinogenesis: an Immunohistochemistry Study of the STAT3 and Adhesion Molecules Expression

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Sergiu Susman1,2, Raphaelle Barnoud3, Frederique Bibeau4, Francesco Borini5, Marc Pocard1,6, Ciprian Tomuleasa7,8, Jean-Cristophe Sabourin1,9

1) Department of Digestive Oncology, Gustave Roussy Institute of Oncology, Villejuif, France;
2) Department of Morphological Sciences, University of Medicine and Pharmacy, Cuj-Napoca,
3) Department of Pathology, H˘pital de la Croix Rouge, Lyon, France
4) Department of Pathology, Oncology Institute, Montpellier, France
5) Department of Pathology, La Sapienza University, Rome, Italy
6) Lariboisiere Universitary Hospital, Paris, France
7) Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy
8) Department of Hematology, Ion Chiricuta Oncology Institute, Cluj Napoca, Romania
9) Department of Pathology, CHU Rouen, France



Background & Aims: 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.

Methods. 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.

Results. 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.

Conclusion. 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.

Key words: gastric cancer - Stat3 - adhesion molecule - EMT.