title: The role of human peritoneal mesothelial cells in the fibrosis and progression             of gastric cancer.
abstract: Peritoneal dissemination is the most frequent metastatic pattern of scirrhous gastric cancer. However, despite extensive research effort, disease outcomes have not improved sufficiently. Tumor progression and metastasis result from interactions between cancer and various cells in the stroma, including endothelial cells, immune cells and fibroblasts. Fibroblasts have been particularly well studied; they are known to change into carcinoma-associated fibroblasts (CAFs) and produce transforming growth factor β (TGF-β), which mediates cancer-stroma interactions. Here, we investigated whether TGF-β derived from cancer cells in the peritoneal microenvironment activates human peritoneal mesothelial cells (HPMCs), leading to the progression and fibrosis of gastric cancer. We found that activated HPMCs (a-HPMCs) took on a spindle shape formation, decreased the expression of E-cadherin and increased that of α-SMA. Furthermore, a-HPMCs became more invasive and upregulated proliferation of human gastric cancer-derived MKN45 cells following direct cell-cell contact. Notably, MKN45 cells co-cultured with a-HPMCs also acquired anchorage-independent cell growth and decreased expression of E-cadherin in vitro. To measure the effects of the co-culture in vivo, we developed a mouse xenograft model into which different culture products were subcutaneously injected. The largest tumors were observed in mice that had been given MKN45 cells co-cultured with a-HPMCs. Furthermore, these tumors contained HPMC-derived fibrous tissue. Thus, the epithelial-mesenchymal transition (EMT) of HPMCs appears to drive peritoneal dissemination and tumor fibrosis.
authors.affiliation: Department of Gastroenterological Surgery, Kanazawa University, Kanazawa, Ishikawa, Japan. tkd_tmy@nifty.com
authors.forename: Tomoya
authors.initials: T
authors.lastname: Tsukada
authors.forename: Sachio
authors.initials: S
authors.lastname: Fushida
authors.forename: Shinichi
authors.initials: S
authors.lastname: Harada
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Yagi
authors.forename: Jun
authors.initials: J
authors.lastname: Kinoshita
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Oyama
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Tajima
authors.forename: Hideto
authors.initials: H
authors.lastname: Fujita
authors.forename: Itasu
authors.initials: I
authors.lastname: Ninomiya
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujimura
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ohta
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D048430:Cell Shape; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000502:physiology*; D004848:Epithelium / Q000473:pathology*; D005260:Female; D005355:Fibrosis; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009852:Omentum / Q000473:pathology*; D013274:Stomach Neoplasms / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D047368:Tumor Burden; D059016:Tumor Microenvironment
chemical_list: D053773:Transforming Growth Factor beta1