title: Transforming growth factor-beta1 signaling blockade attenuates gastric cancer cell-induced peritoneal mesothelial cell fibrosis and alleviates peritoneal dissemination both in vitro and in vivo.
abstract: Peritoneal dissemination is the most frequent metastatic pattern of advanced gastric cancer and the main cause of death in gastric cancer patients. Transforming growth factor-beta1 (TGF- ß1), one of the most potent fibrotic stimuli for human peritoneal mesothelial cells, has been shown to play an important role in this process. In this study, we investigated the effect of TGF- ß1 signaling blockade in gastric cancer cell (GCC)-induced human peritoneal mesothelial cell (HPMC) fibrosis. HPMCs were cocultured with the high TGF- ß1 expressing GCC line SGC-7901 and various TGF- ß1 signaling inhibitors or SGC-7901 transfected with TGF-ß1-specific siRNA. HPMC fibrosis was monitored on the basis of morphology. Expression of the epithelial cell marker, E-cadherin, and the mesenchymal marker, α-smooth muscle actin (α-SMA), was evaluated by Western blotting and immunofluorescence confocal imaging. GCC adhesion to HPMC was also assayed. In nude mouse tumor model, the peritoneal fibrotic status was monitored by immunofluorescent confocal imaging and Masson's trichrome staining; formation of metastatic nodular and ascites fluid was also evaluated. Our study demonstrated that GCC expressing high levels of TGF-ß1 induced HMPC fibrosis, which is characterized by both upregulation of E-cadherin and downregulation of α-SMA. Furthermore, HPMC monolayers fibrosis was reversed by TGF- ß1 signaling blockade. In vivo, the TGF- ß1 receptor inhibitor SB-431542 partially attenuated early-stage gastric cancer peritoneal dissemination (GCPD). In conclusion, our study confirms the significance of TGFß1 signaling blockade in attenuating GCPD and may provide a therapeutic target for clinical therapy.
authors.affiliation: Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, Liaoning Province, China.
authors.forename: Zhi-Feng
authors.initials: ZF
authors.lastname: Miao
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Zhao
authors.forename: Zhen-Ning
authors.initials: ZN
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Miao
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Xu
authors.forename: Xiao-Yun
authors.initials: XY
authors.lastname: Mao
authors.forename: Jian
authors.initials: J
authors.lastname: Gao
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Wu
authors.forename: Xing-Yu
authors.initials: XY
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: You
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.forename: Hui-Mian
authors.initials: HM
authors.lastname: Xu
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology; D004847:Epithelial Cells / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D010537:Peritoneum / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; C541116:ACTA2 protein, human; D000199:Actins; D001549:Benzamides; D004149:Dioxoles; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1