title: Low-dose paclitaxel modulates tumour fibrosis in gastric cancer.
abstract: Various treatments have been used for peritoneal dissemination, which is the most common mode of metastasis in gastric cancer, but sufficiently good clinical outcomes have not yet been obtained because of the presence of rich fibrous components and acquired drug resistance. Epithelial-mesenchymal transition (EMT) is one of the major causes of tissue fibrosis and transforming growth factor-β (TGF-β) has a pivotal function in the progression of EMT. Smad proteins play an important role in the TGF-β signalling pathway. The TGF-β/Smad signalling pathway can be modulated by stabilising microtubules with paclitaxel (PTX). Here, we investigated whether paclitaxel can modulate TGF-β/Smad signalling in human peritoneal methothelial cells (HPMCs). To determine the cytostatic concentrations of antineoplastic agents in HPMCs, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was performed using PTX, 5-fluorouracil and cisplatin. The minimum concentration that caused significant inhibition of TGF-β1-induced morphological changes in human peritoneal methothelial cells on pre-treatment with PTX was 5 nM at 48 h (cell viability: 87.1±1.5%, P<0.01). The TGF-β signalling cascade and the status of various fibrous components were evaluated by immunofluorescence staining, real-time quantitative PCR and western blotting. TGF-β signalling induced morphological changes, α-SMA expression and collagen I synthesis in HPMCs and PTX treatment suppressed these EMT-like changes. Moreover, PTX treatment markedly suppressed Smad2 phosphorylation. These data suggest that at a low-dose, PTX can significantly suppress the TGF-β/Smad signalling pathway by inhibiting Smad2 phosphorylation in the human peritoneum and that this can reduce stromal fibrosis.
authors: Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan. tkd_tmy@nifty.com
authors: Tomoya
authors: T
authors: Tsukada
authors: Sachio
authors: S
authors: Fushida
authors: Shinichi
authors: S
authors: Harada
authors: Shiroh
authors: S
authors: Terai
authors: Yasumichi
authors: Y
authors: Yagi
authors: Jun
authors: J
authors: Kinoshita
authors: Katsunobu
authors: K
authors: Oyama
authors: Hidehiro
authors: H
authors: Tajima
authors: Itasu
authors: I
authors: Ninomiya
authors: Takashi
authors: T
authors: Fujimura
authors: Tetsuo
authors: T
authors: Ohta
mesh_terms: D000199:Actins / Q000378:metabolism; D015703:Antigens, CD; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis; D005472:Fluorouracil / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D000199:Actins; D015703:Antigens, CD; D000972:Antineoplastic Agents, Phytogenic; C513384:CDH1 protein, human; D015820:Cadherins; D024042:Collagen Type I; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D017239:Paclitaxel; D002945:Cisplatin; D005472:Fluorouracil