Low-dose paclitaxel modulates tumour fibrosis in gastric cancer

Int J Oncol. 2013 Apr;42(4):1167-74. doi: 10.3892/ijo.2013.1801. Epub 2013 Jan 29.


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.

MeSH terms

  • Actins / metabolism
  • Antigens, CD
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cell Shape / drug effects
  • Cisplatin / pharmacology
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Dose-Response Relationship, Drug
  • Epithelial-Mesenchymal Transition
  • Fibrosis
  • Fluorouracil / pharmacology
  • Gene Expression
  • Humans
  • Paclitaxel / pharmacology*
  • Phosphorylation
  • Protein Processing, Post-Translational / drug effects
  • Smad2 Protein / genetics
  • Smad2 Protein / metabolism
  • Stomach Neoplasms
  • Transforming Growth Factor beta / physiology


  • Actins
  • Antigens, CD
  • Antineoplastic Agents, Phytogenic
  • CDH1 protein, human
  • Cadherins
  • Collagen Type I
  • SMAD2 protein, human
  • Smad2 Protein
  • Transforming Growth Factor beta
  • Paclitaxel
  • Cisplatin
  • Fluorouracil