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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

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Tumor Biology

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.

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Authors and Affiliations

  1. Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, Liaoning Province, China

    Zhi-Feng Miao, Zhen-Ning Wang, Jian-Hua Wu, Xing-Yu Liu, Yi You, Hao Xu & Hui-Mian Xu

  2. Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China

    Ting-Ting Zhao, Ying-Ying Xu & Xiao-Yun Mao

  3. Department of Digestion, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China

    Feng Miao

  4. Center of Laboratory Technology and Experimental Medicine, China Medical University, Shenyang, Liaoning Province, China

    Jian Gao

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  1. Zhi-Feng Miao
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  2. Ting-Ting Zhao
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  4. Feng Miao
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  11. Hao Xu
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  12. Hui-Mian Xu
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Correspondence to Hui-Mian Xu.

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Miao, ZF., Zhao, TT., Wang, ZN. et al. 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. Tumor Biol. 35, 3575–3583 (2014). https://doi.org/10.1007/s13277-013-1472-x

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  • DOI: https://doi.org/10.1007/s13277-013-1472-x

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