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  3. The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-α/IL-33/ST2L signaling promotes gastric cancer metastasis

The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-α/IL-33/ST2L signaling promotes gastric cancer metastasis

  • Oncogene. 2020 Feb;39(7):1414-1428. doi: 10.1038/s41388-019-1078-x.
Quan Zhou  # 1 2,  Xiongyan Wu  # 1,  Xiaofeng Wang 3,  Zhenjia Yu 1,  Tao Pan 1,  Zhen Li 1,  Xinyu Chang 1,  Zhijian Jin 1,  Jianfang Li 1,  Zhenggang Zhu 1,  Bingya Liu 4,  Liping Su 5
Affiliations

Affiliations

  • 1 Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, People's Republic of China.
  • 2 Department of Urology, Center for Organ Transplantation, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, People's Republic of China.
  • 3 Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, People's Republic of China.
  • 4 Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, People's Republic of China. liubingya@sjtu.edu.cn.
  • 5 Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, People's Republic of China. suliping@shsmu.edu.cn.
  • # Contributed equally.
PMID: 31659258 DOI: 10.1038/s41388-019-1078-x
Abstract

Gastric Cancer (GC) is characterized by extensive local invasion, distant metastasis and poor prognosis. In most cases, GC progression is associated with aberrant expression of cytokines or activation of signaling cascades mediated by tumor-stroma interactions. However, the mechanisms by which these interactions contribute to GC progression are poorly understood. In this study, we find that IL-33 and its receptor ST2L are upregulated in the human GC and served as prognostic markers for poor survival of GC patients. In a co-culture model with GC cells and cancer-associated fibroblasts (CAFs), we further demonstrate that CAFs-derived IL-33 enhances the migration and invasion of GC cells by inducing the epithelial-mesenchymal transition (EMT) through activation of the ERK1/2-SP1-ZEB2 pathway in a ST2L-dependent manner. Furthermore, the secretion of IL-33 by CAFs can be induced by the proinflammatory cytokines TNF-α that is released by GC cells via TNFR2-NF-κB-IRF-1 pathway. Additionally, silencing of IL-33 expression in CAFs or ST2L expression in GC cells inhibits the peritoneal dissemination and metastatic potential of GC cells in nude mice. Taken together, these results characterize a critical role of the interaction between epithelial-stroma mediated by the TNF-α/IL-33/ST2L signaling in GC progression, and provide a rationale for targeting this pathway to treat GC metastasis.

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