HGF-mediated crosstalk between cancer-associated fibroblasts and MET-unamplified gastric cancer cells activates coordinated tumorigenesis and metastasis

  • Cell Death Dis. 2018 Aug 29;9(9):867. doi: 10.1038/s41419-018-0922-1.
Xusheng Ding  1  2 ,  Jun Ji  2 ,  Jinling Jiang  1 ,  Qu Cai  2 ,  Chao Wang  1  2 ,  Min Shi  1 ,  Yingyan Yu  2 ,  Zhenggang Zhu  1  2 ,  Jun Zhang  3  4
Affiliations
  • 1. Department of Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, China.
  • 2. Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, China.
  • 3. Department of Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, China. [email protected].
  • 4. Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, China. [email protected].
PMID: 30158543 DOI: 10.1038/s41419-018-0922-1
Abstract

Cancer-associated fibroblasts (CAFs) are important components of tumor stroma and play a key role in tumor progression. CAFs involve in crosstalk with tumor cells through various kinds of cytokines. In the present study, we screened hepatocyte growth factor (HGF) as a cytokine predominantly originating from CAFs. CAFs-derived HGF was found to promote MET-unamplified gastric Cancer (GC) proliferation, migration, and invasion through the activation of HGF/c-Met/STAT3/twist1 pathway. It also activated interleukin (IL)-6/IL-6R/JAK2/STAT3/twist1 pathway by up-regulating IL-6R expression. As IL-6 was also found to upregulate c-Met expression, we identified the cooperation of HGF and IL-6 in enhancing the characteristics of CAFs. In vivo experiments revealed that CAFs-derived HGF promoted tumorigenesis and metastasis of MET-unamplified GC. Gene set enrichment analysis (GSEA) was performed to confirm our findings. Our study found that the increased expression of HGF in CAFs induced by MET-unamplified GC contributed to the malignant phenotype of both MET-unamplified GC and CAFs in tumor microenvironment.

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