Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination

Cell Rep. 2021 Feb 23;34(8):108779. doi: 10.1016/j.celrep.2021.108779.


In the tumor microenvironment, senescent non-malignant cells, including cancer-associated fibroblasts (CAFs), exhibit a secretory profile under stress conditions; this senescence-associated secretory phenotype (SASP) leads to cancer progression and chemoresistance. However, the role of senescent CAFs in metastatic lesions and the molecular mechanism of inflammation-related SASP induction are not well understood. We show that pro-inflammatory cytokine-driven EZH2 downregulation maintains the SASP by demethylating H3K27me3 marks in CAFs and enhances peritoneal tumor formation of gastric cancer (GC) through JAK/STAT3 signaling in a mouse model. A JAK/STAT3 inhibitor blocks the increase in GC cell viability induced by senescent CAFs and peritoneal tumor formation. Single-cell mass cytometry revealed that fibroblasts exist in the ascites of GC patients with peritoneal dissemination, and the fibroblast population shows p16 expression and SASP factors at high levels. These findings provide insights into the inflammation-related SASP maintenance by histone modification and the role of senescent CAFs in GC peritoneal dissemination.

Keywords: EZH2; H3K27me3 marks; JAK inhibitor; cancer-associated fibroblasts; gastric cancer; peritoneal dissemination; senescence-associated secretory phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Antineoplastic Agents / pharmacology
  • Cancer-Associated Fibroblasts / enzymology*
  • Cancer-Associated Fibroblasts / pathology
  • Cell Line, Tumor
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Inflammation Mediators / metabolism*
  • Janus Kinase Inhibitors / pharmacology
  • Janus Kinases / metabolism
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Peritoneal Neoplasms / drug therapy
  • Peritoneal Neoplasms / genetics
  • Peritoneal Neoplasms / metabolism*
  • Peritoneal Neoplasms / secondary
  • Pyridines / pharmacology
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Senescence-Associated Secretory Phenotype*
  • Signal Transduction
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / pathology
  • Tumor Microenvironment
  • Tyrphostins / pharmacology
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Cytokines
  • Inflammation Mediators
  • Janus Kinase Inhibitors
  • Pyridines
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Tyrphostins
  • WP1066
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Janus Kinases