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

Aged Animals Antineoplastic Agents / pharmacology Cancer-Associated Fibroblasts / enzymology Cell Line, Tumor Cytokines / genetics Enhancer of Zeste Homolog 2 Protein / genetics 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 Pyridines / pharmacology STAT3 Transcription Factor / genetics Senescence-Associated Secretory Phenotype Signal Transduction Stomach Neoplasms / drug therapy Tumor Microenvironment Tyrphostins / pharmacology Xenograft Model Antitumor Assays

EZH2 H3K27me3 marks JAK inhibitor cancer-associated fibroblasts gastric cancer peritoneal dissemination senescence-associated secretory phenotype

Journal

Cell reports

ISSN: 2211-1247

Titre abrégé: Cell Rep

Pays: United States

ID NLM: 101573691

Informations de publication

Date de publication:
23 02 2021

Historique:

received: 29 05 2020

revised: 08 12 2020

accepted: 02 02 2021

entrez: 24 2 2021

pubmed: 25 2 2021

medline: 27 1 2022

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.celrep.2021.108779 PMID: 33626356

pubmed: 33626356

pii: S2211-1247(21)00092-9

doi: 10.1016/j.celrep.2021.108779

pii:

doi:

Substances chimiques

Antineoplastic Agents 0

Cytokines 0

Inflammation Mediators 0

Janus Kinase Inhibitors 0

Pyridines 0

STAT3 Transcription Factor 0

STAT3 protein, human 0

Tyrphostins 0

WP1066 0

EZH2 protein, human EC 2.1.1.43

Enhancer of Zeste Homolog 2 Protein EC 2.1.1.43

Janus Kinases EC 2.7.10.2

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

108779

Informations de copyright

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.