PPARD and Interferon Gamma Promote Transformation of Gastric Progenitor Cells and Tumorigenesis in Mice.
Adenocarcinoma
/ genetics
Animals
Carcinogenesis
/ genetics
Cell Lineage
Cell Transformation, Neoplastic
/ genetics
Chemokine CCL20
/ metabolism
Chemokine CXCL1
/ metabolism
Chemokines
Cytokines
/ immunology
Feedback, Physiological
Gastric Mucosa
/ metabolism
Gene Expression Profiling
Inflammation
Interferon-gamma
/ immunology
Mice
Microbiota
/ immunology
Microfilament Proteins
/ genetics
Receptors, Cytoplasmic and Nuclear
/ genetics
Stem Cells
/ immunology
Stomach
/ immunology
Stomach Neoplasms
/ genetics
IFNG
Mouse Model
Nuclear Factor
Tumor Stem Cell
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
07 2019
07 2019
Historique:
received:
05
09
2018
revised:
20
02
2019
accepted:
12
03
2019
pubmed:
20
3
2019
medline:
31
7
2019
entrez:
20
3
2019
Statut:
ppublish
Résumé
The peroxisome proliferator-activated receptor delta (PPARD) regulates cell metabolism, proliferation, and inflammation and has been associated with gastric and other cancers. Villin-positive epithelial cells are a small population of quiescent gastric progenitor cells. We expressed PPARD from a villin promoter to investigate the role of these cells and PPARD in development of gastric cancer. We analyzed gastric tissues from mice that express the Ppard (PPARD1 and PPARD2 mice) from a villin promoter, and mice that did not carry this transgene (controls), by histology and immunohistochemistry. We performed cell lineage-tracing experiments and analyzed the microbiomes, chemokine and cytokine production, and immune cells and transcriptomes of stomachs of these mice. We also performed immunohistochemical analysis of PPARD levels in 2 sets of human gastric tissue microarrays. Thirty-eight percent of PPARD mice developed spontaneous, invasive gastric adenocarcinomas, with severe chronic inflammation. Levels of PPARD were increased in human gastric cancer tissues, compared with nontumor tissues, and associated with gastric cancer stage and grade. We found an inverse correlation between level of PPARD in tumor tissue and patient survival time. Gastric microbiomes from PPARD and control mice did not differ significantly. Lineage-tracing experiments identified villin-expressing gastric progenitor cells (VGPCs) as the origin of gastric tumors in PPARD mice. In these mice, PPARD up-regulated CCL20 and CXCL1, which increased infiltration of the gastric mucosa by immune cells. Immune cell production of inflammatory cytokines promoted chronic gastric inflammation and expansion and transformation of VGPCs, leading to tumorigenesis. We identified a positive-feedback loop between PPARD and interferon gamma signaling that sustained gastric inflammation to induce VGPC transformation and gastric carcinogenesis. We found PPARD overexpression in VPGCs to result in inflammation, dysplasia, and tumor formation. PPARD and VGPCs might be therapeutic targets for stomach cancer.
Sections du résumé
BACKGROUND & AIMS
The peroxisome proliferator-activated receptor delta (PPARD) regulates cell metabolism, proliferation, and inflammation and has been associated with gastric and other cancers. Villin-positive epithelial cells are a small population of quiescent gastric progenitor cells. We expressed PPARD from a villin promoter to investigate the role of these cells and PPARD in development of gastric cancer.
METHODS
We analyzed gastric tissues from mice that express the Ppard (PPARD1 and PPARD2 mice) from a villin promoter, and mice that did not carry this transgene (controls), by histology and immunohistochemistry. We performed cell lineage-tracing experiments and analyzed the microbiomes, chemokine and cytokine production, and immune cells and transcriptomes of stomachs of these mice. We also performed immunohistochemical analysis of PPARD levels in 2 sets of human gastric tissue microarrays.
RESULTS
Thirty-eight percent of PPARD mice developed spontaneous, invasive gastric adenocarcinomas, with severe chronic inflammation. Levels of PPARD were increased in human gastric cancer tissues, compared with nontumor tissues, and associated with gastric cancer stage and grade. We found an inverse correlation between level of PPARD in tumor tissue and patient survival time. Gastric microbiomes from PPARD and control mice did not differ significantly. Lineage-tracing experiments identified villin-expressing gastric progenitor cells (VGPCs) as the origin of gastric tumors in PPARD mice. In these mice, PPARD up-regulated CCL20 and CXCL1, which increased infiltration of the gastric mucosa by immune cells. Immune cell production of inflammatory cytokines promoted chronic gastric inflammation and expansion and transformation of VGPCs, leading to tumorigenesis. We identified a positive-feedback loop between PPARD and interferon gamma signaling that sustained gastric inflammation to induce VGPC transformation and gastric carcinogenesis.
CONCLUSIONS
We found PPARD overexpression in VPGCs to result in inflammation, dysplasia, and tumor formation. PPARD and VGPCs might be therapeutic targets for stomach cancer.
Identifiants
pubmed: 30885780
pii: S0016-5085(19)33572-3
doi: 10.1053/j.gastro.2019.03.018
pmc: PMC6581611
mid: NIHMS1524109
pii:
doi:
Substances chimiques
CCL20 protein, mouse
0
Chemokine CCL20
0
Chemokine CXCL1
0
Chemokines
0
Cxcl1 protein, mouse
0
Cytokines
0
Microfilament Proteins
0
Ppard protein, mouse
0
Receptors, Cytoplasmic and Nuclear
0
Vil1 protein, mouse
0
Interferon-gamma
82115-62-6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
163-178Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA206539
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA195686
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK056338
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA142969
Pays : United States
Informations de copyright
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
Références
Proc Natl Acad Sci U S A. 2014 May 13;111(19):7084-9
pubmed: 24763687
Gastroenterology. 2010 Jun;138(7):2207-10, 2210.e1
pubmed: 20450866
Gastroenterology. 2012 Mar;142(3):531-42
pubmed: 22155367
Biochem Pharmacol. 2013 Mar 1;85(5):607-611
pubmed: 23041232
Cancer Cell. 2015 Dec 14;28(6):800-814
pubmed: 26585400
Stem Cells Transl Med. 2015 Sep;4(9):1033-43
pubmed: 26136504
Physiol Rev. 2014 Jul;94(3):795-858
pubmed: 24987006
Cell Res. 2016 Jul;26(7):838-49
pubmed: 27091432
Gut. 2015 Apr;64(4):544-53
pubmed: 24951258
J Immunol. 2004 Feb 15;172(4):2595-606
pubmed: 14764733
Stem Cells. 2009 May;27(5):1006-20
pubmed: 19415765
Nature. 2016 Mar 3;531(7592):53-8
pubmed: 26935695
EMBO J. 2015 Oct 14;34(20):2522-36
pubmed: 26271103
Int J Mol Sci. 2017 Dec 28;19(1):
pubmed: 29283429
Infect Immun. 1999 Jan;67(1):279-85
pubmed: 9864227
Dig Dis Sci. 2013 Oct;58(10):2881-6
pubmed: 23907334
Cancers (Basel). 2013 Jan 24;5(1):92-130
pubmed: 24216700
PPAR Res. 2010;2010:571783
pubmed: 21318167
Gut. 2014 Oct;63(10):1550-9
pubmed: 24436142
Cancer Cell. 2008 Nov 4;14(5):408-19
pubmed: 18977329
PLoS Pathog. 2015 Feb 06;11(2):e1004663
pubmed: 25658601
Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4358-63
pubmed: 18332421
J Natl Cancer Inst. 2009 May 20;101(10):762-7
pubmed: 19436036
Gastroenterology. 2007 Dec;133(6):1989-98
pubmed: 18054570
Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13275-80
pubmed: 11087869
Cell Mol Gastroenterol Hepatol. 2017 Feb 20;3(3):331-338
pubmed: 28462375
Am J Pathol. 2012 Dec;181(6):2114-25
pubmed: 23036899
Lab Invest. 2012 Jul;92(7):1045-57
pubmed: 22525425
JCI Insight. 2017 Jan 12;2(1):e91419
pubmed: 28097239
J Immunol. 2013 Apr 1;190(7):3706-15
pubmed: 23460743
Gut. 2014 Mar;63(3):385-94
pubmed: 23729675
Immunity. 2006 Feb;24(2):191-201
pubmed: 16473831
Clin Cancer Res. 2016 May 15;22(10):2329-34
pubmed: 27016309
Biochimie. 2017 May;136:42-48
pubmed: 27916646
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
J Leukoc Biol. 2004 Feb;75(2):163-89
pubmed: 14525967
Cell. 2016 Dec 1;167(6):1540-1554.e12
pubmed: 27912061
Helicobacter. 2000 Sep;5(3):121-8
pubmed: 10971675
Sci Rep. 2016 Sep 14;6:33123
pubmed: 27625115
Methods Mol Biol. 2019;1576:123-133
pubmed: 27704362
Gastroenterology. 2007 Aug;133(2):659-72
pubmed: 17681184
Trends Endocrinol Metab. 2015 Nov;26(11):595-607
pubmed: 26490384
J Gastrointest Cancer. 2014 Jun;45(2):126-32
pubmed: 24557546
Gastroenterology. 2011 Aug;141(2):553-64
pubmed: 21704622
Cancer Res. 2013 Jul 15;73(14):4349-61
pubmed: 23811944
CA Cancer J Clin. 2015 Mar;65(2):87-108
pubmed: 25651787
Infect Immun. 2007 Sep;75(9):4357-63
pubmed: 17562763
Am J Respir Cell Mol Biol. 2008 Dec;39(6):689-96
pubmed: 18566335
J Natl Cancer Inst. 2014 Apr;106(4):dju052
pubmed: 24681603