PPARD and Interferon Gamma Promote Transformation of Gastric Progenitor Cells and Tumorigenesis in Mice

Xiangsheng Zuo; Yasunori Deguchi; Weiguo Xu; Yi Liu; Haiyan S. Li; Daoyan Wei; Rui Tian; Weidong Chen; Min Xu; Yaying Yang; Shen Gao; Jonathan C. Jaoude; Fuyao Liu; Sarah P. Chrieki; Micheline J. Moussalli; Mihai Gagea; Manu M. Sebastian; Xiaofeng Zheng; Dongfeng Tan; Russell Broaddus; Jing Wang; Nadim J. Ajami; Alton G. Swennes; Stephanie S. Watowich; Imad Shureiqi

doi:10.1053/j.gastro.2019.03.018

PPARD and Interferon Gamma Promote Transformation of Gastric Progenitor Cells and Tumorigenesis in Mice

Xiangsheng Zuo, Yasunori Deguchi, Weiguo Xu, Yi Liu, Haiyan S. Li, Daoyan Wei, Rui Tian, Weidong Chen, Min Xu, Yaying Yang, Shen Gao, Jonathan C. Jaoude, Fuyao Liu, Sarah P. Chrieki, Micheline J. Moussalli, Mihai Gagea, Manu M. Sebastian, Xiaofeng Zheng, Dongfeng Tan, Russell BroaddusJing Wang, Nadim J. Ajami, Alton G. Swennes, Stephanie S. Watowich, Imad Shureiqi

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	163-178
Number of pages	16
Journal	Gastroenterology
Volume	157
Issue number	1
DOIs	https://doi.org/10.1053/j.gastro.2019.03.018
State	Published - Jul 2019

Keywords

IFNG
Mouse Model
Nuclear Factor
Tumor Stem Cell

ASJC Scopus subject areas

Hepatology
Gastroenterology

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Bioinformatics Shared Resource
Flow Cytometry and Cellular Imaging Facility
Functional Genomics Core
Genetically Engineered Mouse Facility
Research Animal Support Facility
Laboratory Animal Genetic Services

Access to Document

10.1053/j.gastro.2019.03.018

Cite this

Zuo, X., Deguchi, Y., Xu, W., Liu, Y., Li, H. S., Wei, D., Tian, R., Chen, W., Xu, M., Yang, Y., Gao, S., Jaoude, J. C., Liu, F., Chrieki, S. P., Moussalli, M. J., Gagea, M., Sebastian, M. M., Zheng, X., Tan, D., ... Shureiqi, I. (2019). PPARD and Interferon Gamma Promote Transformation of Gastric Progenitor Cells and Tumorigenesis in Mice. Gastroenterology, 157(1), 163-178. https://doi.org/10.1053/j.gastro.2019.03.018

Zuo, X, Deguchi, Y, Xu, W, Liu, Y, Li, HS, Wei, D, Tian, R, Chen, W, Xu, M, Yang, Y, Gao, S, Jaoude, JC, Liu, F, Chrieki, SP, Moussalli, MJ, Gagea, M , Sebastian, MM , Zheng, X , Tan, D, Broaddus, R, Wang, J, Ajami, NJ, Swennes, AG, Watowich, SS & Shureiqi, I 2019, 'PPARD and Interferon Gamma Promote Transformation of Gastric Progenitor Cells and Tumorigenesis in Mice', Gastroenterology, vol. 157, no. 1, pp. 163-178. https://doi.org/10.1053/j.gastro.2019.03.018

@article{754dcf7ad18c4b1c8020d649a67867be,

title = "PPARD and Interferon Gamma Promote Transformation of Gastric Progenitor Cells and Tumorigenesis in Mice",

abstract = "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.",

keywords = "IFNG, Mouse Model, Nuclear Factor, Tumor Stem Cell",

author = "Xiangsheng Zuo and Yasunori Deguchi and Weiguo Xu and Yi Liu and Li, {Haiyan S.} and Daoyan Wei and Rui Tian and Weidong Chen and Min Xu and Yaying Yang and Shen Gao and Jaoude, {Jonathan C.} and Fuyao Liu and Chrieki, {Sarah P.} and Moussalli, {Micheline J.} and Mihai Gagea and Sebastian, {Manu M.} and Xiaofeng Zheng and Dongfeng Tan and Russell Broaddus and Jing Wang and Ajami, {Nadim J.} and Swennes, {Alton G.} and Watowich, {Stephanie S.} and Imad Shureiqi",

note = "Funding Information: This study made use of the MD Anderson Cancer Center Genetically Engineered Mouse Facility, Functional Genomics Core, Flow Cytometry and Cellular Imaging Facility, Sequencing and Microarray Facility, and Research Animal Support Facility—Smithville Laboratory Animal Genetic Services, supported by Cancer Center Support Grant CA016672. The study also used the Baylor College of Medicine Gnotobiotics Core, supported by P30-DK056338. Funding Information: Funding This work was supported by the National Cancer Institute (R01-CA142969, R01-CA195686, and R01-CA206539 to I.S.), the Cancer Prevention and Research Institute of Texas (RP140224 to I.S.), and MD Anderson Institutional Research Seed Fund (to X. Zuo). Publisher Copyright: {\textcopyright} 2019 AGA Institute",

year = "2019",

month = jul,

doi = "10.1053/j.gastro.2019.03.018",

language = "English (US)",

volume = "157",

pages = "163--178",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "1",

}

TY - JOUR

T1 - PPARD and Interferon Gamma Promote Transformation of Gastric Progenitor Cells and Tumorigenesis in Mice

AU - Zuo, Xiangsheng

AU - Deguchi, Yasunori

AU - Xu, Weiguo

AU - Liu, Yi

AU - Li, Haiyan S.

AU - Wei, Daoyan

AU - Tian, Rui

AU - Chen, Weidong

AU - Xu, Min

AU - Yang, Yaying

AU - Gao, Shen

AU - Jaoude, Jonathan C.

AU - Liu, Fuyao

AU - Chrieki, Sarah P.

AU - Moussalli, Micheline J.

AU - Gagea, Mihai

AU - Sebastian, Manu M.

AU - Zheng, Xiaofeng

AU - Tan, Dongfeng

AU - Broaddus, Russell

AU - Wang, Jing

AU - Ajami, Nadim J.

AU - Swennes, Alton G.

AU - Watowich, Stephanie S.

AU - Shureiqi, Imad

N1 - Funding Information: This study made use of the MD Anderson Cancer Center Genetically Engineered Mouse Facility, Functional Genomics Core, Flow Cytometry and Cellular Imaging Facility, Sequencing and Microarray Facility, and Research Animal Support Facility—Smithville Laboratory Animal Genetic Services, supported by Cancer Center Support Grant CA016672. The study also used the Baylor College of Medicine Gnotobiotics Core, supported by P30-DK056338. Funding Information: Funding This work was supported by the National Cancer Institute (R01-CA142969, R01-CA195686, and R01-CA206539 to I.S.), the Cancer Prevention and Research Institute of Texas (RP140224 to I.S.), and MD Anderson Institutional Research Seed Fund (to X. Zuo). Publisher Copyright: © 2019 AGA Institute

PY - 2019/7

Y1 - 2019/7

N2 - 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.

AB - 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.

KW - IFNG

KW - Mouse Model

KW - Nuclear Factor

KW - Tumor Stem Cell

UR - http://www.scopus.com/inward/record.url?scp=85067176970&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067176970&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2019.03.018

DO - 10.1053/j.gastro.2019.03.018

M3 - Article

C2 - 30885780

AN - SCOPUS:85067176970

SN - 0016-5085

VL - 157

SP - 163

EP - 178

JO - Gastroenterology

JF - Gastroenterology

IS - 1

ER -

PPARD and Interferon Gamma Promote Transformation of Gastric Progenitor Cells and Tumorigenesis in Mice

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

Access to Document

Other files and links

Fingerprint

Cite this