Back to Search
Start Over
Stat6 Promotes Intestinal Tumorigenesis in a Mouse Model of Adenomatous Polyposis by Expansion of MDSCs and Inhibition of Cytotoxic CD8 Response.
- Source :
-
Neoplasia (New York, N.Y.) [Neoplasia] 2017 Aug; Vol. 19 (8), pp. 595-605. Date of Electronic Publication: 2017 Jun 24. - Publication Year :
- 2017
-
Abstract
- Intestinal tumorigenesis in the ApcMin/+ model is initiated by aberrant activation of Wnt pathway. Increased IL-4 expression in human colorectal cancer tissue and growth of colon cancer cell lines implied that IL-4-induced Stat6-mediated tumorigenic signaling likely contributes to intestinal tumor progression in ApcMin/+ mice. Stat6 also appears to promote expansion of myeloid-derived suppressor cells (MDSCs) cells. MDSCs promote polyp formation in the ApcMin/+ model. Hence, Stat6 could have a broad role in coordinating both polyp cell proliferation and MDSC expansion. We found that IL-4-induced Stat6-mediated proliferation of intestinal epithelial cells is augmented by platelet-derived growth factor-BB, a tumor-promoting growth factor. To determine whether polyp progression in ApcMin/+ mice is dependent on Stat6 signaling, we disrupted Stat6 in this model. Total polyps in the small intestine were fewer in ApcMin/+ mice lacking Stat6. Furthermore, proliferation of polyp epithelial cells was reduced, indicating that Stat6 in part controlled polyp formation. Stat6 also promoted expansion of MDSCs in the spleen and lamina propria of ApcMin/+ mice, implying regulation of antitumor T-cell response. More CD8 cells and reduced PD-1 expression on CD4 cells correlated with reduced polyps. In addition, a strong CD8-mediated cytotoxic response led to killing of tumor cells in Stat6-deficient ApcMin/+ mice. Therefore, these findings show that Stat6 has an oncogenic role in intestinal tumorigenesis by promoting polyp cell proliferation and immunosuppressive mediators, and preventing an active cytotoxic process.<br /> (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Adenomatous Polyposis Coli pathology
Animals
Becaplermin
Biomarkers
CD4-Positive T-Lymphocytes drug effects
CD4-Positive T-Lymphocytes immunology
CD4-Positive T-Lymphocytes metabolism
Cell Transformation, Neoplastic genetics
Cytotoxicity, Immunologic genetics
Cytotoxicity, Immunologic immunology
Disease Models, Animal
Disease Progression
Gene Deletion
Gene Expression
Interleukin-4 metabolism
Interleukin-4 pharmacology
Intestinal Mucosa drug effects
Intestinal Mucosa immunology
Intestinal Mucosa metabolism
Intestinal Mucosa pathology
Intestine, Small immunology
Intestine, Small metabolism
Intestine, Small pathology
Mice
Mice, Knockout
Programmed Cell Death 1 Receptor genetics
Programmed Cell Death 1 Receptor metabolism
Proto-Oncogene Proteins c-sis pharmacology
STAT6 Transcription Factor genetics
Adenomatous Polyposis Coli etiology
Adenomatous Polyposis Coli metabolism
CD8-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes metabolism
Cell Transformation, Neoplastic immunology
Cell Transformation, Neoplastic metabolism
Myeloid-Derived Suppressor Cells immunology
Myeloid-Derived Suppressor Cells metabolism
STAT6 Transcription Factor metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5586
- Volume :
- 19
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Neoplasia (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 28654863
- Full Text :
- https://doi.org/10.1016/j.neo.2017.04.006