Loss of SMAD4 Promotes Colorectal Cancer Progression by Recruiting Tumor-Associated Neutrophils via the CXCL1/8-CXCR2 Axis.
Apoptosis
Biomarkers, Tumor
/ genetics
Case-Control Studies
Cell Movement
Cell Proliferation
Chemokine CXCL1
/ genetics
Colorectal Neoplasms
/ genetics
Disease Progression
Follow-Up Studies
Gene Expression Regulation, Neoplastic
Humans
Interleukin-8
/ genetics
Neutrophil Infiltration
Neutrophils
/ pathology
Prognosis
Receptors, Interleukin-8B
/ genetics
Smad4 Protein
/ genetics
Survival Rate
Tumor Cells, Cultured
Tumor Microenvironment
Xenograft Model Antitumor Assays
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 05 2019
01 05 2019
Historique:
received:
09
11
2018
revised:
04
01
2019
accepted:
28
01
2019
pubmed:
2
2
2019
medline:
20
6
2020
entrez:
2
2
2019
Statut:
ppublish
Résumé
SMAD4 is a key transcriptional factor of TGFβ signaling and acts as a tumor suppressor in colorectal cancer. In the present study, we explored the immunologic effect of SMAD4 on the tumor microenvironment. Using 99 clinical specimens and human colorectal cancer cell lines, we investigate the relationship between SMAD4 expression and neutrophil accumulation. We immunohistochemically analyzed expression of SMAD4, CXCL1, CXCL8, CXCR2, and other proteins with clinical specimens. Finally, we determined the serum levels of CXCL1 and CXCL8 in 125 patients with colorectal cancer. SMAD4 knockdown from human colorectal cancer cells upregulated the expression of CXCL1 and CXCL8, which recruited neutrophils to colorectal cancer tumor via CXCR2. In turn, when neutrophils were exposed to the supernatant of SMAD4-negative colorectal cancer cells, they produced a large amount of CXCL1 and CXCL8 by themselves Blockade of the CXCL1/8-CXCR2 axis could be a novel therapeutic approach against SMAD4-negative colorectal cancer.
Identifiants
pubmed: 30705034
pii: 1078-0432.CCR-18-3684
doi: 10.1158/1078-0432.CCR-18-3684
doi:
Substances chimiques
Biomarkers, Tumor
0
CXCL1 protein, human
0
CXCL8 protein, human
0
CXCR2 protein, human
0
Chemokine CXCL1
0
Interleukin-8
0
Receptors, Interleukin-8B
0
SMAD4 protein, human
0
Smad4 Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2887-2899Informations de copyright
©2019 American Association for Cancer Research.