Disrupting Inflammation-Associated CXCL8-CXCR1 Signaling Inhibits Tumorigenicity Initiated by Sporadic- and Colitis-Colon Cancer Stem Cells.
Animals
Biomarkers
Cell Line, Tumor
Cell Proliferation
Cell Transformation, Neoplastic
/ metabolism
Colitis
/ complications
Colonic Neoplasms
/ etiology
Disease Models, Animal
Gene Dosage
Gene Expression
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Heterografts
Humans
Immunophenotyping
Inflammation
/ complications
Interleukin-8
/ genetics
Mice
Models, Biological
Neoplastic Stem Cells
/ metabolism
Neovascularization, Pathologic
/ genetics
Receptors, Interleukin-8A
/ genetics
Signal Transduction
Journal
Neoplasia (New York, N.Y.)
ISSN: 1476-5586
Titre abrégé: Neoplasia
Pays: United States
ID NLM: 100886622
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
02
11
2018
revised:
18
12
2018
accepted:
22
12
2018
pubmed:
10
2
2019
medline:
14
6
2019
entrez:
10
2
2019
Statut:
ppublish
Résumé
Dysfunctional inflammatory pathways are associated with an increased risk of cancer, including colorectal cancer. We have previously identified and enriched for a self-renewing, colon cancer stem cell (CCSC) subpopulation in primary sporadic colorectal cancers (CRC) and a related subpopulation in ulcerative colitis (UC) patients defined by the stem cell marker, aldehyde dehydrogenase (ALDH). Subsequent work demonstrated that CCSC-initiated tumors are dependent on the inflammatory chemokine, CXCL8, a known inducer of tumor proliferation, angiogenesis and invasion. Here, we use RNA interference to target CXCL8 and its receptor, CXCR1, to establish the existence of a functional signaling pathway promoting tumor growth initiated by sporadic and colitis CCSCs. Knocking down either CXCL8 or CXCR1 had a dramatic effect on inhibiting both in vitro proliferation and angiogenesis. Likewise, tumorigenicity was significantly inhibited due to reduced levels of proliferation and angiogenesis. Decreased expression of cycle cell regulators cyclins D1 and B1 along with increased p21 levels suggested that the reduction in tumor growth is due to dysregulation of cell cycle progression. Therapeutically targeting the CXCL8-CXCR1 signaling pathway has the potential to block sustained tumorigenesis by inhibiting both CCSC- and pCCSC-induced proliferation and angiogenesis.
Identifiants
pubmed: 30738331
pii: S1476-5586(18)30593-1
doi: 10.1016/j.neo.2018.12.007
pmc: PMC6370871
pii:
doi:
Substances chimiques
Biomarkers
0
CXCL8 protein, human
0
Interleukin-8
0
Receptors, Interleukin-8A
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
269-281Subventions
Organisme : NCI NIH HHS
ID : R01 CA142808
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA157663
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK105916
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA214300
Pays : United States
Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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