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PMID: 21653678 Published · ppublish English Journal Article Research Support, N.I.H., Intramural

IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells.

Cancer research ·Vol. 71 ·No. 15 ·2011-08-01 ·Pages 5296-306

Fernando RI, Castillo MD, Litzinger M, Hamilton DH, Palena C

Abstract

The switch of tumor cells from an epithelial to a mesenchymal-like phenotype [designated as epithelial-to-mesenchymal transition (EMT)] is known to induce tumor cell motility and invasiveness, therefore promoting metastasis of solid carcinomas. Although multiple studies have focused on elucidating the signaling events that initiate this phenotypic switch, there has been so far no characterization of the pattern of soluble mediators released by tumor cells undergoing EMT, and the potential impact that this phenotypic switch could have on the remodeling of the tumor microenvironment. Here we show that induction of EMT in human carcinoma cells via overexpression of the transcription factor Brachyury is associated with enhanced secretion of multiple cytokines, chemokines, and angiogenic factors and, in particular, with the induction of the IL-8/IL-8R axis. Our results also indicate the essential role of interleukin 8 (IL-8) signaling for the acquisition and/or maintenance of the mesenchymal and invasive features of Brachyury-overexpressing tumor cells and show that IL-8 secreted by tumor cells undergoing EMT could potentiate tumor progression by inducing adjacent epithelial tumor cells into EMT. Altogether, our results emphasize the potential role of EMT in the modulation of the tumor microenvironment via secretion of multiple soluble mediators and suggest that IL-8 signaling blockade may provide a means of targeting mesenchymal-like, invasive tumor cells.

MeSH Terms
Breast Neoplasms/metabolism,pathology Bystander Effect Carcinoma/metabolism,pathology Cell Line, Tumor/metabolism,pathology Cell Movement Chemokines/metabolism Culture Media, Conditioned/pharmacology Culture Media, Serum-Free Cytokines/metabolism Epithelial-Mesenchymal Transition/physiology Fetal Proteins/antagonists & inhibitors,biosynthesis,genetics,physiology Fibronectins/biosynthesis,genetics Gene Expression Regulation, Neoplastic/drug effects Humans Intercellular Signaling Peptides and Proteins/metabolism Interleukin-8/physiology Neoplasm Invasiveness Neoplasm Proteins/antagonists & inhibitors,biosynthesis,genetics,physiology Pancreatic Neoplasms/metabolism,pathology Promoter Regions, Genetic RNA, Small Interfering/pharmacology Receptors, Interleukin-8/biosynthesis,genetics Recombinant Fusion Proteins/antagonists & inhibitors T-Box Domain Proteins/antagonists & inhibitors,biosynthesis,genetics,physiology Tumor Microenvironment/physiology
Chemicals
Chemokines Culture Media, Conditioned Culture Media, Serum-Free Cytokines Fetal Proteins Fibronectins Intercellular Signaling Peptides and Proteins Interleukin-8 Neoplasm Proteins RNA, Small Interfering Receptors, Interleukin-8 Recombinant Fusion Proteins T-Box Domain Proteins Brachyury protein
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Fernando Romaine I
Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
Castillo Marianne D
Litzinger Mary
Hamilton Duane H
Palena Claudia
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Article Info
Journal
Cancer research
Abbr.
Cancer Res
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-11-0156
Published
2011-08-01
Epub
2011-00-08
Pages
5296-306
Language
English
Region
United States
NLM ID
2984705R
PMCID
PMC3148346
Subset
IM
Grants
Intramural NIH HHS · ZIC BC010937-03 · United States
External Links
PubMed source DOI: 10.1158/0008-5472.CAN-11-0156 PMC Full Text View journal details
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