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Cancer-Associated Fibroblasts Promote Tumor Aggressiveness in Head and Neck Cancer through Chemokine Ligand 11 and C-C Motif Chemokine Receptor 3 Signaling Circuit

SIMPLE SUMMARY: Certain tumor aggressiveness-associated mediators from cancer-associated fibroblasts (CAFs) in tumor microenvironment have been reported. Using gene expression analysis, we identified that CAFs overexpress Chemokine ligand 11 (CCL11), which is associated with tumor migration and inva...

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Autores principales: Huang, Wen-Yen, Lin, Yaoh-Shiang, Lin, Yu-Chun, Nieh, Shin, Chang, Yi-Ming, Lee, Tsai-Yu, Chen, Su-Feng, Yang, Kuender D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9264987/
https://www.ncbi.nlm.nih.gov/pubmed/35804913
http://dx.doi.org/10.3390/cancers14133141
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author Huang, Wen-Yen
Lin, Yaoh-Shiang
Lin, Yu-Chun
Nieh, Shin
Chang, Yi-Ming
Lee, Tsai-Yu
Chen, Su-Feng
Yang, Kuender D.
author_facet Huang, Wen-Yen
Lin, Yaoh-Shiang
Lin, Yu-Chun
Nieh, Shin
Chang, Yi-Ming
Lee, Tsai-Yu
Chen, Su-Feng
Yang, Kuender D.
author_sort Huang, Wen-Yen
collection PubMed
description SIMPLE SUMMARY: Certain tumor aggressiveness-associated mediators from cancer-associated fibroblasts (CAFs) in tumor microenvironment have been reported. Using gene expression analysis, we identified that CAFs overexpress Chemokine ligand 11 (CCL11), which is associated with tumor migration and invasion, increased expression of cancer stem cell properties, and induction of the epithelial-to-mesenchymal transition. Neutralization of CAF-induced CCL11 reversed the aggressive phenotype of cancer cells. Based on the immunohistochemical staining of clinical samples, we found that increased co-expression of CCL11 and its receptor, C-C Motif Chemokine Receptor 3 (CCR3), was associated with poor overall survival. Our results suggest that targeting CCL11-CCR3 signaling is a potential therapeutic strategy for patients with aggressive head and neck cancer. ABSTRACT: The tumor microenvironment (TME) plays a crucial role in tumor progression. One of its key stromal components, cancer-associated fibroblasts (CAFs), may crosstalk with cancer cells by secreting certain cytokines or chemokines. However, which important mediator(s) are released by CAFs, and the underlying molecular mechanism, remain largely unknown. In the present study, we isolated patient-derived CAFs and normal fibroblasts (NFs). Using microarray analysis, we detected chemokine ligand 11 (CCL11) overexpression in CAFs compared to NFs. CCL11 administration promoted the migration and invasion of head and neck cancer (HNC) cells with enhanced cancer stem cell-like properties and induction of epithelial-to-mesenchymal transition. Furthermore, neutralization of CCL11 activity reversed the aggressive phenotype of CAF-induced cancer cells. Confocal microscopy showed colocalization of CCL11 and CC chemokine receptor 3 (CCR3) on HNC cells. Moreover, immunohistochemical analysis of clinical samples from 104 patients with HNC showed that expression of CCL11 and CCR3 were significantly correlated with poor overall survival (p = 0.003 and 0.044, respectively). Collectively, CCL11 expressed on CAFs promotes HNC invasiveness, and neutralization of CCL11 reverses this effect. We propose that the CCL11/CCR3 signaling circuit is a potential target for optimizing therapeutic strategies against HNC.
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spelling pubmed-92649872022-07-09 Cancer-Associated Fibroblasts Promote Tumor Aggressiveness in Head and Neck Cancer through Chemokine Ligand 11 and C-C Motif Chemokine Receptor 3 Signaling Circuit Huang, Wen-Yen Lin, Yaoh-Shiang Lin, Yu-Chun Nieh, Shin Chang, Yi-Ming Lee, Tsai-Yu Chen, Su-Feng Yang, Kuender D. Cancers (Basel) Article SIMPLE SUMMARY: Certain tumor aggressiveness-associated mediators from cancer-associated fibroblasts (CAFs) in tumor microenvironment have been reported. Using gene expression analysis, we identified that CAFs overexpress Chemokine ligand 11 (CCL11), which is associated with tumor migration and invasion, increased expression of cancer stem cell properties, and induction of the epithelial-to-mesenchymal transition. Neutralization of CAF-induced CCL11 reversed the aggressive phenotype of cancer cells. Based on the immunohistochemical staining of clinical samples, we found that increased co-expression of CCL11 and its receptor, C-C Motif Chemokine Receptor 3 (CCR3), was associated with poor overall survival. Our results suggest that targeting CCL11-CCR3 signaling is a potential therapeutic strategy for patients with aggressive head and neck cancer. ABSTRACT: The tumor microenvironment (TME) plays a crucial role in tumor progression. One of its key stromal components, cancer-associated fibroblasts (CAFs), may crosstalk with cancer cells by secreting certain cytokines or chemokines. However, which important mediator(s) are released by CAFs, and the underlying molecular mechanism, remain largely unknown. In the present study, we isolated patient-derived CAFs and normal fibroblasts (NFs). Using microarray analysis, we detected chemokine ligand 11 (CCL11) overexpression in CAFs compared to NFs. CCL11 administration promoted the migration and invasion of head and neck cancer (HNC) cells with enhanced cancer stem cell-like properties and induction of epithelial-to-mesenchymal transition. Furthermore, neutralization of CCL11 activity reversed the aggressive phenotype of CAF-induced cancer cells. Confocal microscopy showed colocalization of CCL11 and CC chemokine receptor 3 (CCR3) on HNC cells. Moreover, immunohistochemical analysis of clinical samples from 104 patients with HNC showed that expression of CCL11 and CCR3 were significantly correlated with poor overall survival (p = 0.003 and 0.044, respectively). Collectively, CCL11 expressed on CAFs promotes HNC invasiveness, and neutralization of CCL11 reverses this effect. We propose that the CCL11/CCR3 signaling circuit is a potential target for optimizing therapeutic strategies against HNC. MDPI 2022-06-27 /pmc/articles/PMC9264987/ /pubmed/35804913 http://dx.doi.org/10.3390/cancers14133141 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Huang, Wen-Yen
Lin, Yaoh-Shiang
Lin, Yu-Chun
Nieh, Shin
Chang, Yi-Ming
Lee, Tsai-Yu
Chen, Su-Feng
Yang, Kuender D.
Cancer-Associated Fibroblasts Promote Tumor Aggressiveness in Head and Neck Cancer through Chemokine Ligand 11 and C-C Motif Chemokine Receptor 3 Signaling Circuit
title Cancer-Associated Fibroblasts Promote Tumor Aggressiveness in Head and Neck Cancer through Chemokine Ligand 11 and C-C Motif Chemokine Receptor 3 Signaling Circuit
title_full Cancer-Associated Fibroblasts Promote Tumor Aggressiveness in Head and Neck Cancer through Chemokine Ligand 11 and C-C Motif Chemokine Receptor 3 Signaling Circuit
title_fullStr Cancer-Associated Fibroblasts Promote Tumor Aggressiveness in Head and Neck Cancer through Chemokine Ligand 11 and C-C Motif Chemokine Receptor 3 Signaling Circuit
title_full_unstemmed Cancer-Associated Fibroblasts Promote Tumor Aggressiveness in Head and Neck Cancer through Chemokine Ligand 11 and C-C Motif Chemokine Receptor 3 Signaling Circuit
title_short Cancer-Associated Fibroblasts Promote Tumor Aggressiveness in Head and Neck Cancer through Chemokine Ligand 11 and C-C Motif Chemokine Receptor 3 Signaling Circuit
title_sort cancer-associated fibroblasts promote tumor aggressiveness in head and neck cancer through chemokine ligand 11 and c-c motif chemokine receptor 3 signaling circuit
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9264987/
https://www.ncbi.nlm.nih.gov/pubmed/35804913
http://dx.doi.org/10.3390/cancers14133141
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