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      Involvement of CCR6/CCL20/IL-17 Axis in NSCLC Disease Progression

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          Abstract

          Objectives

          Autocrine and paracrine chemokine/chemokine receptor-based interactions promote non-small-cell-lung-cancer (NSCLC) carcinogenesis. CCL20/CCR6 interactions are involved in prostatic and colonic malignancy pathogenesis. The expression and function of CCL20/CCR6 and its related Th-17 type immune response in NSCLC is not yet defined. We sought to characterize the role of the CCL20/CCR6/IL-17 axis in NSCLC tumor growth.

          Methods

          A specialized histopathologist blindly assessed CCL20/CCR6 expression levels in 49 tissue samples of NSCLC patients operated in our department. Results were correlated to disease progression. Colony assays, ERK signaling and chemokine production were measured to assess cancer cell responsiveness to CCL20 and IL-17 stimulation.

          Results

          CCL20 was highly expressed in the majority (38/49, 77.5%) of tumor samples. Only a minority of samples (8/49, 16.5%) showed high CCR6 expression. High CCR6 expression was associated with a shorter disease-free survival (P = 0.008) and conferred a disease stage-independent 4.87-fold increased risk for disease recurrence (P = 0.0076, CI 95% 1.52–15.563). Cancerous cell colony-forming capacity was increased by CCL20 stimulation; this effect was dependent in part on ERK phosphorylation and signaling. IL-17 expression was detected in NSCLC; IL-17 potentiated the production of CCL20 by cancerous cells.

          Conclusion

          Our findings suggest that the CCL20/CCR6 axis promotes NSCLC disease progression. CCR6 is identified as a potential new prognostic marker and the CCL20/CCR6/IL-17 axis as a potential new therapeutic target. Larger scale studies are required to consolidate these observations.

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          Most cited references32

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          Chemokines: a new classification system and their role in immunity.

          A Zlotnik, O Yoshie (2000)
          Article 0 comments Cited 503 times – based on 0 reviews     Review now
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            Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study.

            Kerby Shedden, Jeremy M. G. Taylor, Steven A. Enkemann … (2008)
            Although prognostic gene expression signatures for survival in early-stage lung cancer have been proposed, for clinical application, it is critical to establish their performance across different subject populations and in different laboratories. Here we report a large, training-testing, multi-site, blinded validation study to characterize the performance of several prognostic models based on gene expression for 442 lung adenocarcinomas. The hypotheses proposed examined whether microarray measurements of gene expression either alone or combined with basic clinical covariates (stage, age, sex) could be used to predict overall survival in lung cancer subjects. Several models examined produced risk scores that substantially correlated with actual subject outcome. Most methods performed better with clinical data, supporting the combined use of clinical and molecular information when building prognostic models for early-stage lung cancer. This study also provides the largest available set of microarray data with extensive pathological and clinical annotation for lung adenocarcinomas.
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              Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients.

              Jing-Ping Zhang, Jing Yan, Jing Jing Xu … (2009)
              To characterize IL-17-producing cells, a newly defined T helper cell subset with potent pro-inflammatory properties, in hepatocellular carcinoma (HCC) and to determine their prognostic values. One hundred and seventy-eight HCC patients were enrolled randomly. Distribution and phenotypic features of IL-17-producing cells were determined by flow cytometry and/or immunohistochemistry. Compared with corresponding non-tumor regions, the levels of Th17 cells were significantly increased in tumors of HCC patients (P<0.001). Most intratumoral Th17 cells exhibited an effector memory phenotype with increased expression of CCR4 and CCR6. Intratumoral IL-17-producing cell density was associated with overall survival (OS, P=0.001) and disease-free survival (DFS, P=0.001) in HCC patients. Multivariate Cox analysis revealed that intratumoral IL-17-producing cell density was an independent prognostic factor for OS (HR=2.351, P=0.009) and DFS (HR=2.256, P=0.002). Moreover, the levels of intratumoral Th17 cells were positively correlated with microvessel density in tumors (r=0.616, P=0.001). Accumulation of intratumoral IL-17-producing cells may promote tumor progression through fostering angiogenesis, and intratumoral IL-17-producing cell could serve as a potential prognostic marker and a novel therapeutic target for HCC.
              Article 0 comments Cited 169 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2011
                Publication date (Electronic): 15 September 2011
                Volume: 6
                Issue: 9
                Electronic Location Identifier: e24856
                Affiliations
                [1 ]Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, Jerusalem, Israel
                [2 ]Department of Cardiothoracic Surgery, Hadassah University Hospital, Jerusalem, Israel
                [3 ]Department of Pathology, Hadassah University Hospital, Jerusalem, Israel
                [4 ]Laboratory for Surgical Research, Hadassah University Hospital, Jerusalem, Israel
                [5 ]Department of Surgery, Hadassah University Hospital, Jerusalem, Israel
                University of Texas Southwestern Medical Center at Dallas, United States of America
                Author notes

                Conceived and designed the experiments: UI OMS AP GZ OW. Performed the experiments: SK KB ZS HW JD. Analyzed the data: JD GA FV OW. Wrote the paper: OW.

                Article
                Publisher ID: PONE-D-11-05479
                DOI: 10.1371/journal.pone.0024856
                PMC ID: 3174223
                PubMed ID: 21949768
                SO-VID: fee8f9c7-1cd4-4995-b6ab-431fd8297a80
                Copyright © Kirshberg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 25 March 2011
                Date accepted : 22 August 2011
                Page count
                Pages: 10
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Anatomy and Physiology
                Subject: Immune Physiology
                Subject: Cytokines
                Subject: Immunology
                Subject: Immune System
                Subject: Cytokines
                Subject: Immunologic Subspecialties
                Subject: Tumor Immunology
                Subject: Molecular Cell Biology
                Subject: Cell Division
                Subject: Cytokinesis
                Subject: Medicine
                Subject: Anatomy and Physiology
                Subject: Immune Physiology
                Subject: Cytokines
                Subject: Clinical Immunology
                Subject: Immune System
                Subject: Cytokines
                Subject: Immunologic Subspecialties
                Subject: Tumor Immunology
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Lung and Intrathoracic Tumors
                Subject: Non-Small Cell Lung Cancer
                Subject: Basic Cancer Research

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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