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Liu Q, Song M, Wang Y, Zhang P, Zhang H. CCL20-CCR6 signaling in tumor microenvironment: Functional roles, mechanisms, and immunotherapy targeting. Biochim Biophys Acta Rev Cancer 2025; 1880:189341. [PMID: 40348067 DOI: 10.1016/j.bbcan.2025.189341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 05/01/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
Chemokine CC motif ligand 20 (CCL20) is a molecule with immunomodulatory properties that is involved in the regulation of diseases such as chronic inflammation, autoimmune diseases, and cancer. It operates by binding to its specific receptor, CC chemokine receptor type 6 (CCR6), and activating a complex intracellular signaling network. Building on its established role in inflammatory diseases, recent research has expanded our understanding of CCL20 to encompass its critical contributions to the tumor microenvironment (TME), highlighting its significance in cancer progression. Numerous studies have emphasized its prominent role in regulating immune responses. Consequently, Monoclonal antibodies against CCL20 and inhibitors of CCR6 have been successfully developed to block downstream signaling, making the CCL20-CCR6 axis a promising and critical target in the TME. This offers potential immunotherapeutic strategies for cancers. In this review, we summarize the biological consequences of CCL20-CCR6 mediated signaling, its role and mechanisms in the TME, and its potential applications. We suggest that the CCL20-CCR6 axis may be a novel biomarker for tumor diagnosis and prognosis, as well as a therapeutic target in various cancers.
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Affiliation(s)
- Qi Liu
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Mingyuan Song
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Yan Wang
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Ping Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Hao Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China.
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Liu Q, Wang Y, Song M, Huang J, Shi J, Sun W, Ji X, Chang Y, Ma B, Zhang P, Yan Y, Zhang H. CCL20/CXCL5 Drives Crosstalk Between Anaplastic Thyroid Cancer Stem Cells and Tumor-Associated Macrophages to Promote Tumor Progression. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2405399. [PMID: 40091357 PMCID: PMC12061268 DOI: 10.1002/advs.202405399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 02/26/2025] [Indexed: 03/19/2025]
Abstract
The dynamic interplay between tumor-associated macrophages (TAMs) and anaplastic thyroid cancer (ATC) shapes the tumor microenvironment and facilitates ATC progression. However, the mechanisms of communication between TAMs and anaplastic thyroid cancer stem cells (ATCSCs) remain largely unelucidated. Integrative analyses of single-cell RNA sequencing, cytokine/chemokine arrays, proteomics, and mRNA expression datasets are performed to reveal crosstalk between TAMs and ATCSCs and signaling pathways in ATCSCs. Subsequently, in vitro experiments are performed to validate the regulatory effects of key cytokines on ATCSC stemness. Last, xenogeneic orthotopic thyroid ATCSCs transplantation models are utilized to corroborate the regulatory effect of cytokines on stemness. CCL20 derived from THP-1-M2 activates the IRAK-1/NF-κB1/2 signaling pathway in ATCSCs, thereby positively regulating stemness characteristics and upregulating CXCL5 secretion. ATCSCs not only exhibit autocrine CXCL5 participation in the regulation of stemness but also demonstrate paracrine CXCL5 activity to recruit THP-1-Mφ and maintain the M2 phenotype. CCL20 and CXCL5 are involved in the crosstalk between TAMs and ATCSCs. The CCL20/CXCL5 axis plays a crucial role in the interaction between TAMs and ATCSCs, establishing a progressive tumor microenvironment.
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Affiliation(s)
- Qi Liu
- Department of Thyroid SurgeryThe First Hospital of China Medical UniversityShenyang110801P. R. China
| | - Yan Wang
- Department of PharmacologySchool of PharmacyChina Medical UniversityShenyang110122P. R. China
| | - Mingyuan Song
- Department of Thyroid SurgeryThe First Hospital of China Medical UniversityShenyang110801P. R. China
| | - Jiapeng Huang
- Department of Thyroid SurgeryThe First Hospital of China Medical UniversityShenyang110801P. R. China
| | - Jinyuan Shi
- Department of Thyroid SurgeryGeneral SurgeryQilu Hospital of Shandong UniversityJinan250012P. R. China
| | - Wei Sun
- Department of Thyroid SurgeryThe First Hospital of China Medical UniversityShenyang110801P. R. China
| | - Xiaoyu Ji
- Department of Thyroid SurgeryThe First Hospital of China Medical UniversityShenyang110801P. R. China
| | - Yuang Chang
- Department of Thyroid SurgeryThe First Hospital of China Medical UniversityShenyang110801P. R. China
| | - Bing Ma
- Department of Clinical Epidemiology and Evidence‐based MedicineThe First Hospital of China Medical UniversityShenyang110801P. R. China
| | - Ping Zhang
- Department of Thyroid SurgeryThe First Hospital of China Medical UniversityShenyang110801P. R. China
| | - Yuanyuan Yan
- Department of PharmacologySchool of PharmacyChina Medical UniversityShenyang110122P. R. China
| | - Hao Zhang
- Department of Thyroid SurgeryThe First Hospital of China Medical UniversityShenyang110801P. R. China
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Barbieri F, Grazia Martina M, Giorgio C, Linda Chiara M, Allodi M, Durante J, Bertoni S, Radi M. Benzofuran-2-Carboxamide Derivatives as Immunomodulatory Agents Blocking the CCL20-Induced Chemotaxis and Colon Cancer Growth. ChemMedChem 2024; 19:e202400389. [PMID: 38923732 DOI: 10.1002/cmdc.202400389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 06/28/2024]
Abstract
The correlation between the CCL20/CCR6 axis and autoimmune and non-autoimmune disorders is widely recognized. Inhibition of the CCL20-dependent cell migration represents therefore a promising approach for the treatment of many diseases, such as inflammatory bowel diseases and colorectal cancer. We report herein our efforts to explore the biologically relevant chemical space around the benzofuran scaffold of MR120, a modulator of the CCL20/CCR6 axis previously discovered by our group. A functional screening allowed us to identify C4 and C5-substituted derivatives as the most effective inhibitors of the CCL20-induced chemotaxis of human peripheral blood mononuclear cells (PBMC). Moreover, selected compounds (16 e and 24 b) also proved to potently inhibit the growth of different colon cancer cell lines, with cytotoxic/cytostatic and antiproliferative activity.
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Affiliation(s)
- Francesca Barbieri
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze, 27/A, 43124, Parma, Italy
| | - Maria Grazia Martina
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze, 27/A, 43124, Parma, Italy
| | - Carmine Giorgio
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze, 27/A, 43124, Parma, Italy
| | - Maria Linda Chiara
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze, 27/A, 43124, Parma, Italy
| | - Marika Allodi
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze, 27/A, 43124, Parma, Italy
| | - Joseph Durante
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze, 27/A, 43124, Parma, Italy
| | - Simona Bertoni
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze, 27/A, 43124, Parma, Italy
| | - Marco Radi
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze, 27/A, 43124, Parma, Italy
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Valdivia-Silva J, Chinney-Herrera A. Chemokine receptors and their ligands in breast cancer: The key roles in progression and metastasis. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 388:124-161. [PMID: 39260935 DOI: 10.1016/bs.ircmb.2024.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
Chemokines and their receptors are a family of chemotactic cytokines with important functions in the immune response in both health and disease. Their known physiological roles such as the regulation of leukocyte trafficking and the development of immune organs generated great interest when it was found that they were also related to the control of early and late inflammatory stages in the tumor microenvironment. In fact, in breast cancer, an imbalance in the synthesis of chemokines and/or in the expression of their receptors was attributed to be involved in the regulation of disease progression, including invasion and metastasis. Research in this area is progressing rapidly and the development of new agents based on chemokine and chemokine receptor antagonists are emerging as attractive alternative strategies. This chapter provides a snapshot of the different functions reported for chemokines and their receptors with respect to the potential to regulate breast cancer progression.
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Affiliation(s)
- Julio Valdivia-Silva
- Centro de Investigación en Bioingenieria (BIO), Universidad de Ingenieria y Tecnologia-UTEC, Barranco, Lima, Peru.
| | - Alberto Chinney-Herrera
- Facultad de Medicina, Universidad Nacional Autonoma de Mexico-UNAM, Ciudad Universitaria, Coyoacan, Ciudad de Mexico, Mexico
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Wu Z, Sun L, Xu Y, Huang H, Wu Z, Qiu B, Yan J, Yin X. The Value of Chemokine and Chemokine Receptors in Diagnosis, Prognosis, and Immunotherapy of Hepatocellular Carcinoma. Cancer Manag Res 2024; 16:403-420. [PMID: 38736589 PMCID: PMC11086648 DOI: 10.2147/cmar.s450959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 04/20/2024] [Indexed: 05/14/2024] Open
Abstract
Background Chemokines and chemokine receptors (CCRs) are involved in a variety of anti-tumour and pro-tumour immune processes in vivo, such as angiogenesis, metastasis, proliferation and invasiveness, and influence patient prognosis and response to therapy. Methods CCRs differentially expressed in HCC and associated with prognosis were extracted from TCGA and GEO databases, and the obtained CCRs were then used to construct signature genes, and the signature gene were selected for expression validation as well as functional experiments to explore the role of CCRs in the treatment and prognosis of HCC. Results We constructed a prognostic model including five CCRs (CCL20, CCL23, CCR3, CCR10, and CXCR3) and validated the expression of signature genes. The model's risk score is an independent prognostic factor for HCC. We have also developed prognostic model nomograms for clinical use. In addition, we validated that CCR3 expression is associated with poor prognosis in HCC, and the proliferation and migration ability of HCC cells was significantly inhibited after interfering with the expression of CCR3 in MHCC-LM3. We also looked at differences in pathway enrichment, immune infiltration and immune checkpoints. Finally, we found that risk scores were also correlated with drug sensitivity, the high-risk group had a better sensitivity to sorafenib. Conclusion The CCRs-related gene signature may better assess HCC prognosis and response to immunotherapy and tyrosine kinase inhibitors such as sorafenib in HCC, providing prospective solutions for diagnosis and treatment.
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Affiliation(s)
- Zhengyi Wu
- Hepatobiliary Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China
| | - Liang Sun
- Hepatobiliary Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China
| | - Yongkang Xu
- Hepatobiliary Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China
| | - He Huang
- Hepatobiliary Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China
| | - Zhipeng Wu
- Hepatobiliary Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China
| | - Bingbing Qiu
- Hepatobiliary Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China
| | - Jinlong Yan
- Hepatobiliary Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China
| | - Xiangbao Yin
- Hepatobiliary Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China
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Wu H, Xu Y, Gong YY, Huntriss J, Routledge MN. Effects of aflatoxin and fumonisin on gene expression of growth factors and inflammation-related genes in a human hepatocyte cell line. Mutagenesis 2024; 39:181-195. [PMID: 38468450 DOI: 10.1093/mutage/geae005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 03/07/2024] [Indexed: 03/13/2024] Open
Abstract
Aflatoxin B1 (AFB1) and fumonisin B1 (FB1) are mycotoxins widely distributed in maize and maized-based products, often occurring together. The implications of co-exposure to aflatoxin and fumonsin for human health are numerous, but a particular concern is the potential of FB1 to modulate AFB1 hepatotoxicity. This study evaluated the toxicity of these mycotoxins, alone or combined, in a human non-tumorigenic liver cell line, HHL-16 cells, and assessed the effects of AFB1 and FB1 on expression of genes involved in immune and growth factor pathways. The results demonstrated that in HHL-16 cells, both AFB1 and FB1 had dose-dependent and time-dependent toxicity, and the combination of them showed a synergistic toxicity in the cells. Moreover, AFB1 caused upregulation of IL6, CCL20, and BMP2, and downregulation of NDP. In combination of AFB1 with FB1, gene expression levels of IL6 and BMP2 were significantly higher compared to individual FB1 treatment, and had a tendency to be higher than individual AFB1 treatment. This study shows that FB1 may increase the hepatoxicity of AFB1 through increasing the inflammatory response and disrupting cell growth pathways.
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Affiliation(s)
- Hang Wu
- School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom
- School of Food Science and Nutrition, University of Leeds, Leeds LS2 9JT, United Kingdom
| | - Ya Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun-Yat University, Guangzhou 51006, China
| | - Yun Yun Gong
- School of Food Science and Nutrition, University of Leeds, Leeds LS2 9JT, United Kingdom
| | - John Huntriss
- School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom
| | - Michael N Routledge
- Leicester Medical School, George Davies Centre, Lancaster Rd, Leicester LE1 7HA, United Kingdom
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
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Shi X, Yu J, Lu C, Luo Q, Xu C, Li J, Wang W. Screening of the shared pathogenic genes of ulcerative colitis and colorectal cancer by integrated bioinformatics analysis. J Cell Mol Med 2024; 28:e17878. [PMID: 37494129 PMCID: PMC10902564 DOI: 10.1111/jcmm.17878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 07/08/2023] [Accepted: 07/19/2023] [Indexed: 07/28/2023] Open
Abstract
Ulcerative colitis (UC) is one of the high-risk pathogenic factors for colorectal cancer (CRC). However, the shared gene and signalling mechanisms between UC and CRC remain unclear. The goal of this study was to delve more into the probable causal relationship between UC and CRC. CRC and UC datasets were downloaded from the Gene Expression Omnibus database. Using R software and Perl, differentially expressed genes (DEGs) in both UC and CRC tissues were re-annotated and screened. The biological activities and signalling pathways involved in DEGs were investigated using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. The STRING database and Cytoscape software were used to construct the gene interaction network. A total of 384 DEGs were selected for further investigation, and functional analysis revealed that inflammatory and immunological responses were crucial in the development of the two diseases. Moreover, the top 15 key genes involved in the UC and CRC were screened using cytoHubba, including IL1B, CXCL10, CCL20, MMP9, ICAM1, CCL4, CXCR1, MMP3, TLR2, PTGS2, IL1RN, IL6, COL1A2, TIMP1 and CXCL1. The identification of these genes in the present study may provide a novel perspective for the prediction, prevention and personalized medicine of UC and CRC patients.
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Affiliation(s)
- Xu Shi
- Department of OrthopaedicsThe Affiliated People's Hospital of Jiangsu UniversityZhenjiangChina
| | - Jun Yu
- Department of PaediatricsAffiliated Hospital of Nanjing University of Chinese Medicine, Taicang Hospital of Traditional Chinese MedicineTaicangChina
| | - Chen Lu
- Department of General SurgerySiyang HospitalSuqianChina
| | - Qian Luo
- Department of General SurgerySiyang HospitalSuqianChina
| | - Caihong Xu
- Department of Obstetrics and GynaecologyNanjing Tongren Hospital, School of Medicine, Southeast UniversityNanjingChina
| | - Jie Li
- Department of General SurgerySiyang HospitalSuqianChina
| | - Wei Wang
- Department of Clinical LaboratoryLianshui County People's HospitalHuai'anChina
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He Y, Shi Q, Ling Y, Guo H, Fei Y, Wu R, Tang C, Zhang X, Yao L. ABLIM1, a novel ubiquitin E3 ligase, promotes growth and metastasis of colorectal cancer through targeting IĸBα ubiquitination and activating NF-ĸB signaling. Cell Death Differ 2024; 31:203-216. [PMID: 38228802 PMCID: PMC10850134 DOI: 10.1038/s41418-024-01256-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 12/29/2023] [Accepted: 01/03/2024] [Indexed: 01/18/2024] Open
Abstract
Actin-binding LIM protein 1 (ABLIM1), a member of the LIM-domain protein family, has been reported as a suppressor in several tumors whereas its role in colorectal cancer (CRC) remains unknown. In this study, we find that ABLIM1 is up-regulated in CRC patients and high levels of ABLIM1 predict short disease-free survival time. Knock-down of ABLIM1 in CRC cell lines by lenti-virus leads to inhibited cell proliferation, migration, and invasion capabilities in vitro and impaired growth of tumor xenografts and liver metastasis lesions in vivo, while ABLIM1 overexpression accelerates tumor growth and invasion in vitro. Mechanistically, we uncover that ABLIM1 activates the NF-ĸB/CCL-20 signaling through modulating IĸBα ubiquitination and proteasomal-mediated degradation. Further co-immunoprecipitation, in vivo and in vitro ubiquitination assays reveal ABLIM1 as a novel ubiquitin E3 ligase binding to IĸBα. Interestingly, The E3 ligase catalysis activity of ABLIM1 depends on its 402-778aa rather than its LIM domains and its interaction with IĸBα relies on the HP domain. Our findings delineate the oncogenic role of ABLIM1 in CRC progression and reveal it as a novel E3 ligase targeting IĸBα, providing new insights into the regulation of NF-ĸB signaling in tumors.
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Affiliation(s)
- Ying He
- Central Laboratory, First Affiliated Hospital of Huzhou University, Huzhou, 313000, Zhejiang, China
- Huzhou Key Laboratory of Translational Medicine, First People's Hospital of Huzhou, Huzhou, 313000, Zhejiang, China
| | - Qian Shi
- Central Laboratory, First Affiliated Hospital of Huzhou University, Huzhou, 313000, Zhejiang, China
- Huzhou Key Laboratory of Translational Medicine, First People's Hospital of Huzhou, Huzhou, 313000, Zhejiang, China
| | - Yuhang Ling
- Central Laboratory, First Affiliated Hospital of Huzhou University, Huzhou, 313000, Zhejiang, China
- Huzhou Key Laboratory of Translational Medicine, First People's Hospital of Huzhou, Huzhou, 313000, Zhejiang, China
| | - Huihui Guo
- Central Laboratory, First Affiliated Hospital of Huzhou University, Huzhou, 313000, Zhejiang, China
- Huzhou Key Laboratory of Translational Medicine, First People's Hospital of Huzhou, Huzhou, 313000, Zhejiang, China
| | - Yi Fei
- Department of Colorectal Surgery, First Affiliated Hospital of Huzhou University, Huzhou, 313000, Zhejiang, China
| | - Ruoyu Wu
- Department of Gastroenterology, First Affiliated Hospital of Huzhou University, Huzhou, 313000, Zhejiang, China
| | - Chengwu Tang
- Central Laboratory, First Affiliated Hospital of Huzhou University, Huzhou, 313000, Zhejiang, China.
- Huzhou Key Laboratory of Translational Medicine, First People's Hospital of Huzhou, Huzhou, 313000, Zhejiang, China.
| | - Xilin Zhang
- Central Laboratory, First Affiliated Hospital of Huzhou University, Huzhou, 313000, Zhejiang, China.
- Huzhou Key Laboratory of Translational Medicine, First People's Hospital of Huzhou, Huzhou, 313000, Zhejiang, China.
| | - Linhua Yao
- Huzhou Key Laboratory of Translational Medicine, First People's Hospital of Huzhou, Huzhou, 313000, Zhejiang, China.
- Department of Gastroenterology, First Affiliated Hospital of Huzhou University, Huzhou, 313000, Zhejiang, China.
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Valdés N, Cortés M, Barraza F, Reyes-López FE, Imarai M. CXCL9-11 chemokines and CXCR3 receptor in teleost fish species. FISH AND SHELLFISH IMMUNOLOGY REPORTS 2022; 3:100068. [PMID: 36569039 PMCID: PMC9782732 DOI: 10.1016/j.fsirep.2022.100068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 09/18/2022] [Accepted: 09/27/2022] [Indexed: 12/27/2022] Open
Abstract
The coordinated migration of immune cells from lymphoid organs to in or out of the bloodstream, and towards the site of infection or tissue damage is fundamental for an efficient innate and adaptive immune response. Interestingly, an essential part of this movement is mediated by chemoattractant cytokines called chemokines. Although the nature and function of chemokines and their receptors are well documented in mammals, much research is needed to accomplish a similar level of understanding of the role of chemokines in fish immunity. The first chemokine gene identified in teleosts (rainbow trout, Oncorhynchus mykiss) was CK1 in 1998. Since then, the identification of fish chemokine orthologue genes and characterization of their role has been more complex than expected, primarily because of the whole genome duplication processes occurring in fish, and because chemokines evolve faster than other immune genes. Some of the most studied chemokines are CXCL9, CXCL10, CXCL11, and the CXCR3 receptor, all involved in T cell migration and in the induction of the T helper 1 (Th1) immune response. Data from the zebrafish and rainbow trout CXCL9-11/CXCR3 axis suggest that these chemokines and the receptor arose early in evolution and must be present in most teleost fish. However, the pieces of knowledge also indicate that different numbers of gene copies can be present in different species, with distinct regulatory expression mechanisms and probably, also with different roles, as the differential expression in fish tissues suggest. Here, we revised the current knowledge of the CXCL9-11/CXCR3 axis in teleost fishes, identifying the gaps in knowledge, and raising some hypotheses for the role of CXCL9, CXCL10 CXCL11, and CXCR3 receptor axis in fish, which can encourage further studies in the field.
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Affiliation(s)
- Natalia Valdés
- Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología. Universidad de Santiago de Chile, Chile,Corresponding author.
| | - Marcos Cortés
- Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología. Universidad de Santiago de Chile, Chile
| | - Felipe Barraza
- Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología. Universidad de Santiago de Chile, Chile
| | - Felipe E. Reyes-López
- Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología. Universidad de Santiago de Chile, Chile,Department of Cell Biology, Physiology, and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Spain,Facultad de Medicina Veterinaria y Agronomía, Universidad de Las Américas, Santiago, Chile
| | - Mónica Imarai
- Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología. Universidad de Santiago de Chile, Chile
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Bhat AA, Nisar S, Singh M, Ashraf B, Masoodi T, Prasad CP, Sharma A, Maacha S, Karedath T, Hashem S, Yasin SB, Bagga P, Reddy R, Frennaux MP, Uddin S, Dhawan P, Haris M, Macha MA. Cytokine- and chemokine-induced inflammatory colorectal tumor microenvironment: Emerging avenue for targeted therapy. Cancer Commun (Lond) 2022; 42:689-715. [PMID: 35791509 PMCID: PMC9395317 DOI: 10.1002/cac2.12295] [Citation(s) in RCA: 92] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/28/2022] [Accepted: 04/24/2022] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is a predominant life-threatening cancer, with liver and peritoneal metastases as the primary causes of death. Intestinal inflammation, a known CRC risk factor, nurtures a local inflammatory environment enriched with tumor cells, endothelial cells, immune cells, cancer-associated fibroblasts, immunosuppressive cells, and secretory growth factors. The complex interactions of aberrantly expressed cytokines, chemokines, growth factors, and matrix-remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes. Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment, which is partly achieved by the recruitment of immunosuppressive cells. These cells impart features such as cancer stem cell-like properties, drug resistance, invasion, and formation of the premetastatic niche in distant organs, promoting metastasis and aggressive CRC growth. A deeper understanding of the cytokine- and chemokine-mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC. Here, we summarized the current knowledge of cytokine- and chemokine-mediated crosstalk in the inflammatory tumor microenvironment, which drives immunosuppression, resistance to therapeutics, and metastasis during CRC progression. We also outlined the potential of this crosstalk as a novel therapeutic target for CRC. The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.
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Affiliation(s)
- Ajaz A. Bhat
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Sabah Nisar
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Mayank Singh
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Bazella Ashraf
- Department of BiotechnologySchool of Life SciencesCentral University of KashmirGanderbalJammu & Kashmir191201India
| | - Tariq Masoodi
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Chandra P. Prasad
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Atul Sharma
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Selma Maacha
- Division of Translational MedicineResearch BranchSidra MedicineDoha26999Qatar
| | | | - Sheema Hashem
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Syed Besina Yasin
- Department of PathologySher‐I‐Kashmir Institute of Medical SciencesSrinagarJammu & Kashmir190011India
| | - Puneet Bagga
- Department of Diagnostic ImagingSt. Jude Children's Research HospitalMemphisTN38105USA
| | - Ravinder Reddy
- Center for Advanced Metabolic Imaging in Precision MedicineDepartment of RadiologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPA19104USA
| | | | - Shahab Uddin
- Translational Research InstituteHamad Medical CorporationDoha3050Qatar
| | - Punita Dhawan
- Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Mohammad Haris
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
- Laboratory Animal Research CenterQatar UniversityDoha2713Qatar
| | - Muzafar A. Macha
- Watson‐Crick Centre for Molecular MedicineIslamic University of Science and TechnologyAwantiporaJammu & Kashmir192122India
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11
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Braoudaki M, Ahmad MS, Mustafov D, Seriah S, Siddiqui MN, Siddiqui SS. Chemokines and chemokine receptors in colorectal cancer; multifarious roles and clinical impact. Semin Cancer Biol 2022; 86:436-449. [PMID: 35700938 DOI: 10.1016/j.semcancer.2022.06.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/07/2022] [Accepted: 06/08/2022] [Indexed: 11/19/2022]
Abstract
Colorectal cancer (CRC) is considered the second cause of cancer death worldwide. The early diagnosis plays a key role in patient prognosis and subsequently overall survival. Similar to several types of cancer, colorectal cancer is also characterised by drug resistance and heterogeneity that contribute to its complexity -especially at advanced stages. However, despite the extensive research related to the identification of biomarkers associated to early diagnosis, accurate prognosis and the management of CRC patients, little progress has been made thus far. Therefore, the mortality rates, especially at advanced stages, remain high. A large family of chemoattractant cytokines called chemokines are known for their significant role in inflammation and immunity. Chemokines released by the different tumorous cells play a key role in increasing the complexity of the tumour's microenvironment. The current review investigates the role of chemokines and chemokine receptors in colorectal cancer and their potential as clinical molecular signatures that could be effectively used as a personalised therapeutic approach. We discussed how chemokine and chemokine receptors regulate the microenvironment and lead to heterogeneity in CRC. An important aspect of chemokines is their role in drug resistance which has been extensively discussed. This review also provides an overview of the current advances in the search for chemokines and chemokine receptors in CRC.
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Affiliation(s)
- Maria Braoudaki
- Dept of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, UK
| | - Mohammed Saqif Ahmad
- Dept of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, UK
| | - Denis Mustafov
- Dept of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, UK
| | - Sara Seriah
- Dept of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, UK
| | - Mohammad Naseem Siddiqui
- Department of Biosciences, Faculty of Natural Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Shoib Sarwar Siddiqui
- Dept of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, UK.
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12
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Kwantwi LB, Wang S, Sheng Y, Wu Q. Multifaceted roles of CCL20 (C-C motif chemokine ligand 20): mechanisms and communication networks in breast cancer progression. Bioengineered 2021; 12:6923-6934. [PMID: 34569432 PMCID: PMC8806797 DOI: 10.1080/21655979.2021.1974765] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 08/20/2021] [Indexed: 12/12/2022] Open
Abstract
Emerging studies have demonstrated notable roles of CCL20 in breast cancer progression. Based on these findings, CCL20 has become a potential therapeutic target for cancer immunotherapy. Accordingly, studies utilizing monoclonal antibodies to target CCL20 are currently being experimented. However, the existence of cytokine network in the tumor microenvironment collectively regulates tumor progression. Hence, a deeper understanding of the role of CCL20 and the underlying signaling pathways regulating the functions of CCL20 may provide a novel strategy for therapeutic interventions. This review provides the current knowledge on how CCL20 interacts with breast cancer cells to influence tumor progression via immunosuppression, angiogenesis, epithelial to mesenchymal transition, migration/invasion and chemoresistance. As a possible candidate biomarker, we also reviewed signal pathways and other factors in the tumor microenvironment regulating the tumor-promoting functions of CCL20.These new insights may be useful to design new potent and selective CCL20 inhibitors against breast cancer in the future.
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Affiliation(s)
- Louis Boafo Kwantwi
- Department of Pathology, School of Basic Medical Science, Anhui Medical University, Hefei, PR China
| | - Shujing Wang
- Department of Pathology, School of Basic Medical Science, Anhui Medical University, Hefei, PR China
- Department of Immunology, School of Basic Medical Science, Anhui Medical University, Hefei, PR China
| | - Youjing Sheng
- Department of Pathology, School of Basic Medical Science, Anhui Medical University, Hefei, PR China
| | - Qiang Wu
- Department of Pathology, School of Basic Medical Science, Anhui Medical University, Hefei, PR China
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, PR China
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13
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Zhang Y, Chen K, Li L, Mao W, Shen D, Yao N, Zhang L. CCR4 is a prognostic biomarker and correlated with immune infiltrates in head and neck squamous cell carcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1443. [PMID: 34733995 PMCID: PMC8506764 DOI: 10.21037/atm-21-3936] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/02/2021] [Indexed: 11/06/2022]
Abstract
Background Increased evidence has indicated that the tumour microenvironment plays an essential in the development, treatment and prognosis of head and neck squamous cell carcinoma (HNSC). Recent studies have indicated CC chemokine receptor 4 (CCR4) plays an essential role in tumor invasion and other adverse biological behavior. This study used data from the Cancer Genome Atlas (TCGA) database to explore the role of CCR4 in HNSC and its clinical significance. Methods The gene expression and clinical data of HNSC patients in the TCGA database were extracted. Gene Expression Profiling Interactive Analysis (GEPIA) was used to analyze the expression of CCR4 in tumor and non-tumor tissue. Kaplan-Meier survival analysis was used to analyze the relationship between CCR4 expression and overall survival rate (OS), disease-specific survival (DSS), and progression-free interval (PFI) in HNSC. A logistic regression model was used to analyze the relationships between various clinical factors and CCR4 expression. Gene Set Enrichment Analysis (GSEA) was used to explore the potential role of CCR4 in HNSC. Additionally, we explored the relationship between CCR4 and immune infiltration. Results The expression of CCR4 in HNSC was not significantly different from that in normal tissue. The expression level of CCR4 in wild-type TP53 was higher than that in mutant TP53. Cox regression analysis showed the expression level of CCR4 was related to the patient's tumor grade and Tumor-Node-Metastasis (TNM) stage. CCR4 expression level is an independent prognostic factor. CCR4 is positively correlated with immune infiltration and immune checkpoints expression levels. The results of GSEA revealed that the high CCR4 expression group genes were enriched in allograft rejection, inflammatory response, IL-6/JAK/STAT3 signaling, interferon gamma response, and KRAS signaling up. Low CCR4 expression group genes were enriched in oxidative phosphorylation, MYC targets v1, DNA repair, reactive oxygen species pathway, and P53 pathway. Further, our study indicated CCR4 can also predict the prognosis of radiotherapy patients. Conclusions Our study found that CCR4 was a prognostic marker related to HNSC immune infiltration, and patients with high expression of CCR4 had a better prognosis.
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Affiliation(s)
- Yijian Zhang
- Department of Otolaryngology-Head and Neck Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Kai Chen
- Department of Radiotherapy, First People's Hospital of Yancheng, Yancheng, China
| | - Li Li
- Department of Oncology, Huaian Hospital, Huai'an, China
| | - Weidong Mao
- Department of Oncology, Jiangyin People's Hospital, Wuxi, China
| | - Dong Shen
- Department of Oncology, Jiangyin People's Hospital, Wuxi, China
| | - Ninghua Yao
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, China
| | - Lei Zhang
- Department of Otolaryngology-Head and Neck Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China
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14
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Hossain MJ, Chowdhury UN, Islam MB, Uddin S, Ahmed MB, Quinn JMW, Moni MA. Machine learning and network-based models to identify genetic risk factors to the progression and survival of colorectal cancer. Comput Biol Med 2021; 135:104539. [PMID: 34153790 DOI: 10.1016/j.compbiomed.2021.104539] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 05/12/2021] [Accepted: 05/26/2021] [Indexed: 01/04/2023]
Abstract
Colorectal cancer (CRC) is one of the most common and lethal malignant lesions. Determining how the identified risk factors drive the formation and development of CRC could be an essential means for effective therapeutic development. Aiming this, we investigated how the altered gene expression resulting from exposure to putative CRC risk factors contribute to prognostic biomarker identification. Differentially expressed genes (DEGs) were first identified for CRC and other eight risk factors. Gene set enrichment analysis (GSEA) through the molecular pathway and gene ontology (GO), as well as protein-protein interaction (PPI) network, were then conducted to predict the functions of these DEGs. Our identified genes were explored through the dbGaP and OMIM databases to compare with the already identified and known prognostic CRC biomarkers. The survival time of CRC patients was also examined using a Cox Proportional Hazard regression-based prognostic model by integrating transcriptome data from The Cancer Genome Atlas (TCGA). In this study, PPI analysis identified 4 sub-networks and 8 hub genes that may be potential therapeutic targets, including CXCL8, ICAM1, SOD2, CXCL2, CCL20, OIP5, BUB1, ASPM and IL1RN. We also identified seven signature genes (PRR5.ARHGAP8, CA7, NEDD4L, GFR2, ARHGAP8, SMTN, OIP5) in independent analysis and among which PRR5. ARHGAP8 was found in both multivariate analyses and in analyses that combined gene expression and clinical information. This approach provides both mechanistic information and, when combined with predictive clinical information, good evidence that the identified genes are significant biomarkers of processes involved in CRC progression and survival.
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Affiliation(s)
- Md Jakir Hossain
- Department of Electrical and Electronic Engineering, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - Utpala Nanda Chowdhury
- Department of Computer Science and Engineering, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - M Babul Islam
- Department of Electrical and Electronic Engineering, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - Shahadat Uddin
- Complex Systems Research Group & Project Management Program, Faculty of Engineering, The University of Sydney, NSW, 2006, Australia
| | - Mohammad Boshir Ahmed
- School of Material Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Julian M W Quinn
- Healthy Ageing Theme, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia
| | - Mohammad Ali Moni
- Healthy Ageing Theme, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia; WHO Collaborating Centre on eHealth, School of Public Health and Community Medicine, Faculty of Medicine, UNSW Sydney, NSW, 2052, Australia.
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15
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Saxena S, Singh RK. Chemokines orchestrate tumor cells and the microenvironment to achieve metastatic heterogeneity. Cancer Metastasis Rev 2021; 40:447-476. [PMID: 33959849 PMCID: PMC9863248 DOI: 10.1007/s10555-021-09970-6] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 04/22/2021] [Indexed: 01/26/2023]
Abstract
Chemokines, a subfamily of the cell cytokines, are low molecular weight proteins known to induce chemotaxis in leukocytes in response to inflammatory and pathogenic signals. A plethora of literature demonstrates that chemokines and their receptors regulate tumor progression and metastasis. With these diverse functionalities, chemokines act as a fundamental link between the tumor cells and their microenvironment. Recent studies demonstrate that the biology of chemokines and their receptor in metastasis is complex as numerous chemokines are involved in regulating site-specific tumor growth and metastasis. Successful treatment of disseminated cancer is a significant challenge. The most crucial problem for treating metastatic cancer is developing therapy regimes capable of overcoming heterogeneity problems within primary tumors and among metastases and within metastases (intralesional). This heterogeneity of malignant tumor cells can be related to metastatic potential, response to chemotherapy or specific immunotherapy, and many other factors. In this review, we have emphasized the role of chemokines in the process of metastasis and metastatic heterogeneity. Individual chemokines may not express the full potential to address metastatic heterogeneity, but chemokine networks need exploration. Understanding the interplay between chemokine-chemokine receptor networks between the tumor cells and their microenvironment is a novel approach to overcome the problem of metastatic heterogeneity. Recent advances in the understanding of chemokine networks pave the way for developing a potential targeted therapeutic strategy to treat metastatic cancer.
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Affiliation(s)
- Sugandha Saxena
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 Nebraska Medical Center, Omaha, NE, 68198-5900, USA
| | - Rakesh K Singh
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 Nebraska Medical Center, Omaha, NE, 68198-5900, USA.
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16
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Jiang W, Zhang C, Kang Y, Li G, Feng Y, Ma H. The roles and mechanisms of the circular RNA circ_104640 in early-stage lung adenocarcinoma: a potential diagnostic and therapeutic target. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:138. [PMID: 33569440 PMCID: PMC7867959 DOI: 10.21037/atm-20-8019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background In recent years, there have been increasing reports that dysregulated circular RNAs (circRNAs) play a key role in the carcinogenesis of lung adenocarcinoma (LUAC). However, the role of circRNAs in early-stage LUAC is poorly understood. Methods The Gene Expression Omnibus (GEO) database and qRT-PCR were used to verify the abnormal expression of circRNAs, miRNAs and genes in early-stage LUAC tissues. shRNA and miRNA inhibitor are designed and synthesized to knock down circ_104640 and microRNA (miR)-145-5p expression. CCK-8 assay, colony formation assay and flow cytometry were used to study the effect of circ_104640 on cell proliferation and apoptosis. Bioinformatics analysis, dual luciferase reporter assays and argonaute 2 (Ago2) RNA immunoprecipitation (RIP) assays were chosen to find out the potential target of circ_104640. Results Based on the GEO database and tissue sample from our institution, we identified that the circRNA circ_104640, the miR-145-5p, and CCL20 (C-C motif chemokine ligand 20) were abnormally expressed in the tissues of early-stage LUAC. In vitro experiments showed that circ_104640 could exist stably in the cytoplasm, and a short pin RNA that targeted circ_104640 (sh-circ) inhibited cell growth and promoted apoptosis of LUAC cells. Dual luciferase reporter assays and Ago2 (RIP) assays confirmed the Ago2-dependent interaction of circ_104640 and miR-145-5p. In terms of mechanisms, we found that circ_104640 increased the expression of CCL20 by sponging miR-145-5p. Conclusions Our research demonstrated that circ_104640 could accelerate the proliferation of LUAC cells, while inhibiting LUAC cell apoptosis. circ_104640 may be a potential novel biomarker and therapeutic target for early-stage LUAC.
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Affiliation(s)
- Wei Jiang
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chengpeng Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yunteng Kang
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Guangbin Li
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yu Feng
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Haitao Ma
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
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17
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Eiger DS, Boldizsar N, Honeycutt CC, Gardner J, Rajagopal S. Biased agonism at chemokine receptors. Cell Signal 2020; 78:109862. [PMID: 33249087 DOI: 10.1016/j.cellsig.2020.109862] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 11/07/2020] [Accepted: 11/24/2020] [Indexed: 12/11/2022]
Abstract
In the human chemokine system, interactions between the approximately 50 known endogenous chemokine ligands and 20 known chemokine receptors (CKRs) regulate a wide range of cellular functions and biological processes including immune cell activation and homeostasis, development, angiogenesis, and neuromodulation. CKRs are a family of G protein-coupled receptors (GPCR), which represent the most common and versatile class of receptors in the human genome and the targets of approximately one third of all Food and Drug Administration-approved drugs. Chemokines and CKRs bind with significant promiscuity, as most CKRs can be activated by multiple chemokines and most chemokines can activate multiple CKRs. While these ligand-receptor interactions were previously regarded as redundant, it is now appreciated that many chemokine:CKR interactions display biased agonism, the phenomenon in which different ligands binding to the same receptor signal through different pathways with different efficacies, leading to distinct biological effects. Notably, these biased responses can be modulated through changes in ligand, receptor, and or the specific cellular context (system). In this review, we explore the biochemical mechanisms, functional consequences, and therapeutic potential of biased agonism in the chemokine system. An enhanced understanding of biased agonism in the chemokine system may prove transformative in the understanding of the mechanisms and consequences of biased signaling across all GPCR subtypes and aid in the development of biased pharmaceuticals with increased therapeutic efficacy and safer side effect profiles.
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Affiliation(s)
| | - Noelia Boldizsar
- Trinity College of Arts and Sciences, Duke University, Durham, NC 27710, USA.
| | | | - Julia Gardner
- Trinity College of Arts and Sciences, Duke University, Durham, NC 27710, USA.
| | - Sudarshan Rajagopal
- Department of Biochemistry, Duke University, Durham, NC 27710, USA; Department of Medicine, Duke University, Durham, NC 27710, USA.
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18
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Mo M, Tong S, Huang W, Cai Y, Zu X, Hu X. High serum CCL20 is associated with tumor progression in penile cancer. J Cancer 2020; 11:6812-6822. [PMID: 33123272 PMCID: PMC7591991 DOI: 10.7150/jca.48939] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 09/14/2020] [Indexed: 12/12/2022] Open
Abstract
Serum cancer biomarker has been proven to be very valuable in cancer diagnosis, disease monitoring and prognosis assessment, despite there is still a lack of serum biomarker for penile cancer (PC). Our initial analysis on public GEO dataset identified CCL20 as a top C-C motif ligand (CCL) gene enriched in PC. The patients with PC exhibited markedly higher preoperative serum CCL20 level than healthy control. The area under the curve (AUC) was 0.855 with the sensitivity of 72.4%, and specificity of 93.5% to distinguish PC. Preoperative serum CCL20 level was significantly associated with clinicopathological characteristics including T stage (P=0.005), nodal status (P=0.008), and pelvic lymph node metastasis (P=0.007). PC Patients with high serum CCL20 level had shorter disease-free survival compared to those with low level (P<0.001). Cox regression analysis showed that serum CCL20 level could serve as an independent prognostic factor for disease-free survival with a HR of 3.980 (95% CI: 1.209-13.098, P=0.023). Furthermore, CCL20 expression was observed in PC tissues and cell lines. Knockdown of CCL20 expression markedly suppressed malignant phenotypes (cell proliferation, clonogenesis, apoptosis escape, migration and invasion), attenuated STAT3 and AKT signaling and reduced MMP2/9 secretion in PC cell lines. Consistently, CCL20 and its receptor CCR6 exhibited correlated expression pattern in PC tissues. In conclusion, serum CCL20 level might serve as a potential diagnostic and prognostic cancer biomarker for PC. CCL20 might activate multiple downstream oncogenic signaling pathways (STAT3, AKT, MMP2/9) to promote malignant progression of PC, which may warrant further investigation in the future.
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Affiliation(s)
- Miao Mo
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Shiyu Tong
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Wei Huang
- Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, P.R. China
| | - Yi Cai
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Xiongbing Zu
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Xiheng Hu
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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19
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Pączek S, Łukaszewicz-Zając M, Mroczko B. Chemokines-What Is Their Role in Colorectal Cancer? Cancer Control 2020; 27:1073274820903384. [PMID: 32103675 PMCID: PMC7066593 DOI: 10.1177/1073274820903384] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related death. It
is the second most frequently diagnosed malignancy in Europe and third
worldwide. Colorectal malignancies diagnosed at an early stage offer a promising
survival rate. However, advanced tumors often present distant metastases even
after the complete resection of a primary tumor. Therefore, novel biomarkers of
CRC are sorely needed in the diagnosis and prognosis of this common malignancy.
A family of chemokines are composed of small, secreted proteins. They are best
known for their ability to stimulate the migration of several cell types. Some
investigations have indicated that chemokines are involved in cancer
development, including CRC. This article presents current knowledge regarding
chemokines and their specific receptors in CRC progression. Moreover, the prime
aim of this review is to summarize the potential role of these proteins as
biomarkers in the diagnosis and prognosis of CRC.
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Affiliation(s)
- Sara Pączek
- Department of Biochemical Diagnostics, Medical University of Bialystok, Poland
| | | | - Barbara Mroczko
- Department of Biochemical Diagnostics, Medical University of Bialystok, Poland.,Department of Neurodegeneration Diagnostics, Medical University of Bialystok, Poland
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20
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Li Y, Liu J, Xiao Q, Tian R, Zhou Z, Gan Y, Li Y, Shu G, Yin G. EN2 as an oncogene promotes tumor progression via regulating CCL20 in colorectal cancer. Cell Death Dis 2020; 11:604. [PMID: 32732864 PMCID: PMC7393501 DOI: 10.1038/s41419-020-02804-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 07/07/2020] [Accepted: 07/13/2020] [Indexed: 02/07/2023]
Abstract
Engrailed-2 (EN2), a member of the engrailed homeobox family, has been shown to be abnormally expressed in a variety of cancers. However, the expression and the clinical significance of EN2 in colorectal cancer (CRC) are largely unknown. Firstly, we found that EN2 acted as an oncogene in CRC. EN2 was upregulated in colorectal cancer tissues compared with adjacent normal tissues. Higher EN2 expression was significantly associated with poorer survival rate. Knockdown of EN2 markedly inhibited proliferation and migration capacities of SW480 cells in vitro, and suppressed tumorigenicity in vivo. Mechanistically, Chemokine ligand 20 (CCL20), a member of the C-C motif chemokine subfamily, was identified as a direct target gene of EN2 in CRC. CCL20 expression was positively correlated with EN2 expression in CRC tissues. Moreover, EN2 promoted the proliferation and migration of CRC cells by regulating the expression of CCL20 in vitro. These results suggest that EN2 plays a critical role in the CRC tumor progression and may serve as a potential target for CRC prevention and therapy.
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Affiliation(s)
- Yimin Li
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Jiaxin Liu
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Qing Xiao
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Ruotong Tian
- School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
| | - Zhengwei Zhou
- School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
| | - Yaqi Gan
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Yuanyuan Li
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Guang Shu
- School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China.
| | - Gang Yin
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, China. .,China-Africa Research Center of Infectious Diseases, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China.
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21
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Laffan SB, Thomson AS, Mai S, Fishman C, Kambara T, Nistala K, Raymond JT, Chen S, Ramani T, Pageon L, Polsky R, Watkins M, Ottolangui G, White JR, Maier C, Herdman M, Bouma G. Immune complex disease in a chronic monkey study with a humanised, therapeutic antibody against CCL20 is associated with complement-containing drug aggregates. PLoS One 2020; 15:e0231655. [PMID: 32325480 PMCID: PMC7180069 DOI: 10.1371/journal.pone.0231655] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 03/27/2020] [Indexed: 12/18/2022] Open
Abstract
Despite the potential for the chemokine class as therapeutic targets in immune mediated disease, success has been limited. Many chemokines can bind to multiple receptors and many receptors have multiple ligands, with few exceptions. One of those exceptions is CCL20, which exclusively pairs to CCR6 and is associated with several immunologic conditions, thus providing a promising therapeutic target. Following successful evaluation in a single dose, first time in human clinical study, GSK3050002—a humanized IgG1 monoclonal antibody against human CCL20—was evaluated in a 26-week cynomolgus monkey toxicology study. A high incidence of unexpected vascular and organ inflammation was observed microscopically, leading to the decision to halt clinical development. Here we report a dose-responsive increase in the incidence and severity of inflammation in multiple organs from monkeys receiving 30 and 300 mg/kg/week by either subcutaneous or intravenous injection. Histomorphological changes resembled an immune complex-mediated pathology, which is often due to formation of anti-drug antibodies in monkeys receiving a human protein therapeutic and thus not predictive of clinical outcome. However, the presentation was atypical in that there was a clear dose response with a very high incidence of inflammation with a low incidence of ADA that did not correlate well individually. Additionally, the immunohistologic presentation was atypical in that the severity and distribution of tissue inflammation was greater than the numbers of associated immune complexes (i.e., granular deposits). An extensive ex vivo analysis of large molecular weight protein complexes in monkey serum from this study and in human serum samples demonstrated a time-dependent aggregation of GSK3050002, that was not predicted by in vitro assays. The aggregates also contained complement components. These findings support the hypothesis that immune complexes of drug aggregates, not necessarily including anti-drug antibodies, can fix complement, accumulate over time, and trigger immune complex disease. A situation which may have increased clinical relevance than typical anti-drug antibody-associated immune complex disease in monkeys administered human antibody proteins.
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Affiliation(s)
- Susan B. Laffan
- In vitro In vivo Translation (IVIVT), R&D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Andrew S. Thomson
- Biopharm Analytical Science, R&D Platform Technology and Science, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America
| | - Shing Mai
- Biopharm Analytical Science, R&D Platform Technology and Science, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America
| | - Cindy Fishman
- In vitro In vivo Translation (IVIVT), R&D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Takahito Kambara
- Pathology, IVIVT, R&D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Kiran Nistala
- Adaptive Immunity Research Unit, GlaxoSmithKline, Stevenage, United Kingdom
| | - James T. Raymond
- Charles River Laboratories, Inc., Frederick, Maryland, United States of America
| | - Shugui Chen
- Biopharm Analytical Science, R&D Platform Technology and Science, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America
| | - Thulasi Ramani
- Envigo CRS, Inc., Princeton, New Jersey, United States of America
| | - Laura Pageon
- Envigo CRS, Inc., Princeton, New Jersey, United States of America
| | - Rodd Polsky
- Biopharm Analytical Science, R&D Platform Technology and Science, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America
| | - Mark Watkins
- In vitro In vivo Translation (IVIVT), R&D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Gemma Ottolangui
- Biopharm Molecular Discovery, R&D Platform Technology and Science, GlaxoSmithKline, Stevenage, United Kingdom
| | - John R. White
- Biopharm Analytical Science, R&D Platform Technology and Science, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America
| | - Curtis Maier
- In vitro In vivo Translation (IVIVT), R&D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Michael Herdman
- Clinical Pharmacology and Experimental Medicine, GlaxoSmithKline, Stevenage, United Kingdom
| | - Gerben Bouma
- Adaptive Immunity Research Unit, GlaxoSmithKline, Stevenage, United Kingdom
- Clinical Pharmacology and Experimental Medicine, GlaxoSmithKline, Stevenage, United Kingdom
- * E-mail:
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22
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Shen T, Cheng X, Liu X, Xia C, Zhang H, Pan D, Zhang X, Li Y. Circ_0026344 restrains metastasis of human colorectal cancer cells via miR-183. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2020; 47:4038-4045. [PMID: 31608699 DOI: 10.1080/21691401.2019.1669620] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background: CircRNA circ_0026344 was previously revealed as a tumour-suppressive gene in colorectal cancer (CRC) progression. The purpose of this research was to investigate the role of circ_0026344 in CRC cells metastasis induced by chemokines. Methods: Two human CRC cell lines SW480 and Caco-2 were treated by CCL20 and CXCL8. Cell proliferation, migration/invasion, expression of epithelial-mesenchymal transition (EMT) inducers and the expression of circ_0026344 were measured using sulforhodamine B assay, Transwell chamber, western blot and qRT-PCR, respectively. The effects of circ_0026344 on CRC cells migration/invasion and the expression of EMT inducers were evaluated. Moreover, the downstream miRNA and signalling pathways of circ_0026344 were studied. Results: CCL20 and CXCL8 synergized to facilitate the proliferation, migration and invasion of CRC cells. At the meantime, E-cadherin was downregulated, whereas N-cadherin, Vimentin and Snail were up-regulated by CCL20 and CXCL8 co-stimulation, which was accompanied by the mobilization of PI3K/AKT/ERK signalling. More interestingly, the expression of circ_0026344 was down-regulated by CCL20 and CXCL8 co-stimulation. Silence of circ_0026344 increased the migratory and invasive capacities of CRC cells and increased EMT process as well. Overexpression of circ_0026344 led to a contrary impact. miR-183 was negatively regulated by circ_0026344, and the inhibitory effects of circ_0026344 overexpression on Wnt/β-catenin pathway were reversed when miR-183 was overexpressed. Conclusion: Overexpression of circ_0026344 restrained CRC metastasis and EMT induced by CCL20 and CXCL8 synergistical treatment. miR-183 was a downstream effector of circ_0026344, and the anti-tumour function of circ_0026344 might be involved in the repressed Wnt/β-catenin signalling. Highlights CCL20 and CXCL8 synergize to decrease the expression of circ_0026344; Silence of circ_0026344 promotes CRC cells migration, invasion and EMT process; miR-183 is a downstream effector of circ_0026344.
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Affiliation(s)
- Tao Shen
- Department of Colorectal Surgery, The Third Affiliated Hospital of Kunming Medical University , Kunming , China
| | - Xianshuo Cheng
- Department of Colorectal Surgery, The Third Affiliated Hospital of Kunming Medical University , Kunming , China
| | - Xin Liu
- Tumor Institute, The Third Affiliated Hospital of Kunming Medical University , Kunming , China
| | - Cuifeng Xia
- Department of Colorectal Surgery, The Third Affiliated Hospital of Kunming Medical University , Kunming , China
| | - Hongtao Zhang
- Department of Colorectal Surgery, The Third Affiliated Hospital of Kunming Medical University , Kunming , China
| | - Dingguo Pan
- Department of Colorectal Surgery, The Third Affiliated Hospital of Kunming Medical University , Kunming , China
| | - Xuan Zhang
- Department of Colorectal Surgery, The Third Affiliated Hospital of Kunming Medical University , Kunming , China
| | - Yunfeng Li
- Department of Colorectal Surgery, The Third Affiliated Hospital of Kunming Medical University , Kunming , China
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23
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Zins K, Abraham D. Comment on：Kadomoto, S. et al. "Tumor-Associated Macrophages Induce Migration of Renal Cell Carcinoma Cells via Activation of the CCL20-CCR6 Axis" Cancers 2020, 12, 89. Cancers (Basel) 2020; 12:E342. [PMID: 32028699 PMCID: PMC7072274 DOI: 10.3390/cancers12020342] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 01/29/2020] [Accepted: 01/30/2020] [Indexed: 12/03/2022] Open
Abstract
Macrophages form a major component of the leukocyte infiltrate in solid tumors and it has become increasingly clear that tumor-associated macrophages (TAMs) have tumor-promoting effects within the stroma [1]. Renal cell carcinoma (RCC) solid tumors are comprised of a heterogeneous microenvironment of both malignant and normal stromal cells containing large numbers of macrophages [2].We read with interest the paper by Suguru Kadomoto et al. entitled "Tumor-associated macrophages induce migration of renal cell carcinoma cells via activation of the CCL20-CCR6 axis", published in Cancers [3], in which they report that the CCL20-CCR6 axis induces migration and epithelial-mesenchymal transition (EMT) of ACHN and Caki-1 RCC cells in co-cultures with THP-1/U937-derived tumor conditioned macrophages.[...].
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Affiliation(s)
| | - Dietmar Abraham
- Center for Anatomy and Cell Biology, Division of Cell and Developmental Biology, Medical University of Vienna, Vienna 1090, Austria;
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24
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Liu F, Wang T, Hu Y, Tian G, Secombes CJ, Wang T. Expansion of fish CCL20_like chemokines by genome and local gene duplication: Characterisation and expression analysis of 10 CCL20_like chemokines in rainbow trout (Oncorhynchus mykiss). DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2020; 103:103502. [PMID: 31568810 DOI: 10.1016/j.dci.2019.103502] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 09/25/2019] [Accepted: 09/25/2019] [Indexed: 06/10/2023]
Abstract
Mammalian CCL20, or macrophage inflammatory protein-3α, can function as a homeostatic and inflammatory chemokine. In relation to the latter, it is responsible for the chemoattraction of lymphocytes and dendritic cells to mucosal immune sites under inflammatory and pathological conditions. CK1, CK8A and CK8B are rainbow trout (Oncorhynchus mykiss) CC chemokines that were reported previously to be phylogenetically related to mammalian CCL20. In the current study, an additional seven CCL20_L paralogues in rainbow trout are reported, that are divided into three subgroups and have been designated here as: CCL20_L1a (also referred to as CK1), CCL20_L1b1-2, CCL20_L2a (CK8A), CCL20_L2b (CK8B), CCL20_L3a, and CCL20_L3b1-4. Multiple CCL20_L genes were also identified in other salmonids that arose from both whole genome duplication and local gene duplication. Phylogenetic tree, homology and synteny analysis support that CCL20_L1-3 found in salmonids are also present in most teleosts arose from the 3 R whole genome duplication and in some species, local gene duplication. Like mammalian CCL20, rainbow trout CCL20_L molecules possess a high positive net charge with a pI of 9.34-10.16, that is reported to be important for antimicrobial activity. Rainbow trout CCL20_L paralogues are differentially expressed and in general highly expressed in mucosal tissues, such as gills, thymus and intestine. The expression levels of rainbow trout CCL20_L paralogues are increased during development and following PAMP/cytokine stimulation. For example, in RTS-11 cells CCL20_L3b1 and CCL20_L3b2 are highly up-regulated by LPS, Poly I:C, recombinant(r) IFNa and rIL-1β. Trout CCL20_L paralogues are also increased after Yersinia ruckeri infection or Poly I:C stimulation in vivo, with CCL20_L3b1 and CCL20_L3b2 again highly up-regulated. Overall, this is the first report of the complete CCL20 chemokine subfamily in rainbow trout, and the analysis of their expression and modulation in vitro and in vivo. These results suggest that teleosts possess divergent CCL20_L molecules that may have important roles in anti-viral/anti-bacterial defence and in mucosal immunity.
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Affiliation(s)
- Fuguo Liu
- Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 2TZ, United Kingdom
| | - Tingyu Wang
- Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 2TZ, United Kingdom
| | - Yehfang Hu
- Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 2TZ, United Kingdom
| | - Guangming Tian
- Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 2TZ, United Kingdom; School of Animal Science, Yangtze University, Jingzhou, 434020, PR China
| | - Christopher J Secombes
- Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 2TZ, United Kingdom.
| | - Tiehui Wang
- Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 2TZ, United Kingdom.
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Elhousiny M, Miller K, Ariyawadana A, Nimmo A. Identification of inflammatory mediators associated with metastasis of oral squamous cell carcinoma in experimental and clinical studies: systematic review. Clin Exp Metastasis 2019; 36:481-492. [PMID: 31559586 DOI: 10.1007/s10585-019-09994-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 09/18/2019] [Indexed: 12/12/2022]
Abstract
Metastasis, whether regional or distant, remains the main cause of morbidity and recurrence in oral cancer. The accumulating evidence suggests that inflammatory mediators are strong drivers for cancer progression and spread. However, the precise role of these inflammatory mediators in mediating specific metastatic stage is poorly understood due to lack of integration/validation of experimental research data and the clinical trials, i.e., the data produced from research is not translated to clinical therapeutic targets. This, in turn, results in the lack of developing reliable biomarker that can be used for accurate diagnosis/prognosis of the tumour spread. We have performed a systematic review to assess the role of inflammatory mediators as potential markers for diagnosis/prognosis of oral squamous cell carcinoma (OSCC) metastasis. We carried out a systematic search the PubMed, Web of Science, Embase and Scopus databases under the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Australian National Health and Medical Research Council (NHMRC). Articles were divided into two groups; experimental (in-vivo) and clinical studies. The REporting recommendations for tumour MARKer prognostic studies Scale (REMARK) was used to assess the quality of the studies for the clinical search while Animal research: Reporting In-vivo experiments (ARRIVE) guidelines were used to assess the quality of the animal studies. Sixteen articles in the clinical group and four articles in the experimental group were included in the final review. We identified nine inflammatory mediators; CXCR4, CXCL12 (SDF-1), CCR7, IL-6, IL-18, CCL20 (MIP-3), CXCL1 (GRO-1), CCL3, CXCR2. This panel of inflammatory mediators can provide a framework for hypothesis testing of the potential value of these mediators in metastatic prognosis. We recommend carrying a large cohort study with data pooling for adequate assessment and testing of the inflammatory panel of mediators.
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Affiliation(s)
- Moustafa Elhousiny
- College of Medicine and Dentistry, James Cook University, Cairns, QLD, 4878, Australia.
| | - Kate Miller
- College of Medicine and Dentistry, James Cook University, Cairns, QLD, 4878, Australia
- College of Public Health, Medical and Veterinary Sciences, James Cook University, Cairns, Australia
| | - Anura Ariyawadana
- College of Medicine and Dentistry, James Cook University, Cairns, QLD, 4878, Australia
- Griffith Health Institute, Gold Coast Campus, Griffith University, Gold Coast, Australia
| | - Alan Nimmo
- College of Medicine and Dentistry, James Cook University, Cairns, QLD, 4878, Australia
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26
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Geismann C, Schäfer H, Gundlach JP, Hauser C, Egberts JH, Schneider G, Arlt A. NF-κB Dependent Chemokine Signaling in Pancreatic Cancer. Cancers (Basel) 2019; 11:cancers11101445. [PMID: 31561620 PMCID: PMC6826905 DOI: 10.3390/cancers11101445] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 09/12/2019] [Accepted: 09/24/2019] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is one of the carcinomas with the worst prognoses, as shown by its five-year survival rate of 9%. Although there have been new therapeutic innovations, the effectiveness of these therapies is still limited, resulting in pancreatic ductal adenocarcinoma (PDAC) becoming the second leading cause of cancer-related death in 2020 in the US. In addition to tumor cell intrinsic resistance mechanisms, this disease exhibits a complex stroma consisting of fibroblasts, immune cells, neuronal and vascular cells, along with extracellular matrix, all conferring therapeutic resistance by several mechanisms. The NF-κB pathway is involved in both the tumor cell-intrinsic and microenvironment-mediated therapeutic resistance by regulating the transcription of a plethora of target genes. These genes are involved in nearly all scenarios described as the hallmarks of cancer. In addition to classical regulators of apoptosis, NF-κB regulates the expression of chemokines and their receptors, both in the tumor cells and in cells of the microenvironment. These chemokines mediate autocrine and paracrine loops among tumor cells but also cross-signaling between tumor cells and the stroma. In this review, we will focus on NF-κB-mediated chemokine signaling, with an emphasis on therapy resistance in pancreatic cancer.
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Affiliation(s)
- Claudia Geismann
- Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany.
| | - Heiner Schäfer
- Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany.
- Institute of Experimental Cancer Research, UKSH Campus Kiel, 24105 Kiel, Germany.
| | | | | | | | - Günter Schneider
- Technische Universität München, Klinikum rechts der Isar, II. Medizinische Klinik, 81675 Munich, Germany.
| | - Alexander Arlt
- Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany.
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27
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Guo W, Li H, Liu H, Ma X, Yang S, Wang Z. DEPDC1 drives hepatocellular carcinoma cell proliferation, invasion and angiogenesis by regulating the CCL20/CCR6 signaling pathway. Oncol Rep 2019; 42:1075-1089. [PMID: 31322256 PMCID: PMC6667871 DOI: 10.3892/or.2019.7221] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 07/03/2019] [Indexed: 12/16/2022] Open
Abstract
DEP domain containing 1 (DEPDC1) functions as an oncogene in hepatocellular carcinoma (HCC). However, the underlying mechanism of DEPDC1 remains largely unknown. The present study revealed that DEPDC1 knockdown inhibited HCC cell proliferation, colony formation and invasion in vitro and suppressed the growth of HCC xenografts in vivo. Furthermore, DEPDC1 overexpression promoted HCC cell proliferation, colony formation and invasion. DNA microarray, reverse transcription-quantitative-PCR and western blotting results demonstrated that DEPDC1 knockdown in Huh-7 significantly inhibited the expression of chemokine (C-C motif) ligand 20 (CCL20) and chemokine (C-C motif) receptor 6 (CCR6). In addition, the expression of CCL20 and CCR6 were upregulated in HCC tissues and cell lines, and were positively correlated with DEPDC1 expression. CCL20 or CCR6 knockdown via small interfering RNA reversed the effects of DEPDC1 overexpression in HCC cells. Furthermore, it was revealed that conditioned medium from DEPDC1 upregulated Li-7 and Hep3B cells led to angiogenesis in vitro, whereas CCL20 knockdown in Li-7 and Hep3B cells or CCR6 knockdown in human umbilical vein endothelial cells reversed the angiogenic effect of DEPDC1 overexpression. In conclusion, DEPDC1 facilitated cell proliferation, invasion and angiogenesis via the CCL20/CCR6 pathway in HCC.
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Affiliation(s)
- Wubin Guo
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Hui Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Huan Liu
- Research Laboratory of Biomedical Engineering, The TCM Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Xin Ma
- Department of General Surgery, The TCM Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Sijin Yang
- Department of Cardiovascular Medicine, The TCM Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Ziwei Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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28
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Ramamourthy G, Arias M, Nguyen LT, Ishida H, Vogel HJ. Expression and Purification of Chemokine MIP-3α (CCL20) through a Calmodulin-Fusion Protein System. Microorganisms 2019; 7:microorganisms7010008. [PMID: 30626048 PMCID: PMC6352211 DOI: 10.3390/microorganisms7010008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 12/22/2018] [Accepted: 01/02/2019] [Indexed: 12/27/2022] Open
Abstract
Human macrophage inflammatory protein 3α (MIP-3α), also known as CCL20, is a 70 amino acid chemokine that selectively binds and activates chemokine receptor 6 (CCR6). This chemokine is responsible for inducing the migration of immature dendritic cells, effector, or memory T-cells, and B-cells. Moreover, the MIP-3α protein has been shown to display direct antimicrobial, antiviral and antiprotozoal activities. Because of the potential therapeutic uses of this protein, the efficient production of MIP-3α is of great interest. However, bacterial recombinant production of the MIP-3α protein has been limited by the toxicity of this extremely basic protein (pI 9.7) toward prokaryotic cells, and by solubility problems during expression and purification. In an attempt to overcome these issues, we have investigated the bacterial recombinant expression of MIP-3α by using several common expression and fusion tags, including 6× histidine (His), small ubiquitin modifier protein (SUMO), thioredoxin (TRX), ketosteroid isomerase (KSI), and maltose binding protein (MBP). We have also evaluated a recently introduced calmodulin (CaM)-tag that has been used for the effective expression of many basic antimicrobial peptides (AMPs). Here, we show that the CaM fusion tag system effectively expressed soluble MIP-3α in the cytoplasm of Escherichia coli with good yields. Rapid purification was facilitated by the His-tag that was integrated in the CaM-fusion protein system. Multidimensional nuclear magnetic resonance (NMR) studies demonstrated that the recombinant protein was properly folded, with the correct formation of disulfide bonds. In addition, the recombinant MIP-3α had antibacterial activity, and was shown to inhibit the formation of Pseudomonas aeruginosa biofilms.
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Affiliation(s)
- Gopal Ramamourthy
- Biochemistry Research Group, Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada.
| | - Mauricio Arias
- Biochemistry Research Group, Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada.
| | - Leonard T Nguyen
- Biochemistry Research Group, Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada.
| | - Hiroaki Ishida
- Biochemistry Research Group, Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada.
| | - Hans J Vogel
- Biochemistry Research Group, Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada.
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29
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Chraa D, Naim A, Olive D, Badou A. T lymphocyte subsets in cancer immunity: Friends or foes. J Leukoc Biol 2018; 105:243-255. [DOI: 10.1002/jlb.mr0318-097r] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 09/15/2018] [Accepted: 09/19/2018] [Indexed: 12/17/2022] Open
Affiliation(s)
- Dounia Chraa
- Cellular and Molecular Pathology LaboratoryFaculty of Medicine and Pharmacy of CasablancaHassan II University Casablanca Morocco
- Team Immunity and Cancer, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068, CNRS, UMR7258Institut Paoli‐CalmettesAix‐Marseille University, UM 105 Marseille France
| | - Asmaa Naim
- Cellular and Molecular Pathology LaboratoryFaculty of Medicine and Pharmacy of CasablancaHassan II University Casablanca Morocco
- University Mohammed VI for Health ScienceCheick Khalifa Hospital Casablanca Morocco
| | - Daniel Olive
- Team Immunity and Cancer, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068, CNRS, UMR7258Institut Paoli‐CalmettesAix‐Marseille University, UM 105 Marseille France
| | - Abdallah Badou
- Cellular and Molecular Pathology LaboratoryFaculty of Medicine and Pharmacy of CasablancaHassan II University Casablanca Morocco
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30
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New Contributions to Asarum Powder on Immunology Related Toxicity Effects in Lung. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:1054032. [PMID: 30245729 PMCID: PMC6139235 DOI: 10.1155/2018/1054032] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 06/25/2018] [Accepted: 07/10/2018] [Indexed: 01/11/2023]
Abstract
Objective. Asarum is widely used in clinical practice of Chinese medicine in the treatment of respiratory diseases. Many toxic ingredients (safrole, etc.) had been found in Asarum that show multiple visceral toxicities. In this study, we performed systematic investigation of expression profiles of genes to take a new insight into unclear mechanism of Asarum toxicities in lung. Methods. mRNAs were extracted from lungs of rats after intragastric administration with/without Asarum powders, and microarray assays were applied to investigate gene expression profiles. Differentially expressed genes with significance were selected to carry out GO analysis. Subsequently, quantitative PCRs were performed to verify the differential expression of Tmprss6, Prkag3, Nptx2, Antxr11, Klk11, Rag2, Olr77, Cd7, Il20, LOC69, C6, Ccl20, LOC68, and Cd163 in lung. Changes of Ampk, Bcl2, Caspase 3, Il1, Il20, Matriptase2, Nfκb, Nptx2, and Rag2 in the lung on protein level were verified by western blotting and immunohistochemistry. Results. Compared with control group, the estimated organ coefficients were relatively increased in Asarum group. Results of GO analysis showed that a group of immune related genes in lung were expressed abnormally. The result of PCRs showed that Ccl20 was downregulated rather than other upregulated genes in the Asarum group. Western blotting and immunohistochemistry images showed that Asarum can upregulate the expression of Ampk, Caspase 3, Il1, Il20, Matriptase2, Nfκb, and Rag2 and downregulate the expression of Bcl2 in lung. Conclusion. Our data suggest that expressions of immune related genes in lung were selectively altered by Asarum. Therefore, inflammatory response was active, by regulating Caspase 3, Il1, Il20, Matriptase2, Nfκb, Rag2, Tmprss6, Prkag3, Nptx2, Antxr1, Klk11, Olr77, Cd7, LOC69, C6, LOC68, Cd163, Ampk, Bcl2, and Ccl20. Our study indicated that inflammatory factors take effect in lung toxicity caused by Asarum, which provides a new insight into molecular mechanism of Asarum toxicities in lung.
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CCL20 triggered by chemotherapy hinders the therapeutic efficacy of breast cancer. PLoS Biol 2018; 16:e2005869. [PMID: 30052635 PMCID: PMC6082578 DOI: 10.1371/journal.pbio.2005869] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 08/08/2018] [Accepted: 07/12/2018] [Indexed: 12/22/2022] Open
Abstract
Chemotherapeutic resistance in triple-negative breast cancer (TNBC) has brought great challenges to the improvement of patient survival. The mechanisms of taxane chemoresistance in TNBC have not been well investigated. Our results illustrated C-C motif chemokine ligand 20 (CCL20) was significantly elevated during taxane-containing chemotherapy in breast cancer patients with nonpathologic complete response. Furthermore, CCL20 promoted the self-renewal and maintenance of breast cancer stem cells (BCSCs) or breast cancer stem-like cells through protein kinase Cζ (PKCζ) or p38 mitogen-activated protein kinase (MAPK)-mediated activation of p65 nuclear factor kappa B (NF-κB) pathway, significantly increasing the frequency and taxane resistance of BCSCs. Moreover, CCL20-promoted NF-κB activation increased ATP-binding cassette subfamily B member 1 (ABCB1)/multidrug resistance 1 (MDR1) expression, leading to the extracellular efflux of taxane. These results suggested that chemotherapy-induced CCL20 mediated chemoresistance via up-regulating ABCB1. In addition, NF-κB activation increased CCL20 expression, forming a positive feedback loop between NF-κB and CCL20 pathways, which provides sustained impetus for chemoresistance in breast cancer cells. Our results suggest that CCL20 can be a novel predictive marker for taxane response, and the blockade of CCL20 or its downstream pathway might reverse the taxane resistance in breast cancer patients.
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In vitro chemokine (C-C motif) receptor 6-dependent non-inflammatory chemotaxis during spermatogenesis. Biol Res 2018; 51:12. [PMID: 29788995 PMCID: PMC5963036 DOI: 10.1186/s40659-018-0161-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Accepted: 05/15/2018] [Indexed: 11/10/2022] Open
Abstract
Background Chemokine (C-C motif) receptor 6 (CCR6) is present in sperm and plays a significant role in sperm motility and chemotaxis acting in the reproductive tracts. However, the expression and functional significance of CCR6 in testis are still poorly understood, especially in the process of spermatogenesis. Methods and results CCR6 was expressed in spermatogenic cell lines and its expression was shown in an age-dependent upregulation manner from puberty to adulthood in mouse testis. Immunostaining results confirmed the localization of CCR 6 in testis. Further chemotaxis assays demonstrated that spermatogenic cells GC-1 and -2 exhibited a directional movement toward CCR6-specific ligand such as CCL20 or Sertoli cells in vitro. Conclusions The present findings indicate that CCR6 is involved in the chemotaxis of spermatogenic cells in vitro and promotes chemotaxis under non-inflammatory conditions during normal spermatogenesis. Electronic supplementary material The online version of this article (10.1186/s40659-018-0161-z) contains supplementary material, which is available to authorized users.
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Wang L, Zhou D, Ren H, Chen Y. Effects of modified FOLFOX-6 chemotherapy on cellular immune function in patients with gastric cancer. Oncol Lett 2018; 15:8635-8640. [PMID: 29805598 DOI: 10.3892/ol.2018.8361] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Accepted: 02/12/2018] [Indexed: 12/13/2022] Open
Abstract
Tumor immunosuppression serves an important role in the occurrence and development of gastric cancer. However, the effect of chemotherapy on the immune function of patients remains unclear. The present study aimed to investigate changes in cellular immune function and regulatory T cells (Tregs) in patients with gastric cancer prior to and following chemotherapy. In the peripheral blood of patients with gastric cancer, the percentage of CD4+ T cells was substantially decreased compared with that of healthy controls (11.39±5.91 vs. 22.34±3.37%, respectively; P<0.05). High frequencies of CD8+ T cells and Tregs were also observed in the peripheral blood of patients. Although the number of T cells decreased following chemotherapy (the proportions of CD4+ and CD8+ cells were 8.99±7.31 and 16.00±4.51%, respectively), the ratio of CD4+/CD8+ T cells increased (0.31±0.17 vs. 0.56±0.22; P<0.05). Furthermore, the level of C-C motif chemokine ligand 20 (CCL20) was increased in patients prior to chemotherapy compared with healthy controls. As the sole receptor for CCL20, a high level of expression of C-C motif chemokine receptor 6 on circulating Tregs was also identified in the patients, which decreased following chemotherapy. These results suggest that chemotherapy may efficiently promote cellular immune function and inhibit immunosuppression in patients with gastric cancer.
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Affiliation(s)
- Liang Wang
- Department of Hepatobiliary-Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Donger Zhou
- Department of Hepatobiliary-Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Haitao Ren
- Department of Burns and Wound Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Yan Chen
- Emergency Department, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
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Jin P, Shin SH, Chun YS, Shin HW, Shin YJ, Lee Y, Kim D, Nam DH, Park JW. Astrocyte-derived CCL20 reinforces HIF-1-mediated hypoxic responses in glioblastoma by stimulating the CCR6-NF-κB signaling pathway. Oncogene 2018. [PMID: 29535421 DOI: 10.1038/s41388-018-0182-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
During tumor development, stromal cells are co-opted to the tumor milieu and provide favorable conditions for the tumor. Hypoxia stimulates cancer cells to acquire a more malignant phenotype via activation of hypoxia-inducible factor 1 (HIF-1). Given that cancer cells and astrocytes in glioblastomas coexist in a hypoxic microenvironment, we examined whether astrocytes affect the adaptation of glioblastoma cells to hypoxia. Immunoblotting, reporter assays, quantitative RT-PCR, and chromatin immunoprecipitation were performed to evaluate HIF-1 signaling in glioblastoma cells. Astrocyte-derived chemokine C-C motif ligand 20 (CCL20) was identified using cytokine arrays, and its role in glioblastoma development was evaluated in orthotopic xenografts. Astrocytes augmented HIF-1α expression in glioblastoma cells under hypoxia. The expression of HIF-1 downstream genes, cancer colony formation, and Matrigel invasion of glioblastoma cells were stimulated by conditioned medium from astrocytes pre-exposed to hypoxia. CCL20 was secreted in a hypoxia-dependent manner from astrocytes and busted the hypoxic induction of HIF-1α in glioblastoma cells. Mechanistically, the CCL20/CCR6 signaling pathway upregulates HIF-1α by stimulating nuclear factor kappa B-driven transactivation of the HIF1A gene. Compared with the control tumors, CCR6-deficient glioblastoma xenografts grew more slowly, with poor vascularization, and expressed lower levels of HIF-1α and its downstream proteins. Furthermore, CCR6 expression was correlated with HIF-1α expression in GEO and TCGA datasets from human glioblastoma tissues. These results suggest that glioblastoma cells adapt well to hypoxic stress by virtue of CCL20 derived from neighboring astrocytes.
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Affiliation(s)
- Peng Jin
- Department of Biomedical Sciences, BK21-plus education program, Seoul National University College of Medicine, Seoul, Korea.,Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.,Ischemic/Hypoxic Disease Institute and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Seung-Hyun Shin
- Department of Biomedical Sciences, BK21-plus education program, Seoul National University College of Medicine, Seoul, Korea.,Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.,Ischemic/Hypoxic Disease Institute and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yang-Sook Chun
- Department of Biomedical Sciences, BK21-plus education program, Seoul National University College of Medicine, Seoul, Korea.,Ischemic/Hypoxic Disease Institute and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun-Woo Shin
- Department of Biomedical Sciences, BK21-plus education program, Seoul National University College of Medicine, Seoul, Korea.,Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.,Ischemic/Hypoxic Disease Institute and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yong Jae Shin
- Institute for Refractory Cancer Research, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.,Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yeri Lee
- Institute for Refractory Cancer Research, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Donggeon Kim
- Institute for Refractory Cancer Research, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Do-Hyun Nam
- Institute for Refractory Cancer Research, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.,Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong-Wan Park
- Department of Biomedical Sciences, BK21-plus education program, Seoul National University College of Medicine, Seoul, Korea. .,Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea. .,Ischemic/Hypoxic Disease Institute and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
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35
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Samaniego R, Gutiérrez-González A, Gutiérrez-Seijo A, Sánchez-Gregorio S, García-Giménez J, Mercader E, Márquez-Rodas I, Avilés JA, Relloso M, Sánchez-Mateos P. CCL20 Expression by Tumor-Associated Macrophages Predicts Progression of Human Primary Cutaneous Melanoma. Cancer Immunol Res 2018; 6:267-275. [PMID: 29362221 DOI: 10.1158/2326-6066.cir-17-0198] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 10/03/2017] [Accepted: 01/09/2018] [Indexed: 11/16/2022]
Abstract
The chemokine axis CCR6/CCL20 is involved in cancer progression in a variety of tumors. Here, we show that CCR6 is expressed by melanoma cells. The CCR6 ligand, CCL20, induces migration and proliferation in vitro, and enhances tumor growth and metastasis in vivo Confocal analysis of melanoma tissues showed that CCR6 is expressed by tumor cells, whereas CCL20 is preferentially expressed by nontumoral cells in the stroma of certain tumors. Stromal CCL20, but not tumoral CCR6, predicted poor survival in a cohort of 40 primary melanoma patients. Tumor-associated macrophages (TAM), independently of their M1/M2 polarization profile, were identified as the main source of CCL20 in primary melanomas that developed metastasis. In addition to CCL20, TAMs expressed TNF and VEGF-A protumoral cytokines, suggesting that melanoma progression is supported by macrophages with a differential activation state. Our data highlight the synergistic interaction between melanoma tumor cells and prometastatic macrophages through a CCR6/CCL20 paracrine loop. Stromal levels of CCL20 in primary melanomas may be a clinically useful marker for assessing patient risk, making treatment decisions, and planning or analyzing clinical trials. Cancer Immunol Res; 6(3); 267-75. ©2018 AACR.
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Affiliation(s)
- Rafael Samaniego
- Unidad de Microscopía Confocal, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
| | | | - Alba Gutiérrez-Seijo
- Unidad de Microscopía Confocal, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Laboratorio de Inmuno-oncología, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Sandra Sánchez-Gregorio
- Unidad de Microscopía Confocal, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Laboratorio de Inmuno-oncología, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Jorge García-Giménez
- Unidad de Microscopía Confocal, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Laboratorio de Inmuno-oncología, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Enrique Mercader
- Servicio de Cirugía General, Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
| | - Iván Márquez-Rodas
- Servicio de Oncología, Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
| | - José Antonio Avilés
- Servicio de Dermatología, Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
| | - Miguel Relloso
- Grupo de Inmuno-fisiología, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Paloma Sánchez-Mateos
- Laboratorio de Inmuno-oncología, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
- Departamento de Inmunología, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
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36
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Dai W, Li Y, Mo S, Feng Y, Zhang L, Xu Y, Li Q, Cai G. A robust gene signature for the prediction of early relapse in stage I-III colon cancer. Mol Oncol 2018; 12:463-475. [PMID: 29377588 PMCID: PMC5891048 DOI: 10.1002/1878-0261.12175] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 12/23/2017] [Accepted: 12/23/2017] [Indexed: 01/09/2023] Open
Abstract
Colon cancer patients experiencing early relapse consistently exhibited poor survival. The aim of our study was to develop an mRNA signature that can help to detect early relapse cases in stage I-III colon cancer. Public microarray datasets of stage I-III colon cancer samples were extracted from the Gene Expression Omnibus database. Propensity score matching analysis was performed between patients in the early relapse group and the long-term survival group from GSE39582 discovery series (N = 386), and patients were 1 : 1 matched. Global mRNA expression changes were then analyzed between the paired groups to identify the differentially expressed genes. Lasso Cox regression modeling analysis was conducted for the selection of prognostic mRNA. Fifteen mRNA were finally identified to build an early relapse classifier. With specific risk score formula, patients were classified into a high-risk group and a low-risk group. Relapse-free survival was significantly different between the two groups in every series, including discovery [hazard ratio (HR): 2.547, 95% confidence interval (CI): 1.708-3.797, P < 0.001)], internal validation (HR: 5.146, 95% CI: 1.968-13.457, P < 0.001), and external validation (HR: 1.977, 95% CI: 1.295-3.021, P < 0.001) sets of patients. Time-dependent receiver-operating characteristic at 1 year suggested more prognostic accuracy of the classifier [area under curve (AUC = 0.703)] than the American Joint Commission on Cancer tumor-node-metastasis staging system (AUC = 0.659) in all 951 patients. In conclusion, we developed a robust mRNA signature that can effectively classify colon cancer patients into groups with low and high risks of early relapse. This mRNA signature may help select high-risk colon cancer patients who require more aggressive therapeutic intervention.
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Affiliation(s)
- Weixing Dai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, China.,Department of Oncology, Shanghai Medical College, Fudan University, China
| | - Yaqi Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, China.,Department of Oncology, Shanghai Medical College, Fudan University, China
| | - Shaobo Mo
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, China.,Department of Oncology, Shanghai Medical College, Fudan University, China
| | - Yang Feng
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, China.,Department of Oncology, Shanghai Medical College, Fudan University, China
| | - Long Zhang
- Shanghai Medical College, Collaborative Innovation Center of Cancer Medicine, Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, China
| | - Ye Xu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, China.,Department of Oncology, Shanghai Medical College, Fudan University, China
| | - Qingguo Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, China.,Department of Oncology, Shanghai Medical College, Fudan University, China
| | - Guoxiang Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, China.,Department of Oncology, Shanghai Medical College, Fudan University, China
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37
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Zhiming W, Luman W, Tingting Q, Yiwei C. Chemokines and receptors in intestinal B lymphocytes. J Leukoc Biol 2018; 103:807-819. [PMID: 29443417 DOI: 10.1002/jlb.1ru0717-299rr] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2017] [Revised: 01/11/2018] [Accepted: 01/11/2018] [Indexed: 02/06/2023] Open
Abstract
Recent studies indicate that chemoattractant cytokines (chemokines) and their receptors modulate intestinal B lymphocytes in different ways, including regulating their maturity and differentiation in the bone marrow and homing to intestinal target tissues. Here, we review several important chemokine/chemokine receptor axes that guide intestinal B cells, focusing on the homing and migration of IgA antibody-secreting cells (IgA-ASCs) to intestinal-associated lymphoid tissues. We describe the selective regulation of these chemokine axes in coordinating the IgA-ASC trafficking in intestinal diseases. Finally, we discuss the role of B cells as chemokine producers serving dual roles in regulating the mucosal immune microenvironment.
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Affiliation(s)
- Wang Zhiming
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Wang Luman
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Biotherapy Research Center, Fudan University, Shanghai, China
| | - Qian Tingting
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Chu Yiwei
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Biotherapy Research Center, Fudan University, Shanghai, China
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38
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Liu Y, Wang J, Ni T, Wang L, Wang Y, Sun X. CCL20 mediates RANK/RANKL-induced epithelial-mesenchymal transition in endometrial cancer cells. Oncotarget 2018; 7:25328-39. [PMID: 27015366 PMCID: PMC5041907 DOI: 10.18632/oncotarget.8291] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 03/10/2016] [Indexed: 12/16/2022] Open
Abstract
RANK/RANKL facilitates migration/invasion via epithelial-mesenchymal transition (EMT) in certain malignant tumors. The relationship and mechanism between RANK/RANKL and EMT in endometrial cancer (EC) cells, however, remain unclear. In this study, we firstly showed that RANK/RANKL activation was correlated with EC staging and EMT markers in human EC tissue specimen. RANK/RANKL promoted migration/invasion and initiated EMT of EC cell lines. Then, protein chip analysis and enzyme-linked immunosorbent assay (ELISA) revealed that the expression and secretion of chemokine ligand 20 (CCL20) was dramatically enhanced in RANKL-treated RANK over-expressed EC cells. Moreover, the higher level of CCL20 in both serum and tumor tissue was detected in orthotopic transplantation mouse models. Finally, we confirmed that CCL20 contributed to invasion and EMT of RANK over-expressed EC cells. In summary, all data supported the hypothesis that RANK/RANKL elevated the expression and secretion of CCL20 in EC cells, which promoted cancer progression through EMT.
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Affiliation(s)
- Yao Liu
- Department of Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Wang
- Department of Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ting Ni
- Department of Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lihua Wang
- Department of Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yudong Wang
- Department of Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiao Sun
- Laboratory for Gynecologic Oncology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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39
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Ikeda S, Kitadate A, Ito M, Abe F, Nara M, Watanabe A, Takahashi N, Miyagaki T, Sugaya M, Tagawa H. Disruption of CCL20-CCR6 interaction inhibits metastasis of advanced cutaneous T-cell lymphoma. Oncotarget 2017; 7:13563-74. [PMID: 26789110 PMCID: PMC4924661 DOI: 10.18632/oncotarget.6916] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 12/31/2015] [Indexed: 12/19/2022] Open
Abstract
We recently demonstrated that upregulation of a chemokine receptor CCR6 and its ligand CCL20 led to metastasis of advanced cutaneous T-cell lymphoma (CTCL) cells, suggesting the involvement of CCL20-CCR6 interaction in initiating CTCL cell metastasis. In this study, we determined whether this interaction is functional in metastatic CTCL cells. We first demonstrated increased STAT3 expression during the progression of primary CTCL. STAT3 was spontaneously activated and mediated the transcription of CCL20 in CTCL cell lines. Next, to determine whether the transient knockdown of STAT3, CCL20, or CCR6 or treatment with neutralizing antibody against CCL20 (neutralizing CCL20 antibody) could reduce the migration ability of CTCL cells, we conducted an in vitro migration assay. All treatments reduced the nutrition-dependent migration activity of CTCL cells. Notably, treatment with neutralizing CCL20 antibody reduced the migration ability of the cells without decreasing the expression of CCL20 and CCR6. This demonstrated that the CCL20-CCR6 interaction is actually functional in metastatic CTCL cells. Finally, to examine the in vivo effect of neutralizing CCL20 antibody, we used NOD/Shi-scid IL-2γnul mice inoculated with CTCL cells. These mice were expected to die due to metastasis of CTCL cells into multiple organs. However, administration of neutralizing CCL20 antibody significantly prolonged the survival of the xenografted mice. These findings suggested that automatic activation of the STAT3/CCL20/CCR6 cascade was involved in CTCL lymphomagenesis and that disruption of CCL20-CCR6 interaction could be a key therapeutic strategy against advanced CTCL.
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Affiliation(s)
- Sho Ikeda
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | - Akihiro Kitadate
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | - Mitsugu Ito
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | - Fumito Abe
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | - Miho Nara
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | - Atsushi Watanabe
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | - Naoto Takahashi
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | | | - Makoto Sugaya
- Department of Dermatology, University of Tokyo, Tokyo, Japan
| | - Hiroyuki Tagawa
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
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40
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Pierini S, Perales-Linares R, Uribe-Herranz M, Pol JG, Zitvogel L, Kroemer G, Facciabene A, Galluzzi L. Trial watch: DNA-based vaccines for oncological indications. Oncoimmunology 2017; 6:e1398878. [PMID: 29209575 DOI: 10.1080/2162402x.2017.1398878] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 10/24/2017] [Indexed: 12/16/2022] Open
Abstract
DNA-based vaccination is a promising approach to cancer immunotherapy. DNA-based vaccines specific for tumor-associated antigens (TAAs) are indeed relatively simple to produce, cost-efficient and well tolerated. However, the clinical efficacy of DNA-based vaccines for cancer therapy is considerably limited by central and peripheral tolerance. During the past decade, considerable efforts have been devoted to the development and characterization of novel DNA-based vaccines that would circumvent this obstacle. In this setting, particular attention has been dedicated to the route of administration, expression of modified TAAs, co-expression of immunostimulatory molecules, and co-delivery of immune checkpoint blockers. Here, we review preclinical and clinical progress on DNA-based vaccines for cancer therapy.
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Affiliation(s)
- Stefano Pierini
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Ovarian Cancer Research Center (OCRC), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Renzo Perales-Linares
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Ovarian Cancer Research Center (OCRC), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Mireia Uribe-Herranz
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Ovarian Cancer Research Center (OCRC), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jonathan G Pol
- Université Paris Descartes/Paris V, France.,Université Pierre et Marie Curie/Paris VI, Paris.,Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.,INSERM, Paris, France
| | - Laurence Zitvogel
- Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.,INSERM, Villejuif, France.,Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France.,Université Paris Sud/Paris XI, Le Kremlin-Bicêtre, France
| | - Guido Kroemer
- Université Paris Descartes/Paris V, France.,Université Pierre et Marie Curie/Paris VI, Paris.,Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.,INSERM, Paris, France.,Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.,Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.,Pôle de Biologie, Hopitâl Européen George Pompidou, AP-HP; Paris, France
| | - Andrea Facciabene
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Ovarian Cancer Research Center (OCRC), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Lorenzo Galluzzi
- Université Paris Descartes/Paris V, France.,Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.,Sandra and Edward Meyer Cancer Center, New York, NY, USA
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41
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Zhang XP, Hu ZJ, Meng AH, Duan GC, Zhao QT, Yang J. Role of CCL20/CCR6 and the ERK signaling pathway in lung adenocarcinoma. Oncol Lett 2017; 14:8183-8189. [PMID: 29250193 DOI: 10.3892/ol.2017.7253] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 05/08/2017] [Indexed: 12/24/2022] Open
Abstract
Previous studies have revealed that carcinoma-associated fibroblasts communicate microenvironment-derived signals through chemokine/chemokine receptor interaction, resulting in carcinogenesis. C-C motif chemokine ligand 20 (CCL20)/C-C motif chemokine receptor 6 (CCR6) interactions are involved in the pathogenesis of colonic malignancies. The present study aimed to characterize the roles of CCL20/CCR6 and the extracellular signal-regulated kinase (ERK) signaling pathway in lung adenocarcinoma growth. Lung adenocarcinoma samples obtained at surgery were assessed for the expression, tissue localization and production of CCL20/CCR6. In addition, colony formation, ERK signaling and chemokine production were measured to assess the responsiveness of the A549 cell line to CCL20 stimulation. CCL20 and CCR6 were found to be highly expressed in the majority of samples in the recurrence group (76 and 66%, respectively). The staining indexes of CCL20 and CCR6 in the recurrence group were 149.3 and 134.4, respectively, which were significantly higher than those in the non-recurrence group (57.2 and 58.0, respectively); the protein and mRNA expression levels determined by western blot and reverse transcription-quantitative polymerase chain reaction were also found to be high in the recurrence group For A549 cells, the colony-forming capacity was increased by CCL20 stimulation, and this effect was dependent in part on ERK phosphorylation. Collectively, the findings suggest that CCR6 and CCL20 may serve a role in lung adenocarcinoma, leading to proliferation and migration via autocrine or paracrine mechanisms. The disruption of CCL20/CCR6 interactions may be a promising strategy for the treatment of cancer.
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Affiliation(s)
- Xiao-Peng Zhang
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Zhi-Juan Hu
- Department of Nephrology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Ai-Hong Meng
- Respiratory Division, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050050, P.R. China
| | - Guo-Chen Duan
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Qing-Tao Zhao
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Jing Yang
- Respiratory Division, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
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42
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Nedaeinia R, Avan A, Ahmadian M, Nia SN, Ranjbar M, Sharifi M, Goli M, Piroozmand A, Nourmohammadi E, Manian M, Ferns GA, Ghayour-Mobarhan M, Salehi R. Current Status and Perspectives Regarding LNA-Anti-miR Oligonucleotides and microRNA miR-21 Inhibitors as a Potential Therapeutic Option in Treatment of Colorectal Cancer. J Cell Biochem 2017; 118:4129-4140. [PMID: 28401648 DOI: 10.1002/jcb.26047] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 04/10/2017] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is among the leading causes of cancer-related death, principally due to its metastatic spread and multifactorial chemoresistance. The therapeutic failure can also be explained by inter- or intra-tumor genetic heterogeneity and tumor stromal content. Thus, the identification of novel prognostic biomarkers and therapeutic options are warranted in the management of CRC patients. There are data showing that microRNA-21 is elevated in different types of cancer, particularly colon adenocarcinoma and that this is association with a poor prognosis. This suggests that microRNA-21 may be of value as a potential therapeutic target. Furthermore, locked nucleic acid (LNA)-modified oligonucleotides have recently emerged as a therapeutic option for targeting dysregulated miRNAs in cancer therapy, through antisense-based gene silencing. Further work is required to identify innovative anticancer drugs that improve the current therapy either through novel combinatorial approaches or with better efficacy than conventional drugs. We aimed to provide an overview of the preclinical and clinical studies targeting key dysregulated signaling pathways in CRC as well as the therapeutic application of LNA-modified oligonucleotides, and miR inhibitors in the treatment of CRC patients. J. Cell. Biochem. 118: 4129-4140, 2017. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Reza Nedaeinia
- Deputy of Food and Drug, Isfahan University of Medical Sciences, Isfahan, Iran.,Student Research Committee, Department of medical biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehdi Ahmadian
- Department of Gastroentrology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sasan Nedaee Nia
- Department of Agricultural engineering and Weed science, Shiraz Branch, Islamic Azad University, Shiraz, Iran
| | - Maryam Ranjbar
- Deputy of Food and Drug, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammadreza Sharifi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Goli
- Department of Food Science and Technology, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran
| | - Ahmad Piroozmand
- School of Medicine, Kashan University of Medical Sciences, Autoimmune Diseases Research Center, Kashan, Iran
| | - Esmail Nourmohammadi
- Student Research Committee, Department of medical biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mostafa Manian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Gordon A Ferns
- Brighton and Sussex Medical School, Division of Medical Education, Falmer, Brighton BN1 9PH, Sussex, UK
| | - Majid Ghayour-Mobarhan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Rasoul Salehi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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43
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Flemer B, Lynch DB, Brown JMR, Jeffery IB, Ryan FJ, Claesson MJ, O'Riordain M, Shanahan F, O'Toole PW. Tumour-associated and non-tumour-associated microbiota in colorectal cancer. Gut 2017; 66:633-643. [PMID: 26992426 PMCID: PMC5529966 DOI: 10.1136/gutjnl-2015-309595] [Citation(s) in RCA: 548] [Impact Index Per Article: 68.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2015] [Revised: 12/18/2015] [Accepted: 12/21/2015] [Indexed: 12/12/2022]
Abstract
OBJECTIVE A signature that unifies the colorectal cancer (CRC) microbiota across multiple studies has not been identified. In addition to methodological variance, heterogeneity may be caused by both microbial and host response differences, which was addressed in this study. DESIGN We prospectively studied the colonic microbiota and the expression of specific host response genes using faecal and mucosal samples ('ON' and 'OFF' the tumour, proximal and distal) from 59 patients undergoing surgery for CRC, 21 individuals with polyps and 56 healthy controls. Microbiota composition was determined by 16S rRNA amplicon sequencing; expression of host genes involved in CRC progression and immune response was quantified by real-time quantitative PCR. RESULTS The microbiota of patients with CRC differed from that of controls, but alterations were not restricted to the cancerous tissue. Differences between distal and proximal cancers were detected and faecal microbiota only partially reflected mucosal microbiota in CRC. Patients with CRC can be stratified based on higher level structures of mucosal-associated bacterial co-abundance groups (CAGs) that resemble the previously formulated concept of enterotypes. Of these, Bacteroidetes Cluster 1 and Firmicutes Cluster 1 were in decreased abundance in CRC mucosa, whereas Bacteroidetes Cluster 2, Firmicutes Cluster 2, Pathogen Cluster and Prevotella Cluster showed increased abundance in CRC mucosa. CRC-associated CAGs were differentially correlated with the expression of host immunoinflammatory response genes. CONCLUSIONS CRC-associated microbiota profiles differ from those in healthy subjects and are linked with distinct mucosal gene-expression profiles. Compositional alterations in the microbiota are not restricted to cancerous tissue and differ between distal and proximal cancers.
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Affiliation(s)
- Burkhardt Flemer
- APC Microbiome Institute, University College Cork, Cork, Ireland,School of Microbiology, University College Cork, Cork, Ireland
| | - Denise B Lynch
- APC Microbiome Institute, University College Cork, Cork, Ireland,School of Microbiology, University College Cork, Cork, Ireland
| | - Jillian M R Brown
- APC Microbiome Institute, University College Cork, Cork, Ireland,School of Microbiology, University College Cork, Cork, Ireland
| | - Ian B Jeffery
- APC Microbiome Institute, University College Cork, Cork, Ireland,School of Microbiology, University College Cork, Cork, Ireland
| | - Feargal J Ryan
- APC Microbiome Institute, University College Cork, Cork, Ireland,School of Microbiology, University College Cork, Cork, Ireland
| | - Marcus J Claesson
- APC Microbiome Institute, University College Cork, Cork, Ireland,School of Microbiology, University College Cork, Cork, Ireland
| | | | - Fergus Shanahan
- APC Microbiome Institute, University College Cork, Cork, Ireland,Department of Medicine, University College Cork, Cork, Ireland
| | - Paul W O'Toole
- APC Microbiome Institute, University College Cork, Cork, Ireland,School of Microbiology, University College Cork, Cork, Ireland
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44
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Geismann C, Grohmann F, Dreher A, Häsler R, Rosenstiel P, Legler K, Hauser C, Egberts JH, Sipos B, Schreiber S, Linkermann A, Hassan Z, Schneider G, Schäfer H, Arlt A. Role of CCL20 mediated immune cell recruitment in NF-κB mediated TRAIL resistance of pancreatic cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2017; 1864:782-796. [PMID: 28188806 DOI: 10.1016/j.bbamcr.2017.02.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 01/25/2017] [Accepted: 02/06/2017] [Indexed: 01/11/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers. From a clinical view, the transcription factor NF-κB is of particular importance, since this pathway confers apoptosis resistance and limits drug efficacy. Whereas the role of the most abundant NF-κB subunit p65/RelA in therapeutic resistance is well documented, only little knowledge of the RelA downstream targets and their functional relevance in TRAIL mediated apoptosis in PDAC is available. In the present study TRAIL resistant and sensitive PDAC cell lines were analyzed for differentially expressed RelA target genes, to define RelA downstream targets mediating TRAIL resistance. The most upregulated target gene was then further functionally characterized. Unbiased genome-wide expression analysis demonstrated that the chemokine CCL20 represents the strongest TRAIL inducible direct RelA target gene in resistant PDAC cells. Unexpectedly, targeting CCL20 by siRNA, blocking antibodies or by downregulation of the sole CCL20 receptor CCR6 had no effect on PDAC cell death or cancer cell migration, arguing against an autocrine role of CCL20 in PDAC. However, by using an ex vivo indirect co-culture system we were able to show that CCL20 acts paracrine to recruit immune cells. Importantly, CCL20-recruited immune cells further increase TRAIL resistance of CCL20-producing PDAC cells. In conclusion, our data show a functional role of a RelA-CCL20 pathway in PDAC TRAIL resistance. We demonstrate how the therapy-induced cross-talk of cancer cells with immune cells affects treatment responses, knowledge needed to tailor novel bi-specific treatments, which target tumor cell as well as immune cells.
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Affiliation(s)
- Claudia Geismann
- Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany
| | - Frauke Grohmann
- Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany
| | - Anita Dreher
- Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany
| | - Robert Häsler
- Institute of Clinical Molecular Biology, UKSH Campus Kiel, Germany
| | | | - Karen Legler
- Division of Molecular Oncology, Institute for Experimental Cancer Research, UKSH Campus Kiel, Kiel, Germany
| | | | | | - Bence Sipos
- Institute of Pathology, University Hospital Tübingen, Tübingen, Germany
| | - Stefan Schreiber
- Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany; Institute of Clinical Molecular Biology, UKSH Campus Kiel, Germany
| | - Andreas Linkermann
- Clinic for Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany
| | - Zonera Hassan
- Technische Universität München, Klinikum rechts der Isar, II. Medizinische Klinik, Munich, Germany
| | - Günter Schneider
- Technische Universität München, Klinikum rechts der Isar, II. Medizinische Klinik, Munich, Germany
| | - Heiner Schäfer
- Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany; Institute of Experimental Cancer Research, UKSH Campus Kiel, Germany
| | - Alexander Arlt
- Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany.
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45
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Nedaeinia R, Manian M, Jazayeri MH, Ranjbar M, Salehi R, Sharifi M, Mohaghegh F, Goli M, Jahednia SH, Avan A, Ghayour-Mobarhan M. Circulating exosomes and exosomal microRNAs as biomarkers in gastrointestinal cancer. Cancer Gene Ther 2017; 24:48-56. [PMID: 27982021 DOI: 10.1038/cgt.2016.77] [Citation(s) in RCA: 157] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 11/13/2016] [Accepted: 11/14/2016] [Indexed: 02/07/2023]
Abstract
The most important biological function of exosomes is their possible use as biomarkers in clinical diagnosis. Compared with biomarkers identified in conventional specimens such as serum or urine, exosomal biomarkers provide the highest amount of sensitivity and specificity, which can be attributed to their excellent stability. Exosomes, which harbor different types of proteins, nucleic acids and lipids, are present in almost all bodily fluids. The molecular constituents of exosomes, especially exosomal proteins and microRNAs (miRNAs), are promising as biomarkers in clinical diagnosis. This discovery that exosomes also contain messenger RNAs and miRNAs shows that they could be carriers of genetic information. Although the majority of RNAs found in exosomes are degraded RNA fragments with a length of <200 nucleotides, some full-length RNAs might be present that may affect protein production in the recipient cell. In addition, exosomal miRNAs have been found to be associated with certain diseases. Several studies have pointed out miRNA contents of circulating exosomes that are similar to those of originating cancer cells. In this review, the recent advances in circulating exosomal miRNAs as biomarkers in gastrointestinal cancers are discussed. These studies indicated that miRNAs can be detected in exosomes isolated from body fluids such as saliva, which suggests potential advantages of using exosomal miRNAs as noninvasive novel biomarkers.
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Affiliation(s)
- R Nedaeinia
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Biotechnology, Student Research Committee, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - M Manian
- Immunology Research Center, Department of Immunology, Iran University of Medical Science, Tehran, Iran
| | - M H Jazayeri
- Immunology Research Center, Department of Immunology, Iran University of Medical Science, Tehran, Iran
| | - M Ranjbar
- Deputy of Food and Drug, Department of Food Control Administration, Isfahan University of Medical Sciences, Isfahan, Iran
| | - R Salehi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - M Sharifi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - F Mohaghegh
- Department of Radiotherapy, Arak University of Medical Sciences, Arak, Iran
| | - M Goli
- Department of Food Science and Technology, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran
| | - S H Jahednia
- Department of Immunology, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - A Avan
- Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - M Ghayour-Mobarhan
- Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Biochemistry of Nutrition Research Center, Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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46
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Lin SS, Li FF, Sun L, Fan W, Gu M, Zhang LY, Qin S, Yuan ST. Marsdenia tenacissima extract suppresses A549 cell migration through regulation of CCR5-CCL5 axis, Rho C, and phosphorylated FAK. Chin J Nat Med 2016; 14:203-9. [PMID: 27025367 DOI: 10.1016/s1875-5364(16)30017-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Indexed: 12/14/2022]
Abstract
Marsdenia tenacissima, a traditional Chinese medicine, is long been used to treat various diseases including asthma, cancer, trachitis, tonsillitis, pharyngitis, cystitis, and pneumonia. Although Marsdenia tenacissima has been demonstrated to have strong anti-tumor effects against primary tumors, its effect on cancer metastasis remains to be defined, and the molecular mechanism underlying the anti-metastatic effect is unknown. In the present study, we investigated the effects of XAP (an extract of Marsdenia tenacissima) on A549 lung cancer cell migration and explored the role of CCR5-CCL5 axis in the anti-metastatic effects of XAP. Our resutls showed that XAP inhibited A549 lung cancer cell migration and invasion in a dose-dependent manner. The protein levels of CCR5, but not CCR9 and CXCR4, were decreased by XAP. The secretion of CCL5, the ligand of CCR5, was reduced by XAP. XAP down-regulated Rho C expression and FAK phosphorylation. In conclusion, XAP inhibited A549 cell migration and invasion through down-regulation of CCR5-CCL5 axis, Rho C, and FAK.
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Affiliation(s)
- Sen-Sen Lin
- New Drug Screen Center, China Pharmaceutical University, Nanjing 210009, China
| | - Fang-Fang Li
- New Drug Screen Center, China Pharmaceutical University, Nanjing 210009, China
| | - Li Sun
- New Drug Screen Center, China Pharmaceutical University, Nanjing 210009, China.
| | - Wei Fan
- New Drug Screen Center, China Pharmaceutical University, Nanjing 210009, China
| | - Ming Gu
- New Drug Screen Center, China Pharmaceutical University, Nanjing 210009, China
| | - Lu-Yong Zhang
- New Drug Screen Center, China Pharmaceutical University, Nanjing 210009, China
| | - Song Qin
- Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing, 210046, China
| | - Sheng-Tao Yuan
- New Drug Screen Center, China Pharmaceutical University, Nanjing 210009, China.
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47
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Lacalle RA, Blanco R, Carmona-Rodríguez L, Martín-Leal A, Mira E, Mañes S. Chemokine Receptor Signaling and the Hallmarks of Cancer. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2016; 331:181-244. [PMID: 28325212 DOI: 10.1016/bs.ircmb.2016.09.011] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The chemokines are a family of chemotactic cytokines that mediate their activity by acting on seven-transmembrane-spanning G protein-coupled receptors. Both the ability of the chemokines and their receptors to form homo- and heterodimers and the promiscuity of the chemokine-chemokine receptor interaction endow this protein family with enormous signaling plasticity and complexity that are not fully understood at present. Chemokines were initially identified as essential regulators of homeostatic and inflammatory trafficking of innate and adaptive leucocytes from lymphoid organs to tissues. Chemokines also mediate the host response to cancer. Nevertheless, chemokine function in this response is not limited to regulating leucocyte infiltration into the tumor microenvironment. It is now known that chemokines and their receptors influence most-if not all-hallmark processes of cancer; they act on both neoplastic and untransformed cells in the tumor microenvironment, including fibroblasts, endothelial cells (blood and lymphatic), bone marrow-derived stem cells, and, obviously, infiltrating leucocytes. This review begins with an overview of chemokine and chemokine receptor structure, to better define how chemokines affect the proliferation, survival, stemness, and metastatic potential of neoplastic cells. We also examine the main mechanisms by which chemokines regulate tumor angiogenesis and immune cell infiltration, emphasizing the pro- and antitumorigenic activity of this protein superfamily in these interrelated processes.
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Affiliation(s)
- R A Lacalle
- Centro Nacional de Biotecnología/CSIC, Madrid, Spain
| | - R Blanco
- Centro Nacional de Biotecnología/CSIC, Madrid, Spain
| | | | - A Martín-Leal
- Centro Nacional de Biotecnología/CSIC, Madrid, Spain
| | - E Mira
- Centro Nacional de Biotecnología/CSIC, Madrid, Spain
| | - S Mañes
- Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
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48
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Roy I, Getschman AE, Volkman BF, Dwinell MB. Exploiting agonist biased signaling of chemokines to target cancer. Mol Carcinog 2016; 56:804-813. [PMID: 27648825 DOI: 10.1002/mc.22571] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Revised: 09/12/2016] [Accepted: 09/16/2016] [Indexed: 12/20/2022]
Abstract
As knowledge of growth-independent functions of cancer cells is expanding, exploration into the role of chemokines in modulating cancer pathogenesis, particularly metastasis, continues to develop. However, more study into the mechanisms whereby chemokines direct the migration of cancer cells is needed before specific therapies can be generated to target metastasis. Herein, we draw attention to the longstanding conundrum in the field of chemokine biology that chemokines stimulate migration in a biphasic manner; and explore this phenomenon's impact on chemokine function in the context of cancer. Typically, low concentrations of chemokines lead to chemotactic migration and higher concentrations halt migration. The signaling mechanisms that govern this phenomenon remain unclear. Over the last decade, we have defined a novel signaling mechanism for regulation of chemokine migration through ligand oligomerization and biased agonist signaling. We provide insight into this new paradigm for chemokine signaling and discuss how it will impact future exploration into chemokine function and biology. In the pursuit of producing more novel cancer therapies, we suggest a framework for pharmaceutical application of the principles of chemokine oligomerization and biased agonist signaling in cancer. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Ishan Roy
- Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Anthony E Getschman
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Brian F Volkman
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Michael B Dwinell
- Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin.,MCW Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin
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49
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Mejía-Rangel J, Córdova E, Orozco L, Ventura-Gallegos JL, Mitre-Aguilar I, Escalona-Guzmán A, Vadillo F, Vázquez-Prado J, Gariglio P, Zentella-Dehesa A. Pro-adhesive phenotype of normal endothelial cells responding to metastatic breast cancer cell conditioned medium is linked to NFκB-mediated transcriptomic regulation. Int J Oncol 2016; 49:2173-2185. [DOI: 10.3892/ijo.2016.3705] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 07/26/2016] [Indexed: 11/06/2022] Open
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50
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Fabre J, Giustiniani J, Garbar C, Antonicelli F, Merrouche Y, Bensussan A, Bagot M, Al-Dacak R. Targeting the Tumor Microenvironment: The Protumor Effects of IL-17 Related to Cancer Type. Int J Mol Sci 2016; 17:ijms17091433. [PMID: 27589729 PMCID: PMC5037712 DOI: 10.3390/ijms17091433] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 08/10/2016] [Accepted: 08/24/2016] [Indexed: 12/25/2022] Open
Abstract
The inflammatory process contributes to immune tolerance as well as to tumor progression and metastasis. By releasing extracellular signals, cancerous cells constantly shape their surrounding microenvironment through their interactions with infiltrating immune cells, stromal cells and components of extracellular matrix. Recently, the pro-inflammatory interleukin 17 (IL-17)-producing T helper lymphocytes, the Th17 cells, and the IL-17/IL-17 receptor (IL-17R) axis gained special attention. The IL-17 family comprises at least six members, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F. Secreted as disulfide-linked homo- or heterodimers, the IL-17 bind to the IL-17R, a type I cell surface receptor, of which there are five variants, IL-17RA to IL-17RE. This review focuses on the current advances identifying the promoting role of IL-17 in carcinogenesis, tumor metastasis and resistance to chemotherapy of diverse solid cancers. While underscoring the IL-17/IL-17R axis as promising immunotherapeutic target in the context of cancer managing, this knowledge calls upon further in vitro and in vivo studies that would allow the development and implementation of novel strategies to combat tumors.
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Affiliation(s)
- Joseph Fabre
- Institut Jean Godinot, Unicancer, 1 rue du Général Koenig, F-51726 Reims, France.
- Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51 rue Cognacq-Jay, F-51095 Reims, France.
- Centre Hospitalo-Universitaire Henri Mondor, Service de Radiothérapie, 51 Avenue du Maréchal de Lattre de Tassigny, F-94010 Créteil, France.
| | - Jerome Giustiniani
- Institut Jean Godinot, Unicancer, 1 rue du Général Koenig, F-51726 Reims, France.
- Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51 rue Cognacq-Jay, F-51095 Reims, France.
| | - Christian Garbar
- Institut Jean Godinot, Unicancer, 1 rue du Général Koenig, F-51726 Reims, France.
- Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51 rue Cognacq-Jay, F-51095 Reims, France.
| | - Frank Antonicelli
- Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51 rue Cognacq-Jay, F-51095 Reims, France.
| | - Yacine Merrouche
- Institut Jean Godinot, Unicancer, 1 rue du Général Koenig, F-51726 Reims, France.
- Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, 51 rue Cognacq-Jay, F-51095 Reims, France.
| | - Armand Bensussan
- Institut National de la Santé et de la Recherche Médicale (INSERM) U976, Hôpital Saint Louis, F-75010 Paris, France.
- Université Paris Diderot, Sorbonne Paris Cité, Laboratoire Immunologie Dermatologie & Oncologie, UMR-S 976, F-75475 Paris, France.
- OREGA Biotech, 69130 Ecully, France.
| | - Martine Bagot
- Institut National de la Santé et de la Recherche Médicale (INSERM) U976, Hôpital Saint Louis, F-75010 Paris, France.
- Université Paris Diderot, Sorbonne Paris Cité, Laboratoire Immunologie Dermatologie & Oncologie, UMR-S 976, F-75475 Paris, France.
| | - Reem Al-Dacak
- Université Paris Diderot, Sorbonne Paris Cité, Laboratoire Immunologie Dermatologie & Oncologie, UMR-S 976, F-75475 Paris, France.
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