|
1
|
Qi L, Zhang C, Liu Y, Li W, Ren J, Zhao M. Plasma proteomes and metabolism with genome-wide association data for causal effect identification in ovarian cancer. Discov Oncol 2025; 16:388. [PMID: 40131661 PMCID: PMC11936866 DOI: 10.1007/s12672-025-02087-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 03/06/2025] [Indexed: 03/27/2025] Open
Abstract
BACKGROUND This study seeks to investigate the relationship between plasma metabolites or proteins and the risk of ovarian cancer through Mendelian randomization analysis and construct, while also developing a predictive model for resistance to chemotherapy. METHODOLOGY/PRINCIPAL FINDINGS Appropriate SNPs from GWAS data were selected as instrumental variables. Multiple methods, such as IVW, MR-Egger regression, and WME, were employed to investigate the causal relationship. A predictive model was established utilizing binary logistic regression based on the identified plasma protein genes. Four plasma metabolites and four plasma proteins were recognized as risk factors for ovarian cancer, whereas four plasma proteins were identified as protective factors. A predictive model for chemotherapy resistance was formulated with an AUC of 0.844 (p = 0.002). CONCLUSIONS Plasma metabolites and proteins may affect the risk of ovarian cancer and its resistance to chemotherapy. This study presents potential predictive factors and the underlying mechanisms influencing the onset, progression, and resistance of the disease.
Collapse
Affiliation(s)
- Lin Qi
- Department of Gynecology and Obstetrics, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong, People's Republic of China
| | - Cheng Zhang
- Department of Gynecology and Obstetrics, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong, People's Republic of China
| | - Yinuo Liu
- Qingdao Medical College of Qingdao University, Qingdao, Shandong, People's Republic of China
| | - Wenshu Li
- Department of Gynecology and Obstetrics, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong, People's Republic of China
| | - Jingjing Ren
- Department of Gynecology, The Women and Children's Hospital of Qingdao University, Qingdao, Shandong, People's Republic of China.
| | - Manyin Zhao
- Department of Gynecology and Obstetrics, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong, People's Republic of China.
| |
Collapse
|
|
2
|
Zhang X, Li B, Lan T, Chiari C, Ye X, Wang K, Chen J. The role of interleukin-17 in inflammation-related cancers. Front Immunol 2025; 15:1479505. [PMID: 39906741 PMCID: PMC11790576 DOI: 10.3389/fimmu.2024.1479505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 12/27/2024] [Indexed: 02/06/2025] Open
Abstract
Emerging evidence indicates a correlation between inflammation and the development and progression of cancer. Among the various inflammatory signals, interleukin-17 (IL-17) family cytokines serve as a critical link between inflammation and cancer. IL-17 is a highly versatile pro-inflammatory cytokine that plays a pivotal role in host defense, tissue repair, the pathogenesis of inflammatory diseases, and cancer progression. During the early stages of tumorigenesis, IL-17 signaling directly promotes the proliferation of tumor cells. Conversely, IL-17 has been shown to exhibit antitumor immunity in several models of grafted subcutaneous tumors. Additionally, dynamic changes in the microbiome can influence the secretion of IL-17, thereby affecting tumor development. The specific role of IL-17 is contingent upon its functional classification, spatiotemporal characteristics, and the stage of tumor development. In this review, we introduce the fundamental biology of IL-17 and the expression profile of its receptors in cancer, while also reviewing and discussing recent advancements regarding the pleiotropic effects and mechanisms of IL-17 in inflammation-related cancers. Furthermore, we supplement our discussion with insights into the mechanisms by which IL-17 impacts cancer progression through interactions with the microbiota, and we explore the implications of IL-17 in cancer therapy. This comprehensive analysis aims to enhance our understanding of IL-17 and its potential role in cancer treatment.
Collapse
Affiliation(s)
- Xingru Zhang
- The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan Hospital of Traditional Chinese Medicine, Foshan, Guangdong, China
- Department of Pharmacology, School of Life Sciences and Biopharmaceutical Science, Shenyang Pharmaceutical University, Shenyang, China
| | - Bangjie Li
- The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan Hospital of Traditional Chinese Medicine, Foshan, Guangdong, China
| | - Tian Lan
- The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan Hospital of Traditional Chinese Medicine, Foshan, Guangdong, China
- Department of Pharmacology, School of Life Sciences and Biopharmaceutical Science, Shenyang Pharmaceutical University, Shenyang, China
| | - Conner Chiari
- Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT, United States
| | - Xiaoyang Ye
- College of Engineering, Northeastern University, Seattle, WA, United States
| | - Kepeng Wang
- Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT, United States
| | - Ju Chen
- The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan Hospital of Traditional Chinese Medicine, Foshan, Guangdong, China
| |
Collapse
|
|
3
|
Ye Y, Yu S, Guo T, Zhang S, Shen X, Han G. Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer Management: Opportunities and Challenges. Biomolecules 2024; 14:1523. [PMID: 39766230 PMCID: PMC11673737 DOI: 10.3390/biom14121523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 11/07/2024] [Accepted: 11/25/2024] [Indexed: 01/11/2025] Open
Abstract
Lung cancer, the leading cause of death worldwide, is associated with the highest morbidity. Non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer cases. Advances in the domain of cancer treatment have improved the prognosis and quality of life of patients with metastatic NSCLC. Nevertheless, tumor progression or metastasis owing to treatment failure caused by primary or secondary drug resistance remains the cause of death in the majority of cases. Epithelial-mesenchymal transition (EMT), a vital biological process wherein epithelial cancer cells lose their inherent adhesion and transform into more invasive mesenchymal-like cells, acts as a powerful engine driving tumor metastasis. EMT can also induce immunosuppression in the tumor environment, thereby promoting cancer development and poor prognosis among patients with NSCLC. This review aims to elucidate the effect of EMT on metastasis and the tumor immune microenvironment. Furthermore, it explores the possible roles of EMT inhibition in improving the treatment efficacy of NSCLC. Targeting EMT may be an ideal mechanism to inhibit tumor growth and progression at multiple steps.
Collapse
Affiliation(s)
- Yunyao Ye
- Department of Oncology, Taizhou People’s Hospital Affiliated to Nanjing Medical University, Taizhou 225300, China; (Y.Y.); (S.Y.); (S.Z.); (X.S.)
| | - Shanxun Yu
- Department of Oncology, Taizhou People’s Hospital Affiliated to Nanjing Medical University, Taizhou 225300, China; (Y.Y.); (S.Y.); (S.Z.); (X.S.)
| | - Ting Guo
- Central Lab, Taizhou People’s Hospital Affiliated to Nanjing Medical University, Taizhou 225300, China;
| | - Sihui Zhang
- Department of Oncology, Taizhou People’s Hospital Affiliated to Nanjing Medical University, Taizhou 225300, China; (Y.Y.); (S.Y.); (S.Z.); (X.S.)
| | - Xiaozhou Shen
- Department of Oncology, Taizhou People’s Hospital Affiliated to Nanjing Medical University, Taizhou 225300, China; (Y.Y.); (S.Y.); (S.Z.); (X.S.)
| | - Gaohua Han
- Department of Oncology, Taizhou People’s Hospital Affiliated to Nanjing Medical University, Taizhou 225300, China; (Y.Y.); (S.Y.); (S.Z.); (X.S.)
| |
Collapse
|
|
4
|
Alexandru I, Davidescu L, Motofelea AC, Ciocarlie T, Motofelea N, Costachescu D, Marc MS, Suppini N, Șovrea AS, Coșeriu RL, Bondor DA, Bobeică LG, Crintea A. Emerging Nanomedicine Approaches in Targeted Lung Cancer Treatment. Int J Mol Sci 2024; 25:11235. [PMID: 39457017 PMCID: PMC11508987 DOI: 10.3390/ijms252011235] [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: 07/30/2024] [Revised: 10/15/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
Lung cancer, the leading cause of cancer-related deaths worldwide, is characterized by its aggressive nature and poor prognosis. As traditional chemotherapy has the disadvantage of non-specificity, nanomedicine offers innovative approaches for targeted therapy, particularly through the development of nanoparticles that can deliver therapeutic agents directly to cancer cells, minimizing systemic toxicity and enhancing treatment efficacy. VEGF and VEGFR are shown to be responsible for activating different signaling cascades, which will ultimately enhance tumor development, angiogenesis, and metastasis. By inhibiting VEGF and VEGFR signaling pathways, these nanotherapeutics can effectively disrupt tumor angiogenesis and proliferation. This review highlights recent advancements in nanoparticle design, including lipid-based, polymeric, and inorganic nanoparticles, and their clinical implications in improving lung cancer outcomes, exploring the role of nanomedicine in lung cancer diagnoses and treatment.
Collapse
Affiliation(s)
- Isaic Alexandru
- Department X of General Surgery, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| | - Lavinia Davidescu
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Alexandru Cătălin Motofelea
- Department of Internal Medicine, Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| | - Tudor Ciocarlie
- Department VII Internal Medicine II, Discipline of Cardiology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| | - Nadica Motofelea
- Department of Obstetrics and Gynecology, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania;
| | - Dan Costachescu
- Radiology Department, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| | - Monica Steluta Marc
- Discipline of Pulmonology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania; (M.S.M.); (N.S.)
| | - Noemi Suppini
- Discipline of Pulmonology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania; (M.S.M.); (N.S.)
| | - Alina Simona Șovrea
- Department of Morphological Sciences, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania;
| | - Răzvan-Lucian Coșeriu
- Department of Microbiology, University of Medicine, Pharmacy, Science and Technology “George Emil Palade”, 540142 Târgu-Mures, Romania;
| | - Daniela-Andreea Bondor
- Department of Medical Biochemistry, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (D.-A.B.); (L.-G.B.); (A.C.)
| | - Laura-Gabriela Bobeică
- Department of Medical Biochemistry, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (D.-A.B.); (L.-G.B.); (A.C.)
| | - Andreea Crintea
- Department of Medical Biochemistry, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (D.-A.B.); (L.-G.B.); (A.C.)
| |
Collapse
|
|
5
|
Zhang C, Xu S, Hu R, Liu X, Yue S, Li X, Dai B, Liang C, Zhan C. Unraveling CCL20's role by regulating Th17 cell chemotaxis in experimental autoimmune prostatitis. J Cell Mol Med 2024; 28:e18445. [PMID: 38801403 PMCID: PMC11129727 DOI: 10.1111/jcmm.18445] [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: 10/31/2023] [Revised: 03/09/2024] [Accepted: 05/13/2024] [Indexed: 05/29/2024] Open
Abstract
Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS), a prevalent urological ailment, exerts a profound influence upon the well-being of the males. Autoimmunity driven by Th17 cells has been postulated as a potential factor in CP/CPPS pathogenesis. Nonetheless, elucidating the precise mechanisms governing Th17 cell recruitment to the prostate, triggering inflammation, remained an urgent inquiry. This study illuminated that CCL20 played a pivotal role in attracting Th17 cells to the prostate, thereby contributing to prostatitis development. Furthermore, it identified prostate stromal cells and immune cells as likely sources of CCL20. Additionally, this research unveiled that IL-17A, released by Th17 cells, could stimulate macrophages to produce CCL20 through the NF-κB/MAPK/PI3K pathway. The interplay between IL-17A and CCL20 establishes a positive feedback loop, which might serve as a critical mechanism underpinning the development of chronic prostatitis, thus adding complexity to its treatment challenges.
Collapse
Affiliation(s)
- Cheng Zhang
- Department of UrologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
- Institute of UrologyAnhui Medical UniversityHefeiChina
- Anhui Province Key Laboratory of Genitourinary DiseasesAnhui Medical UniversityHefeiChina
| | - Shun Xu
- Department of UrologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
- Institute of UrologyAnhui Medical UniversityHefeiChina
- Anhui Province Key Laboratory of Genitourinary DiseasesAnhui Medical UniversityHefeiChina
| | - Rui‐Jie Hu
- Department of UrologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
- Institute of UrologyAnhui Medical UniversityHefeiChina
- Anhui Province Key Laboratory of Genitourinary DiseasesAnhui Medical UniversityHefeiChina
| | - Xian‐Hong Liu
- Department of UrologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
- Institute of UrologyAnhui Medical UniversityHefeiChina
- Anhui Province Key Laboratory of Genitourinary DiseasesAnhui Medical UniversityHefeiChina
| | - Shao‐Yu Yue
- Department of UrologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
- Institute of UrologyAnhui Medical UniversityHefeiChina
- Anhui Province Key Laboratory of Genitourinary DiseasesAnhui Medical UniversityHefeiChina
| | - Xiao‐Ling Li
- Department of UrologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
- Institute of UrologyAnhui Medical UniversityHefeiChina
- Anhui Province Key Laboratory of Genitourinary DiseasesAnhui Medical UniversityHefeiChina
| | - Bang‐Shun Dai
- Department of UrologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
- Institute of UrologyAnhui Medical UniversityHefeiChina
- Anhui Province Key Laboratory of Genitourinary DiseasesAnhui Medical UniversityHefeiChina
| | - Chao‐Zhao Liang
- Department of UrologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
- Institute of UrologyAnhui Medical UniversityHefeiChina
- Anhui Province Key Laboratory of Genitourinary DiseasesAnhui Medical UniversityHefeiChina
| | - Chang‐Sheng Zhan
- Department of UrologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
- Institute of UrologyAnhui Medical UniversityHefeiChina
- Anhui Province Key Laboratory of Genitourinary DiseasesAnhui Medical UniversityHefeiChina
| |
Collapse
|
|
6
|
Xing J, Man C, Liu Y, Zhang Z, Peng H. Factors impacting the benefits and pathogenicity of Th17 cells in the tumor microenvironment. Front Immunol 2023; 14:1224269. [PMID: 37680632 PMCID: PMC10481871 DOI: 10.3389/fimmu.2023.1224269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 08/07/2023] [Indexed: 09/09/2023] Open
Abstract
Tumor development is closely associated with a complex tumor microenvironment, which is composed of tumor cells, blood vessels, tumor stromal cells, infiltrating immune cells, and associated effector molecules. T helper type 17 (Th17) cells, which are a subset of CD4+ T cells and are renowned for their ability to combat bacterial and fungal infections and mediate inflammatory responses, exhibit context-dependent effector functions. Within the tumor microenvironment, different molecular signals regulate the proliferation, differentiation, metabolic reprogramming, and phenotypic conversion of Th17 cells. Consequently, Th17 cells exert dual effects on tumor progression and can promote or inhibit tumor growth. This review aimed to investigate the impact of various alterations in the tumor microenvironment on the antitumor and protumor effects of Th17 cells to provide valuable clues for the exploration of additional tumor immunotherapy strategies.
Collapse
Affiliation(s)
- Jie Xing
- Department of Laboratory Medicine, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China
| | - Changfeng Man
- Department of Oncology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China
| | - Yingzhao Liu
- Department of Endocrinology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China
| | - Zhengdong Zhang
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
- Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Huiyong Peng
- Department of Laboratory Medicine, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China
- Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
7
|
Baran K, Kordiak J, Jabłoński S, Brzeziańska-Lasota E. Panel of miR-150 and linc00673, regulators of CCR6/CCL20 may serve as non-invasive diagnostic marker of non-small cell lung cancer. Sci Rep 2023; 13:9642. [PMID: 37316552 DOI: 10.1038/s41598-023-36485-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 06/05/2023] [Indexed: 06/16/2023] Open
Abstract
The C-C motif ligand 20 (CCL20) is a chemokine that specifically binds to the chemokine receptor 6 (CCR6) and the CCL20/CCR6 axis has been implicated in the non-small lung cancer (NSCLC) development and progression. Its expression is regulated by mutual interactions of non-coding RNAs (ncRNAs). This goals of presented study was to evaluate the expression level of CCR6/CCL20 mRNA in NSCLC tissue comparative to selected ncRNAs: miR-150, linc00673. The expression level of the studied ncRNAs was also assessed in serum extracellular vesicles (EVs). Thirty patients (n = 30) were enrolled as the study cohort. Total RNA was isolated from tumor tissue, adjacent macroscopically unchanged tissue and serum EVs. The expression level of studied genes and ncRNAs were estimated based on the qPCR method. Higher expression level of CCL20 mRNA but lower expression level of CCR6 mRNA were observed in tumor in comparison to control tissue. Relative to the smoking status, higher CCL20 (p < 0.05) and CCR6 mRNA (p > 0.05) expression levels were observed in current smokers than in never smokers. In serum EVs the expression level of miR-150 has a negative correlation with AJCC tumor staging, whereas the expression level of linc00673 positively correlated (p > 0.05). The lower expression level of miR-150 and higher expression level of linc00673 in serum EVs were observed in NSCLC patients with lymph nodes metastases (p > 0.05). Regarding the histopathological type, significantly lower expression level of miR-150 and higher expression level of linc00673 were observed in the serum EVs of patients with AC compared to patient with SCC. Our findings revealed that smoking significantly changed the expression level of CCL20 mRNA in NSCLC tissue. Changes in expression levels of miR-150 and linc00673 in the serum EVs of NSCLC patients in relation to presence of lymph node metastases and the stage of cancer development may serve as a non-invasive molecular biomarkers of tumor progression. Furthermore, expression levels of miR-150 and linc00673 may serve as non-intrusive diagnostic biomarkers differentiating adenocarcinoma from squamous cell carcinoma.
Collapse
Affiliation(s)
- Kamila Baran
- Department of Biomedicine and Genetics, Chair of Biology and Medical Microbiology, Medical University of Lodz, Lodz, Poland.
| | - Jacek Kordiak
- Department of Thoracic, General and Oncological Surgery, Medical University of Lodz, Lodz, Poland
| | - Sławomir Jabłoński
- Department of Thoracic, General and Oncological Surgery, Medical University of Lodz, Lodz, Poland
| | - Ewa Brzeziańska-Lasota
- Department of Biomedicine and Genetics, Chair of Biology and Medical Microbiology, Medical University of Lodz, Lodz, Poland
| |
Collapse
|
|
8
|
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.
Collapse
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
| |
Collapse
|
|
9
|
Marques HS, de Brito BB, da Silva FAF, Santos MLC, de Souza JCB, Correia TML, Lopes LW, Neres NSDM, Dórea RSDM, Dantas ACS, Morbeck LLB, Lima IS, de Almeida AA, Dias MRDJ, de Melo FF. Relationship between Th17 immune response and cancer. World J Clin Oncol 2021; 12:845-867. [PMID: 34733609 PMCID: PMC8546660 DOI: 10.5306/wjco.v12.i10.845] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/21/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
Cancer is the second leading cause of death worldwide and epidemiological projections predict growing cancer mortality rates in the next decades. Cancer has a close relationship with the immune system and, although Th17 cells are known to play roles in the immune response against microorganisms and in autoimmunity, studies have emphasized their roles in cancer pathogenesis. The Th17 immune response profile is involved in several types of cancer including urogenital, respiratory, gastrointestinal, and skin cancers. This type of immune response exerts pro and antitumor functions through several mechanisms, depending on the context of each tumor, including the protumor angiogenesis and exhaustion of T cells and the antitumor recruitment of T cells and neutrophils to the tumor microenvironment. Among other factors, the paradoxical behavior of Th17 cells in this setting has been attributed to its plasticity potential, which makes possible their conversion into other types of T cells such as Th17/Treg and Th17/Th1 cells. Interleukin (IL)-17 stands out among Th17-related cytokines since it modulates pathways and interacts with other cell profiles in the tumor microenvironment, which allow Th17 cells to prevail in tumors. Moreover, the IL-17 is able to mediate pro and antitumor processes that influence the development and progression of various cancers, being associated with variable clinical outcomes. The understanding of the relationship between the Th17 immune response and cancer as well as the singularities of carcinogenic processes in each type of tumor is crucial for the identification of new therapeutic targets.
Collapse
Affiliation(s)
- Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45083-900, Bahia, Brazil
| | - Breno Bittencourt de Brito
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Maria Luísa Cordeiro Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Júlio César Braga de Souza
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Thiago Macêdo Lopes Correia
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Luana Weber Lopes
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Nayara Silva de Macêdo Neres
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Anna Carolina Saúde Dantas
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Lorena Lôbo Brito Morbeck
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Iasmin Souza Lima
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Amanda Alves de Almeida
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Maiara Raulina de Jesus Dias
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| |
Collapse
|
|
10
|
Kryczka J, Kryczka J, Czarnecka-Chrebelska KH, Brzeziańska-Lasota E. Molecular Mechanisms of Chemoresistance Induced by Cisplatin in NSCLC Cancer Therapy. Int J Mol Sci 2021; 22:8885. [PMID: 34445588 PMCID: PMC8396273 DOI: 10.3390/ijms22168885] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 12/11/2022] Open
Abstract
Cancer cells utilise several mechanisms to increase their survival and progression as well as their resistance to anticancer therapy: deregulation of growth regulatory pathways by acquiring grow factor independence, immune system suppression, reducing the expression of antigens activating T lymphocyte cells (mimicry), induction of anti-apoptotic signals to counter the action of drugs, activation of several DNA repair mechanisms and driving the active efflux of drugs from the cell cytoplasm, and epigenetic regulation by microRNAs (miRNAs). Because it is commonly diagnosed late, lung cancer remains a major malignancy with a low five-year survival rate; when diagnosed, the cancer is often highly advanced, and the cancer cells may have acquired drug resistance. This review summarises the main mechanisms involved in cisplatin resistance and interactions between cisplatin-resistant cancer cells and the tumour microenvironment. It also analyses changes in the gene expression profile of cisplatin sensitive vs. cisplatin-resistant non-small cell lung cancer (NSCLC) cellular model using the GSE108214 Gene Expression Omnibus database. It describes a protein-protein interaction network that indicates highly dysregulated TP53, MDM2, and CDKN1A genes as they encode the top networking proteins that may be involved in cisplatin tolerance, these all being upregulated in cisplatin-resistant cells. Furthermore, it illustrates the multifactorial nature of cisplatin resistance by examining the diversity of dysregulated pathways present in cisplatin-resistant NSCLC cells based on KEGG pathway analysis.
Collapse
Affiliation(s)
- Jolanta Kryczka
- Department of Biomedicine and Genetics, Medical University of Lodz, 92-213 Lodz, Poland; (K.H.C.-C.); (E.B.-L.)
| | - Jakub Kryczka
- Institute of Medical Biology, Polish Academy of Sciences, 93-232 Lodz, Poland;
| | | | - Ewa Brzeziańska-Lasota
- Department of Biomedicine and Genetics, Medical University of Lodz, 92-213 Lodz, Poland; (K.H.C.-C.); (E.B.-L.)
| |
Collapse
|
|
11
|
Jin L, Cao L, Zhu Y, Cao J, Li X, Zhou J, Liu B, Zhao T. Enhance anti-lung tumor efficacy of chimeric antigen receptor-T cells by ectopic expression of C-C motif chemokine receptor 6. Sci Bull (Beijing) 2021; 66:803-812. [PMID: 36654137 DOI: 10.1016/j.scib.2020.12.027] [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: 05/21/2020] [Revised: 08/21/2020] [Accepted: 10/13/2020] [Indexed: 01/20/2023]
Abstract
Chimeric antigen receptor-T (CAR-T) cells have limited therapeutic efficacy against solid tumors, partially due to their limited ability to reach and invade into the neoplastic foci. By gene expression profiling interactive analysis, we identified that the C-C motif chemokine ligand (CCL) 20 is highly expressed in lung and other most incidence and/or mortality cancers such as colon, rectum, stomach, and liver cancers. Forced expression of C-C motif chemokine receptor 6 (CCR6), the biunique receptor of CCL20, results in robust trafficking of CAR-T cells toward CCL20-secreting tumor cells. In a lung cancer xenograft mouse model, CCR6-expressing CAR-T cells efficiently migrate to and infiltrate into solid tumors upon infusion, leading to effective tumor clearance and significantly prolonged survival of tumor-bearing mice. In addition, culturing CCR6-CAR-T cells with interleukin (IL)-7 and IL-15 further improved their anti-lung cancer activity. Our findings provide supporting evidence for the clinical development of chemokine receptor-engineered CAR-T cells for solid tumor immunotherapy.
Collapse
Affiliation(s)
- Liyuan Jin
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Lei Cao
- Department of Thoracic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yingjie Zhu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jiani Cao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Xiaoyan Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Jianxia Zhou
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Bing Liu
- State Key Laboratory of Proteomics, Translational Medicine Center of Stem Cells, 307-Ivy Translational Medicine Center, Laboratory of Oncology, Affiliated Hospital, Academy of Military Medical Sciences, Beijing 100071, China
| | - Tongbiao Zhao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| |
Collapse
|
|
12
|
Cendrowicz E, Sas Z, Bremer E, Rygiel TP. The Role of Macrophages in Cancer Development and Therapy. Cancers (Basel) 2021; 13:1946. [PMID: 33919517 PMCID: PMC8073377 DOI: 10.3390/cancers13081946] [Citation(s) in RCA: 216] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/13/2021] [Accepted: 04/15/2021] [Indexed: 02/06/2023] Open
Abstract
Macrophages are critical mediators of tissue homeostasis and influence various aspects of immunity. Tumor-associated macrophages are one of the main cellular components of the tumor microenvironment. Depending on their activation status, macrophages can exert a dual influence on tumorigenesis by either antagonizing the cytotoxic activity of immune cells or, less frequently, by enhancing antitumor responses. In most situations, TAMs suppress T cell recruitment and function or regulate other aspects of tumor immunity. The importance of TAMs targeting in cancer therapy is derived from the strong association between the high infiltration of TAMs in the tumor tissue with poor patient prognosis. Several macrophage-targeting approaches in anticancer therapy are developed, including TAM depletion, inhibition of new TAM differentiation, or re-education of TAM activation for cancer cell phagocytosis. In this review, we will describe the role of TAMs in tumor development, including such aspects as protumorigenic inflammation, immune suppression, neoangiogenesis, and enhancement of tissue invasion and distant metastasis. Furthermore, we will discuss therapeutic approaches that aim to deplete TAMs or, on the contrary, re-educate TAMs for cancer cell phagocytosis and antitumor immunity.
Collapse
Affiliation(s)
- Ewa Cendrowicz
- Department of Hematology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (E.C.); (E.B.)
| | - Zuzanna Sas
- Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, Building F, 02-097 Warsaw, Poland;
| | - Edwin Bremer
- Department of Hematology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (E.C.); (E.B.)
| | - Tomasz P. Rygiel
- Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, Building F, 02-097 Warsaw, Poland;
| |
Collapse
|
|
13
|
Recruitment and Expansion of Tregs Cells in the Tumor Environment-How to Target Them? Cancers (Basel) 2021; 13:cancers13081850. [PMID: 33924428 PMCID: PMC8069615 DOI: 10.3390/cancers13081850] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/04/2021] [Accepted: 04/08/2021] [Indexed: 12/22/2022] Open
Abstract
Simple Summary The immune response against cancer is generated by effector T cells, among them cytotoxic CD8+ T cells that destroy cancer cells and helper CD4+ T cells that mediate and support the immune response. This antitumor function of T cells is tightly regulated by a particular subset of CD4+ T cells, named regulatory T cells (Tregs), through different mechanisms. Even if the complete inhibition of Tregs would be extremely harmful due to their tolerogenic role in impeding autoimmune diseases in the periphery, the targeted blockade of their accumulation at tumor sites or their targeted depletion represent a major therapeutic challenge. This review focuses on the mechanisms favoring Treg recruitment, expansion and stabilization in the tumor microenvironment and the therapeutic strategies developed to block these mechanisms. Abstract Regulatory T cells (Tregs) are present in a large majority of solid tumors and are mainly associated with a poor prognosis, as their major function is to inhibit the antitumor immune response contributing to immunosuppression. In this review, we will investigate the mechanisms involved in the recruitment, amplification and stability of Tregs in the tumor microenvironment (TME). We will also review the strategies currently developed to inhibit Tregs’ deleterious impact in the TME by either inhibiting their recruitment, blocking their expansion, favoring their plastic transformation into other CD4+ T-cell subsets, blocking their suppressive function or depleting them specifically in the TME to avoid severe deleterious effects associated with Treg neutralization/depletion in the periphery and normal tissues.
Collapse
|
|
14
|
Mirlekar B, Pylayeva-Gupta Y. IL-12 Family Cytokines in Cancer and Immunotherapy. Cancers (Basel) 2021; 13:E167. [PMID: 33418929 PMCID: PMC7825035 DOI: 10.3390/cancers13020167] [Citation(s) in RCA: 168] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/22/2020] [Accepted: 12/29/2020] [Indexed: 12/16/2022] Open
Abstract
The IL-12 family cytokines are a group of unique heterodimeric cytokines that include IL-12, IL-23, IL-27, IL-35 and, most recently, IL-39. Recent studies have solidified the importance of IL-12 cytokines in shaping innate and adaptive immune responses in cancer and identified multipronged roles for distinct IL-12 family members, ranging from effector to regulatory immune functions. These cytokines could serve as promising candidates for the development of immunomodulatory therapeutic approaches. Overall, IL-12 can be considered an effector cytokine and has been found to engage anti-tumor immunity by activating the effector Th1 response, which is required for the activation of cytotoxic T and NK cells and tumor clearance. IL-23 and IL-27 play dual roles in tumor immunity, as they can both activate effector immune responses and promote tumor growth by favoring immune suppression. IL-35 is a potent regulatory cytokine and plays a largely pro-tumorigenic role by inhibiting effector T cells. In this review, we summarize the recent findings on IL-12 family cytokines in the control of tumor growth with an emphasis primarily on immune regulation. We underscore the clinical implications for the use of these cytokines either in the setting of monotherapy or in combination with other conventional therapies for the more effective treatment of malignancies.
Collapse
Affiliation(s)
- Bhalchandra Mirlekar
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA;
| | - Yuliya Pylayeva-Gupta
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA;
- Department of Genetics, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA
| |
Collapse
|
|
15
|
Duan J, Pan Y, Yang X, Zhong L, Jin Y, Xu J, Zhuang J, Han S. Screening of T Cell-Related Long Noncoding RNA-MicroRNA-mRNA Regulatory Networks in Non-Small-Cell Lung Cancer. BIOMED RESEARCH INTERNATIONAL 2020; 2020:5816763. [PMID: 33274216 PMCID: PMC7684158 DOI: 10.1155/2020/5816763] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 10/14/2020] [Accepted: 10/28/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Lung cancer (LC) has the highest mortality rate among all the other types of cancer in the world. T cells are known to be the key factor in inducing the immune response during LC. OBJECTIVE In this study, we aimed to screen and analyze RNAs associated with CD8(+) T cells and activated memory CD4(+) T cells in lung adenocarcinomas, a subtype of non-small-cell lung cancer (NSCLC-LUAD). METHODS Gene expression RNA-seq data and clinical data of NSCLC-LUAD were downloaded from the XENA database. The data were divided into low scores and high scores based on the Stromal and Immune scores. Then, all the genes were screened for identifying those specifically associated with CD8(+) T cells and activated memory CD4(+) T cells. The screened genes were used for the construction of the protein-protein interaction (PPI) network and for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis along with prognosis analysis. Based on the results of the prognostic analysis, the prognostic-related genes were used to analyze long noncoding (lnc)RNA-micro(mi)RNA-mRNA networks and to predict small chemical molecules. RESULTS According to the Immune and Stromal scores, a total of 885 upregulated and 29 downregulated RNAs were identified. A total of 90 differentially expressed genes (DEGs) were found to be related to CD8(+) T immune cells, and 48 DEGs were related to activated memory CD4(+) T cells. GPR174 and CD226 suggested a favorable prognosis. For CD8(+) and activated memory CD4(+) T cells, 112 and 113 PPI edges were obtained, respectively. GPR174 was found to be regulated by hsa-miR-19b-5p and hsa-miR-19b-2-5p, and both of these two miRNAs were regulated by lncRNA PCED1B-AS1. CD226 was regulated by hsa-miR-379-5p, which was in turn regulated by lncRNA RP11-81H14.2. CONCLUSION Our findings provide a deeper understanding of the T cell-related ceRNA regulatory mechanism in NSCLC-LUAD pathogenesis.
Collapse
Affiliation(s)
- Jinlong Duan
- Department of Oncology, Huzhou Hospital of Traditional Chinese Medicine, No. 315 South Street, Huzhou, Zhejiang Province, China 313000
| | - Yuefen Pan
- Department of Oncology, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No. 1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, China 313000
| | - Xi Yang
- Department of Oncology, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No. 1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, China 313000
| | - Liping Zhong
- Department of Oncology, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No. 1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, China 313000
| | - Yin Jin
- Department of Laboratory Medicine, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No. 1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, China 313000
| | - Jiamin Xu
- Graduate School of Nursing, Huzhou University, Huzhou, Zhejiang, No. 1 Bachelor Road, Huzhou, Zhejiang Province, China 313000
| | - Jing Zhuang
- Graduate School of Nursing, Huzhou University, Huzhou, Zhejiang, No. 1 Bachelor Road, Huzhou, Zhejiang Province, China 313000
| | - Shuwen Han
- Department of Oncology, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No. 1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, China 313000
| |
Collapse
|
|
16
|
EGFR/Ras-induced CCL20 production modulates the tumour microenvironment. Br J Cancer 2020; 123:942-954. [PMID: 32601464 PMCID: PMC7493992 DOI: 10.1038/s41416-020-0943-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 04/07/2020] [Accepted: 05/28/2020] [Indexed: 12/14/2022] Open
Abstract
Background The activation of the EGFR/Ras-signalling pathway in tumour cells induces a distinct chemokine repertoire, which in turn modulates the tumour microenvironment. Methods The effects of EGFR/Ras on the expression and translation of CCL20 were analysed in a large set of epithelial cancer cell lines and tumour tissues by RT-qPCR and ELISA in vitro. CCL20 production was verified by immunohistochemistry in different tumour tissues and correlated with clinical data. The effects of CCL20 on endothelial cell migration and tumour-associated vascularisation were comprehensively analysed with chemotaxis assays in vitro and in CCR6-deficient mice in vivo. Results Tumours facilitate progression by the EGFR/Ras-induced production of CCL20. Expression of the chemokine CCL20 in tumours correlates with advanced tumour stage, increased lymph node metastasis and decreased survival in patients. Microvascular endothelial cells abundantly express the specific CCL20 receptor CCR6. CCR6 signalling in endothelial cells induces angiogenesis. CCR6-deficient mice show significantly decreased tumour growth and tumour-associated vascularisation. The observed phenotype is dependent on CCR6 deficiency in stromal cells but not within the immune system. Conclusion We propose that the chemokine axis CCL20–CCR6 represents a novel and promising target to interfere with the tumour microenvironment, and opens an innovative multimodal strategy for cancer therapy.
Collapse
|
|
17
|
Xu X, Wei T, Zhong W, Zhu Z, Liu F, Li Q. IL-17 regulates the expression of major histocompatibility complex II and VEGF in DLBCL mice on tumor growth. ACTA ACUST UNITED AC 2020. [DOI: 10.31491/apt.2020.06.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
|
|
18
|
Chao X, Yi L, Lan LL, Wei HY, Wei D. Long-term PM 2.5 exposure increases the risk of non-small cell lung cancer (NSCLC) progression by enhancing interleukin-17a (IL-17a)-regulated proliferation and metastasis. Aging (Albany NY) 2020; 12:11579-11602. [PMID: 32554855 PMCID: PMC7343463 DOI: 10.18632/aging.103319] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 04/28/2020] [Indexed: 05/03/2023]
Abstract
PM2.5 is a class of airborne particles and droplets with sustained high levels in many developing countries. Epidemiological studies have indicated that PM2.5 is closely associated with the increased morbidity and mortality of lung cancer in the world. Unfortunately, the effects of PM2.5 on lung cancer are largely unknown. In the present study, we attempted to explore the role of PM2.5 in the etiology of NSCLC. Here, we found that long-term PM2.5 exposure led to significant pulmonary injury. Epithelial-mesenchymal transition (EMT) and cancer stem cells (CSC) properties were highly induced by PM2.5 exposure. EMT was evidenced by the significant up-regulation of MMP2, MMP9, TGF-β1, α-SMA, Fibronectin and Vimentin. Lung cancer progression was associated with the increased expression of Kras, c-Myc, breast cancer resistance protein BCRP (ABCG2), OCT4, SOX2 and Aldh1a1, but the decreased expression of p53 and PTEN. Importantly, mice with IL-17a knockout (IL-17a-/-) showed significantly alleviated lung injury and CSC properties following PM2.5 exposure. Also, IL-17a-/--attenuated tumor growth was recovered in PM2.5-exposed mice injected with recombinant mouse IL-17a, accompanied with significantly restored lung metastasis. Taken together, these data revealed that PM2.5 could promote the progression of lung cancer by enhancing the proliferation and metastasis through IL-17a signaling.
Collapse
Affiliation(s)
- Xie Chao
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, P.R. China
| | - Liu Yi
- Centers of Disease Control and Prevention of Shandong Province, Jinan 250014, Shandong Province, P.R. China
| | - Li Lan Lan
- Affiliated Hospital of Binzhou Medical College, Binzhou 256603, Shandong Province, P.R. China
| | - Han Yun Wei
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Shihuan Province, P.R. China
| | - Dong Wei
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, P.R. China
| |
Collapse
|
|
19
|
Miyashita N, Horie M, Mikami Y, Urushiyama H, Fukuda K, Miyakawa K, Matsuzaki H, Makita K, Morishita Y, Harada H, Backman M, Lindskog C, Brunnström H, Micke P, Nagase T, Saito A. ASCL1 promotes tumor progression through cell-autonomous signaling and immune modulation in a subset of lung adenocarcinoma. Cancer Lett 2020; 489:121-132. [PMID: 32534174 DOI: 10.1016/j.canlet.2020.06.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/29/2020] [Accepted: 06/01/2020] [Indexed: 01/05/2023]
Abstract
The master regulator of neuroendocrine differentiation, achaete-scute complex homolog 1 (ASCL1) defines a subgroup of lung adenocarcinoma. However, the mechanistic role of ASCL1 in lung tumorigenesis and its relation to the immune microenvironment is principally unknown. Here, the immune landscape of ASCL1-positive lung adenocarcinomas was characterized by immunohistochemistry. Furthermore, ASCL1 was transduced in mouse lung adenocarcinoma cell lines and comparative RNA-sequencing and secretome analyses were performed. The effects of ASCL1 on tumorigenesis were explored in an orthotopic syngeneic transplantation model. ASCL1-positive lung adenocarcinomas revealed lower infiltration of CD8+, CD4+, CD20+, and FOXP3+ lymphocytes and CD163+ macrophages indicating an immune desert phenotype. Ectopic ASCL1 upregulated cyclin transcript levels, stimulated cell proliferation, and enhanced tumor growth in mice. ASCL1 suppressed secretion of chemokines, including CCL20, CXCL2, CXCL10, and CXCL16, indicating effects on immune cell trafficking. In accordance with lower lymphocytes infiltration, ASCL1-positive lung adenocarcinomas demonstrated lower abundance of CXCR3-and CCR6-expressing cells. In conclusion, ASCL1 mediates its tumor-promoting effect not only through cell-autonomous signaling but also by modulating chemokine production and immune responses. These findings suggest that ASCL1-positive tumors represent a clinically relevant lung cancer entity.
Collapse
Affiliation(s)
- Naoya Miyashita
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Masafumi Horie
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan; Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yu Mikami
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan; Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Hirokazu Urushiyama
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Kensuke Fukuda
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Kazuko Miyakawa
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Hirotaka Matsuzaki
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Kosuke Makita
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan; Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada
| | - Yasuyuki Morishita
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Hiroaki Harada
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Max Backman
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-75185, Uppsala, Sweden
| | - Cecilia Lindskog
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-75185, Uppsala, Sweden
| | - Hans Brunnström
- Lund University, Laboratory Medicine Region Skåne, Department of Clinical Sciences Lund, Pathology, SE-22185, Lund, Sweden
| | - Patrick Micke
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-75185, Uppsala, Sweden
| | - Takahide Nagase
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Akira Saito
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan; Division for Health Service Promotion, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
| |
Collapse
|
|
20
|
Armstrong D, Chang CY, Lazarus DR, Corry D, Kheradmand F. Lung Cancer Heterogeneity in Modulation of Th17/IL17A Responses. Front Oncol 2019; 9:1384. [PMID: 31921642 PMCID: PMC6914699 DOI: 10.3389/fonc.2019.01384] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 11/22/2019] [Indexed: 12/12/2022] Open
Abstract
The interplay between tumors and their immune microenvironment is critical for cancer development and progression. The discovery of tumor heterogeneity has provided a window into a complex interplay between tumors, their secreted products, and host immune responses at the cellular and molecular levels. Tumor heterogeneity can also act as a driving force in promoting treatment resistance and correlates with distinct tumor-mediated acquired immune responses. A prevailing question is how genetic aberrations in solid tumors can shape the immune landscape, resulting in pro-tumor or anti-tumor activities. Here we review evidence for clinical and pathophysiological mechanisms that underlie different types of non-small cell lung cancer (NSCLC) and provide new insights for future immunomodulatory-based therapies. Some of the more common driver mutations in NSCLC heterogeneity includes the opposing immune responses in oncogenic mutations in K-ras vs. non-K-ras models and their pro-inflammatory cytokines such as interleukin (IL)17A. We will discuss possible molecular and metabolic mechanisms that may govern the opposing immune responses observed in distinct genetic models of NSCLCs. A deeper understanding of how tumor heterogeneity modulates immune response can improve current therapeutic strategies and provide precise treatment to individual lung cancer patients.
Collapse
Affiliation(s)
- Dominique Armstrong
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Cheng-Yen Chang
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Donald R Lazarus
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States.,Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Department of Veterans Affairs, Houston, TX, United States
| | - David Corry
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States.,Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Department of Veterans Affairs, Houston, TX, United States.,Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, United States.,Biology of Inflammation Center, Baylor College of Medicine, Houston, TX, United States
| | - Farrah Kheradmand
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States.,Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Department of Veterans Affairs, Houston, TX, United States.,Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, United States.,Biology of Inflammation Center, Baylor College of Medicine, Houston, TX, United States
| |
Collapse
|
|
21
|
Evaluation of the relationship between the IL-17A gene expression level and regulatory miRNA-9 in relation to tumor progression in patients with non-small cell lung cancer: a pilot study. Mol Biol Rep 2019; 47:583-592. [PMID: 31707599 DOI: 10.1007/s11033-019-05164-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 10/24/2019] [Indexed: 12/30/2022]
Abstract
A pro-inflammatory cytokine, IL-17A, is associated with increased risk of developing numerous cancers, including non-small cell lung cancer (NSCLC). IL-17A is a target gene for miR-9. This encouraged us to analyze these two genes in terms of their usefulness as prognostic markers in NSCLC. The expression levels of IL-17A gene and miR-9 was assessed in 26 NSCLC tissue samples and 26 unchanged lung tissue adjacent to lung tumors (control tissue), using qPCR. In both tissue groups, a decreased expression of IL-17A was observed in 100% of samples. Increased expression of miRNA-9 was observed in 92% of tumor samples, and in 100% of control samples. Neither statistical differences in the level of expression IL-17A depending on the patient's age, gender, smoking status, nor histopathology of the cancer was found. Regarding the presence of nodule metastasis ('N' value in TNM classification), significantly lower expression level of IL-17A was observed in cN2 as compared with cN1 group. Additionally, statistically lower IL-17A expression was found in III versus II tumor stage (cAJCC classification). Significant negative correlation between both studied genes was revealed in SCC subgroup. This leads to the conclusion that miRNA-9 can regulate the expression of IL-17A as an IL-17A mRNA antagonistic mediator. Inhibition of proinflammatory action of IL-17A in correlation with tumor progression can be related to various activity of Th17 cells on cancer development according to its immunogenicity, and also may suggest suppressive role of IL-17A in tumor progression. However, because of low number of analyzed samples, further studies on the functional role of IL-17A in development and/or progression NSCLC seem warranted.
Collapse
|
|
22
|
Li Z, Qian J, Li J, Zhu C. Clinical Significance of Serum Chemokines in Esophageal Cancer. Med Sci Monit 2019; 25:5850-5855. [PMID: 31385574 PMCID: PMC6693365 DOI: 10.12659/msm.916846] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The aim of this study was to detect the expression levels of chemokines (CX3CL1, CXCL-11, CXCL-12, CCL3, CCL4, and CCL20) in the serum of esophageal cancer patients and a normal control group, and to explore the correlations of those expression levels with the pathological type, progression, and metastasis of esophageal cancer. MATERIAL AND METHODS A total of 50 normal people and 50 untreated patients initially diagnosed with esophageal cancer (including 17 cases of non-metastatic esophageal cancer, 33 cases of metastatic esophageal cancer, 36 cases of esophageal squamous cell carcinoma and 14 cases of esophageal adenocarcinoma) were collected. The liquid chip (Luminex) technology was applied to detect the expression levels of the above-mentioned serum chemokines in the two groups. The results were analyzed using Statistical Product and Service Solution 20.0 software. RESULTS The expression levels of CX3CL1, CXCL-12, and CCL20 in esophageal cancer group were evidently higher than those in normal control group (P<0.001, P<0.001 and P=0.003, respectively). There were no statistically significant differences in chemokine expressions between metastatic esophageal cancer group and non-metastatic esophageal cancer group (P>0.05). The expression level of serum CCL4 in esophageal adenocarcinoma group was remarkably higher than that in esophageal squamous cell carcinoma group [18.45 (11.94) versus 13.37 (9.29), Z=-2.039, P=0.031]. In esophageal cancer group and normal control group, the serum CX3CL1 was positively correlated with CCL20 (r=0.649, P<0.001, r=0.758, P<0.001). CONCLUSIONS The expressions of serum CX3CL1, CXCL-12, and CCL20 are increased markedly in the patients, which may promote the occurrence, development and metastasis of esophageal cancer.
Collapse
Affiliation(s)
- Zhixiang Li
- Department of Tumor Surgery, The 1st Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China (mainland)
| | - Jun Qian
- Department of Tumor Surgery, The 1st Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China (mainland)
| | - Jing Li
- Department of Tumor Surgery, The 1st Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China (mainland)
| | - Chao Zhu
- Department of Tumor Surgery, The 1st Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China (mainland)
| |
Collapse
|
|
23
|
Cooke M, Casado-Medrano V, Ann J, Lee J, Blumberg PM, Abba MC, Kazanietz MG. Differential Regulation of Gene Expression in Lung Cancer Cells by Diacyglycerol-Lactones and a Phorbol Ester Via Selective Activation of Protein Kinase C Isozymes. Sci Rep 2019; 9:6041. [PMID: 30988374 PMCID: PMC6465381 DOI: 10.1038/s41598-019-42581-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 03/29/2019] [Indexed: 02/06/2023] Open
Abstract
Despite our extensive knowledge on the biology of protein kinase C (PKC) and its involvement in disease, limited success has been attained in the generation of PKC isozyme-specific modulators acting via the C1 domain, the binding site for the lipid second messenger diacylglycerol (DAG) and the phorbol ester tumor promoters. Synthetic efforts had recently led to the identification of AJH-836, a DAG-lactone with preferential affinity for novel isozymes (nPKCs) relative to classical PKCs (cPKCs). Here, we compared the ability of AJH-836 and a prototypical phorbol ester (phorbol 12-myristate 13-acetate, PMA) to induce changes in gene expression in a lung cancer model. Gene profiling analysis using RNA-Seq revealed that PMA caused major changes in gene expression, whereas AJH-836 only induced a small subset of genes, thus providing a strong indication for a major involvement of cPKCs in their control of gene expression. MMP1, MMP9, and MMP10 were among the genes most prominently induced by PMA, an effect impaired by RNAi silencing of PKCα, but not PKCδ or PKCε. Comprehensive gene signature analysis and bioinformatics efforts, including functional enrichment and transcription factor binding site analyses of dysregulated genes, identified major differences in pathway activation and transcriptional networks between PMA and DAG-lactones. In addition to providing solid evidence for the differential involvement of individual PKC isozymes in the control of gene expression, our studies emphasize the importance of generating targeted C1 domain ligands capable of differentially regulating PKC isozyme-specific function in cellular models.
Collapse
Affiliation(s)
- Mariana Cooke
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Victoria Casado-Medrano
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Jihyae Ann
- Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Jeewoo Lee
- Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Peter M Blumberg
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, NCI, Bethesda, MD, 20892, USA
| | - Martin C Abba
- Centro de Investigaciones Inmunológicas Básicas y Aplicadas, Universidad Nacional de La Plata, CP1900, La Plata, Argentina.
| | - Marcelo G Kazanietz
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
| |
Collapse
|
|
24
|
Zhao C, Li Y, Zhang W, Zhao D, Ma L, Ma P, Yang F, Wang Y, Shu Y, Qiu W. IL‑17 induces NSCLC A549 cell proliferation via the upregulation of HMGA1, resulting in an increased cyclin D1 expression. Int J Oncol 2018; 52:1579-1592. [PMID: 29512693 DOI: 10.3892/ijo.2018.4307] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 02/16/2018] [Indexed: 11/06/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is considered to be an inflammation-associated carcinoma. Although interleukin‑17 (IL‑17) production contributes to the proliferation and growth of NSCLC, the mechanisms underlying IL‑17-induced NSCLC cell proliferation have not been fully elucidated. In the present study, by using ELISA and immunohistochemical analyses, we first found that the expression levels of IL‑17, IL‑17 receptor (IL‑17R), high-mobility group A1 (HMGA1) and cyclin D1 were elevated in the samples of patients with NSCLC. Subsequently, by RT-qPCR, western blot analysis and cell proliferation assay in vitro, we revealed that stimulation with recombinant human IL‑17 (namely IL‑17A) markedly induced the expression of HMGA1 and cyclin D1 in the A549 cells (a human lung adenocarcinoma cell line) and promoted cell proliferation. Furthermore, luciferase reporter and ChIP assays confirmed that upregulated HMGA1 directly bound to the cyclin D1 gene promoter and activated its transcription. Notably, the response element of HMGA1 binding to the cyclin D1 promoter was disclosed for the first time, at least to the best of our knowledge. Taken together, our findings indicate that the IL‑17/HMGA1/cyclin D1 axis plays an important role in NSCLC cell proliferation and may provide new insight into NSCLC pathogenesis and may thus aid in the development of novel therapeutic targets for NSCLC.
Collapse
Affiliation(s)
- Chenhui Zhao
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Yongting Li
- Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Weiming Zhang
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Dan Zhao
- Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Ling Ma
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Pei Ma
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Fengming Yang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Yingwei Wang
- Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Yongqian Shu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Wen Qiu
- Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| |
Collapse
|
|
25
|
Abe F, Kitadate A, Ikeda S, Yamashita J, Nakanishi H, Takahashi N, Asaka C, Teshima K, Miyagaki T, Sugaya M, Tagawa H. Histone deacetylase inhibitors inhibit metastasis by restoring a tumor suppressive microRNA-150 in advanced cutaneous T-cell lymphoma. Oncotarget 2018; 8:7572-7585. [PMID: 27935859 PMCID: PMC5352344 DOI: 10.18632/oncotarget.13810] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 11/24/2016] [Indexed: 12/17/2022] Open
Abstract
Tumor suppressive microRNA (miR)-150 inhibits metastasis by combining with the C-C chemokine receptor 6 (CCR6) “seed sequence” mRNA of the 3′-untranslated region (3′-UTR) in advanced cutaneous T-cell lymphoma (CTCL). Because the histone deacetylase inhibitor (HDACI) vorinostat showed excellent outcomes for treating advanced CTCL, HDACIs may reduce the metastasis of CTCL by targeting miR-150 and/ or CCR6. To examine whether these candidate molecules are essential HDACI targets in advanced CTCL, we used the My-La, HH, and HUT78 CTCL cell lines for functional analysis because we previously demonstrated that their xenografts in NOD/Shi-scid IL-2γnul mice (CTCL mice) induced multiple metastases. We found that pan- HDACIs (vorinostat and panobinostat) inhibited the migration of CTCL cells and downregulated CCR6. The miRNA microarray analysis against CTCL cell lines demonstrated that these pan-HDACIs commonly upregulated 161 miRNAs, including 34 known tumor suppressive miRNAs such as miR-150. Although 35 miRNAs possessing the CCR6 “seed sequence” were included in these 161 miRNAs, miR-150 and miR-185-5p were downregulated in CTCL cells compared to in normal CD4+ T-cells. The transduction of 12 candidate miRNAs against CTCL cells revealed that miR-150 most efficiently inhibited their migration capabilities and downregulated CCR6. Quantitative reverse transcriptase-polymerase chain reaction demonstrated that miR-150 was downregulated in advanced but not early CTCL primary cases. Finally, we injected miR-150 or siCCR6 into CTCL mice and found that mouse survival was significantly prolonged. These results indicate that miR-150 and its target, CCR6, are essential therapeutic targets of pan-HDACIs in advanced CTCL with metastatic potential.
Collapse
Affiliation(s)
- Fumito Abe
- 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
| | - Sho Ikeda
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | - Junsuke Yamashita
- Division of Bioscience Center, Radioisotope, Akita University, Akita, Japan
| | | | - Naoto Takahashi
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | - Chikara Asaka
- Department of Otolaryngology, Noshiro Kousei Medical Center, Noshiro, Japan
| | - Kazuaki Teshima
- Department of Hematology, Hiraka General Hospital, Yokote, 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
| |
Collapse
|
|
26
|
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: 59] [Impact Index Per Article: 8.4] [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.
Collapse
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
| |
Collapse
|
|
27
|
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.
Collapse
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
| |
Collapse
|
|
28
|
CXCL6 promotes non-small cell lung cancer cell survival and metastasis via down-regulation of miR-515-5p. Biomed Pharmacother 2017; 97:1182-1188. [PMID: 29136957 DOI: 10.1016/j.biopha.2017.11.004] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 10/29/2017] [Accepted: 11/03/2017] [Indexed: 02/04/2023] Open
Abstract
Chemokine plays an important role in lung cancer and CXCL6 is one of chemokine, however, its effect on miRNAs profile and its roles in non-small cell lung cancer cell (NSCLC) is not elucidated. This study is purposed to explore the influence of CXCL6 on miRNA expression profile and found that CXCL6 could reduce the expression of miR-515-5p in NSCLC cells. MiR-515-5p in NSCLC cells could inhibit NSCLC survival and metastasis. MiR-515-5p acted as a tumor suppressor by targeting CXCL6 in NSCLC cells. These data highlighted a novel molecular interaction between miR-515-5p and CXCL6. MiR-515-5p may constitute a potential therapy target for NSCLC.
Collapse
|
|
29
|
Abstract
The global incidence of thyroid cancer is increasing, and metastatic spread to the lymph nodes is common in papillary thyroid carcinoma. The metastatic course of thyroid carcinoma is an intricate process involving invasion, angiogenesis, cell trafficking, extravasation, organ specific homing, and growth. A key aspect in this process involves a multitude of interactions between chemokines and their receptors. Chemokines are a group of small proteins, which act to elicit normal physiologic and immune responses principally through recruitment of specific cell populations to the site of infection or malignancy. Thyroid cancer cells, like other tumors, possess the ability to corrupt the chemokine system to their advantage by altering cell movement into the tumor microenvironment and affecting all aspects of thyroid cancer progression.
Collapse
Affiliation(s)
- Sharinie Yapa
- 1 Department of Otolaryngology and Head and Neck Surgery, Castle Hill Hospital , Cottingham, United Kingdom
| | - Omar Mulla
- 1 Department of Otolaryngology and Head and Neck Surgery, Castle Hill Hospital , Cottingham, United Kingdom
| | - Victoria Green
- 2 School of Life Sciences, University of Hull , Hull, United Kingdom
| | - James England
- 1 Department of Otolaryngology and Head and Neck Surgery, Castle Hill Hospital , Cottingham, United Kingdom
| | - John Greenman
- 2 School of Life Sciences, University of Hull , Hull, United Kingdom
| |
Collapse
|
|
30
|
Gene expression profile of renal cell carcinomas after neoadjuvant treatment with sunitinib: new pathways revealed. Int J Biol Markers 2017; 32:e210-e217. [PMID: 27834463 DOI: 10.5301/jbm.5000234] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/20/2016] [Indexed: 01/03/2023]
Abstract
BACKGROUND In renal cell carcinoma (RCC) of the clear cell type, inactivity of the VHL gene induces overexpression of HIF1 α and its targets, the tyrosine kinase receptors, promoting RCC development and progression. The discovery of tyrosine kinase inhibitors (TKIs) changed the treatment of these tumors. Other molecular pathways involved in the TKI mechanisms of action have not been described in the literature. The aim of our study was to elucidate alternative mechanisms of action of sunitinib in tumor tissue after neoadjuvant treatment of RCC. METHODS The gene expression profile was accessed using microarray (Affymetrix Human Genome U133 Plus 2.0 platform) and frozen RCC tissues collected from 5 patients with locally advanced non-metastatic tumors who underwent nephrectomy after being treated with 2 cycles of neoadjuvant sunitinib. The results were compared with matched controls comprising 6 patients with no neoadjuvant intervention. RESULTS There was underexpression of the majority of genes after sunitinib treatment. The lower expression levels of IGFBP1, CCL20, CXCL6 and FGB were confirmed by qRT-PCR in all cases. The downregulation of gene expression leads us to search for methylation as a mechanism of action of the TKI. IGFBP1 was shown to be methylated by methylation-sensitive high-resolution melting technique. CONCLUSIONS The ultimate genetic effects of sunitinib may explain its actions as an antitumor drug that apparently suppresses the expression of important genes related to cell survival, adhesion, invasion and immunomodulation. The methylation of gene promoters was shown to be part of the mechanism of action of this class of drugs.
Collapse
|
|
31
|
The Role of Interleukin-17 in Lung Cancer. Mediators Inflamm 2016; 2016:8494079. [PMID: 27872514 PMCID: PMC5107223 DOI: 10.1155/2016/8494079] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 08/28/2016] [Accepted: 08/31/2016] [Indexed: 01/08/2023] Open
Abstract
Tumour-associated inflammation is a hallmark of malignant carcinomas, and lung cancer is a typical inflammation-associated carcinoma. Interleukin-17 (IL-17) is an important inflammatory cytokine that plays an important role in chronic inflammatory and autoimmune diseases and in inflammation-associated tumours. Numerous studies have shown that IL-17 directly or indirectly promotes tumour angiogenesis and cell proliferation and that it inhibits apoptosis via the activation of inflammatory signalling pathways. Therefore, IL-17 contributes to the metastasis and progression of lung cancer. Research advances with respect to the role of IL-17 in lung cancer will be presented as a review in this paper.
Collapse
|
|
32
|
Ignacio RMC, Kabir SM, Lee ES, Adunyah SE, Son DS. NF-κB-Mediated CCL20 Reigns Dominantly in CXCR2-Driven Ovarian Cancer Progression. PLoS One 2016; 11:e0164189. [PMID: 27723802 PMCID: PMC5056735 DOI: 10.1371/journal.pone.0164189] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 09/19/2016] [Indexed: 12/19/2022] Open
Abstract
Ovarian cancer is an inflammation-associated malignancy with a high mortality rate. CXCR2 expressing ovarian cancers are aggressive with poorer outcomes. We previously demonstrated that CXCR2-driven ovarian cancer progression potentiated NF-κB activation through EGFR-transactivated Akt. Here, we identified the chemokine signature involved in CXCR2-driven ovarian cancer progression using a mouse peritoneal xenograft model for ovarian cancer spreading with CXCR2-negative (SKA) and positive (SKCXCR2) cells generated previously from parental SKOV-3 cells. Compared to SKA bearing mice, SKCXCR2 bearing mice had the following characteristics: 1) shorter survival time, 2) greater tumor spreading in the peritoneal cavity and 3) higher tumor weight in the omentum and pelvic site. Particularly, SKCXCR2-derived tumor tissues induced higher activation of the NF-κB signaling pathway, while having no change in EGFR-activated signaling such as Raf, MEK, Akt, mTOR and Erk compared to SKA-derived tumors. Chemokine PCR array revealed that CCL20 mRNA levels were significantly increased in SKCXCR2-derived tumor tissues. The CCL20 promoter activity was regulated by NF-κB dependent pathways. Interestingly, all three κB-like sites in the CCL20 promoter were involved in regulating CCL20 and the proximal region between -92 and -83 was the most critical κB-like site. In addition, SKCXCR2-derived tumor tissues maintained high CCL20 mRNA expression and induced greater CCL24 and CXCR4 compared to SKCXCR2 cells, indicating the shift of chemokine network during the peritoneal spreading of tumor cells via interaction with other cell types in tumor microenvironment. Furthermore, we compared expression profiling array between human ovarian cancer cell lines and tumor tissues based on GEO datasets. The expression profiles in comparison with cell lines revealed that dominant chemokines expressed in ovarian tumor tissues are likely shifted from CXCL1-3 and 8 to CCL20. Taken together, the progression of ovarian cancer in the peritoneal cavity involves NF-κB-mediated CCL20 as a main chemokine network, which is potentiated by CXCR2 expression.
Collapse
Affiliation(s)
- Rosa Mistica C. Ignacio
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee, United States of America
| | - Syeda M. Kabir
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee, United States of America
| | - Eun-Sook Lee
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, Florida, United States of America
| | - Samuel E. Adunyah
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee, United States of America
| | - Deok-Soo Son
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee, United States of America
- * E-mail:
| |
Collapse
|
|
33
|
CCR6 expression in colon cancer is associated with advanced disease and supports epithelial-to-mesenchymal transition. Br J Cancer 2016; 114:1343-51. [PMID: 27149649 PMCID: PMC4984452 DOI: 10.1038/bjc.2016.113] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 03/22/2016] [Accepted: 03/29/2016] [Indexed: 12/11/2022] Open
Abstract
Background: Adjuvant chemotherapy offered to treat colon cancer is based on the TNM staging system, which often fails due to molecular heterogeneity and undefined molecular mechanisms independent of TNM. Therefore, identification of markers to better predict therapeutic option and outcome is needed. In this study we have characterised the clinical association of CCR6 with colon cancer and defined CCR6-mediated molecular pathway. Methods: Immunohistochemistry, RT-qPCR, western blot and FACS were used to determine expression of CCR6 and/or EMT markers in colon tissues/cells. BrdU assay and trans-well system were used to determine cell proliferation, migration and invasion in response to CCL20. Results: CCR6 was higher in cancer cases compared to normal adjacent tissue and expression was associated with nodal status and distant metastasis. Similarly, CCR6 expression was higher in cells derived from node-positive cases and highest expression was in cells derived from metastatic cases. Significant changes in EMT markers, that is, E-cadherin, vimentin, β-catenin, N-cadherin, α-SMA, SNAILl and ZEB1 were observed in response to CCL20 along with decreased proliferation, increased migratory and invasive potential. Conclusions: Results suggest CCR6 as a potential therapeutic target as well as biomarker in addition to nodal status for predicting therapeutic option.
Collapse
|
|
34
|
Wang B, Shi L, Sun X, Wang L, Wang X, Chen C. Production of CCL20 from lung cancer cells induces the cell migration and proliferation through PI3K pathway. J Cell Mol Med 2016; 20:920-9. [PMID: 26968871 PMCID: PMC4831357 DOI: 10.1111/jcmm.12781] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 12/07/2015] [Indexed: 11/28/2022] Open
Abstract
Tumour inflammatory microenvironment is considered to play a role in the sensitivity of tumour cells to therapies and prognosis of patients with lung cancer. The expression of CCL20, one of the critical chemoattractants responsible for inflammation cells recruitment, has been shown overexpressed in variety of tumours. This study aimed at investigating potential mechanisms of CCL20 function and production in human non-small cell lung cancer (NSCLC). Expression of CCL20 gene and protein in lung tissues of patients with NSCLC and NSCLC cells (A549) were determined. The interleukin (IL)-1β-induced signal pathways in A549 and the effect of CCL20-induced A549 cell migration and proliferation were determined using migration assays and cell-alive monitoring system. Mechanisms of signal pathways involved in the migration of CCL20 were also studied. We initially found that NSCLC tumour tissues markedly overexpressed CCL20 in comparison with normal lung samples. In addition, IL-1β could directly promote CCL20 production in lung cancer cells, which was inhibited by extracellular signal-regulated kinase (ERK)1/2 inhibitor, p38 mitogen-activated protein kinase (p38 MARP) inhibitor or PI3K inhibitors. CCL20 promoted lung cancer cells migration and proliferation in an autocrine manner via activation of ERK1/2-MAPK and PI3K pathways. Our data indicated that IL-1β could stimulate CCL20 production from lung cancer cells through the activation of MAPKs and PI3K signal pathways, and the auto-secretion of CCL20 could promote lung cancer cell migration and proliferation through the activation of ERK and PI3K signal pathways. Our results may provide a novel evidence that CCL20 could be a new therapeutic target for lung cancer.
Collapse
Affiliation(s)
- Beibei Wang
- Department of Lung Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Lin Shi
- Zhongshan Hospital Biomedical Research Center, Shanghai Institute of Clinical Bioinformatics, Fudan University Center for Clinical Bioinformatics, Fudan University Shanghai Medical College, Shanghai, China
| | - Xiaoru Sun
- Department of Lung Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Lingyan Wang
- Zhongshan Hospital Biomedical Research Center, Shanghai Institute of Clinical Bioinformatics, Fudan University Center for Clinical Bioinformatics, Fudan University Shanghai Medical College, Shanghai, China
| | - Xiangdong Wang
- Department of Lung Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
- Zhongshan Hospital Biomedical Research Center, Shanghai Institute of Clinical Bioinformatics, Fudan University Center for Clinical Bioinformatics, Fudan University Shanghai Medical College, Shanghai, China
| | - Chengshui Chen
- Department of Lung Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| |
Collapse
|
|
35
|
Bremnes RM, Busund LT, Kilvær TL, Andersen S, Richardsen E, Paulsen EE, Hald S, Khanehkenari MR, Cooper WA, Kao SC, Dønnem T. The Role of Tumor-Infiltrating Lymphocytes in Development, Progression, and Prognosis of Non-Small Cell Lung Cancer. J Thorac Oncol 2016; 11:789-800. [PMID: 26845192 DOI: 10.1016/j.jtho.2016.01.015] [Citation(s) in RCA: 336] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 01/24/2016] [Accepted: 01/26/2016] [Indexed: 12/25/2022]
Abstract
A malignant tumor is not merely an accumulation of neoplastic cells, but constitutes a microenvironment containing endothelial cells, fibroblasts, structural components, and infiltrating immune cells that impact tumor development, invasion, metastasis, and outcome. Hence, the evolution of cancers reflects intricate cellular and molecular interactions between tumor cells and constituents of the tumor microenvironment. Recent studies have shed new light on this complex interaction between tumor and host immune cells and the resulting immune response. The composition of the immune microenvironment differs across patients as well as in cancers of the same type, including various populations of T cells, B cells, dendritic cells, natural killer cells, myeloid-derived suppressor cells, neutrophils, and macrophages. The type, density, location, and organization of immune cells within solid tumors define the immune contexture, which has proved to be a major determinant of tumor characteristics and patient outcome. Lung cancer consists mostly of non-small cell lung cancer (85%); it is our most deadly malignant disease, with the 5-year survival rate being merely 15%. This review focuses on the immune contexture; the tumor-suppressing roles of tumor-infiltrating lymphocytes; and the relevance of this immune contexture for cancer diagnostics, prognostication, and treatment allocation, with an emphasis on non-small cell lung cancer.
Collapse
Affiliation(s)
- Roy M Bremnes
- Institute of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway; Department of Oncology, University Hospital of Northern Norway, Tromsø, Norway.
| | - Lill-Tove Busund
- Institute of Medical Biology, The Arctic University of Norway, Tromsø, Norway; Department of Pathology, University Hospital of Northern Norway, Tromsø, Norway
| | - Thomas L Kilvær
- Institute of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway; Department of Oncology, University Hospital of Northern Norway, Tromsø, Norway
| | - Sigve Andersen
- Institute of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway; Department of Oncology, University Hospital of Northern Norway, Tromsø, Norway
| | - Elin Richardsen
- Institute of Medical Biology, The Arctic University of Norway, Tromsø, Norway; Department of Pathology, University Hospital of Northern Norway, Tromsø, Norway
| | - Erna Elise Paulsen
- Institute of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway; Department of Oncology, University Hospital of Northern Norway, Tromsø, Norway
| | - Sigurd Hald
- Institute of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway; Department of Oncology, University Hospital of Northern Norway, Tromsø, Norway
| | | | - Wendy A Cooper
- Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; School of Medicine, University of Western Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, New South Wales, Australia
| | - Steven C Kao
- Chris O'Brien Lifehouse, Sydney, New South Wales, Australia; Asbestos Diseases Research Institute, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia
| | - Tom Dønnem
- Institute of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway; Department of Oncology, University Hospital of Northern Norway, Tromsø, Norway
| |
Collapse
|
|
36
|
Huang Q, Fan J, Qian X, Lv Z, Zhang X, Han J, Wu F, Chen C, Du J, Guo M, Hu G, Jin Y. Retinoic acid-related orphan receptor C isoform 2 expression and its prognostic significance for non-small cell lung cancer. J Cancer Res Clin Oncol 2016; 142:263-72. [PMID: 26319393 DOI: 10.1007/s00432-015-2040-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 08/24/2015] [Indexed: 12/27/2022]
Abstract
BACKGROUND Retinoic acid-related orphan receptor C isoform 2 (RORC2) is regarded as a pathogenic factor for autoimmune and inflammatory diseases and tumours. Previous studies have primarily focused on RORC2 expression in IL-17-producing immune cells but not in carcinoma cells; thus, little is known about the roles of RORC2 in the progression of human non-small cell lung cancer (NSCLC). In this study, we analysed the expression of RORC2 and its participation in tumour progression in NSCLC. METHODS RORC2 expression in NSCLC and adjacent normal lung tissues was assessed via quantitative real-time PCR (qRT-PCR) and immunohistochemistry. RORC2 expression in NSCLC cell lines was examined by qRT-PCR, Western blotting and flow cytometry. The effects of inhibiting RORC2 activity on the proliferation of NSCLC cells were evaluated. The prognostic value of RORC2 for NSCLC was revealed based on Kaplan-Meier analysis. RESULTS High RORC2 expression was observed in lung cancer tissues and was significantly related to age (p = 0.013) and regional lymph node metastasis (p = 0.009). RORC2 expression was higher in the A549, H460, SPC-A1 and H1299 cell lines than in a control cell line. In addition, cell proliferation was decreased in NSCLC cells upon the blocking of RORC2 activity using a specific inhibitor. High RORC2 expression correlated with worse overall survival (p = 0.030). CONCLUSIONS Our study suggests that RORC2 is expressed by lung cancer cells and greatly contributes to tumour cell proliferation and overall survival in NSCLC. These findings strongly imply that RORC2 is associated with tumour progression.
Collapse
MESH Headings
- Adenocarcinoma/genetics
- Adenocarcinoma/metabolism
- Adenocarcinoma/mortality
- Adenocarcinoma/secondary
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Blotting, Western
- Carcinoma, Adenosquamous/genetics
- Carcinoma, Adenosquamous/metabolism
- Carcinoma, Adenosquamous/mortality
- Carcinoma, Adenosquamous/secondary
- Carcinoma, Large Cell/genetics
- Carcinoma, Large Cell/metabolism
- Carcinoma, Large Cell/mortality
- Carcinoma, Large Cell/secondary
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Non-Small-Cell Lung/mortality
- Carcinoma, Non-Small-Cell Lung/secondary
- Cell Proliferation
- Female
- Flow Cytometry
- Follow-Up Studies
- Humans
- Immunoenzyme Techniques
- Lung/metabolism
- Lung/pathology
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/mortality
- Lung Neoplasms/pathology
- Lymphatic Metastasis
- Male
- Middle Aged
- Neoplasm Staging
- Nuclear Receptor Subfamily 1, Group F, Member 3/genetics
- Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
- Prognosis
- Protein Isoforms
- RNA, Messenger/genetics
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Survival Rate
- Tumor Cells, Cultured
Collapse
Affiliation(s)
- Qi Huang
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of the Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Jinshuo Fan
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of the Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Xin Qian
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of the Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China
- Department of Respiratory Medicine, Taihe Hospital, Hubei University of Medicine, No. 98 South Renmin Road, Shiyan, 442000, Hubei, People's Republic of China
| | - Zhilei Lv
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of the Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Xiuxiu Zhang
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of the Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Jieli Han
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of the Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Feng Wu
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of the Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Caiyun Chen
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of the Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China
- Department of Respiratory, the First Hospital of Xi'an City, Xi'an, 710002, Shanxi, People's Republic of China
| | - Jiao Du
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of the Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China
- Zhongshan Hospital, Xiamen University, 201-209 Hubin Road, Xiamen, 361004, Fujian, People's Republic of China
| | - Mengfei Guo
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of the Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Guorong Hu
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of the Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Yang Jin
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of the Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China.
| |
Collapse
|
|
37
|
Stec M, Szatanek R, Baj-Krzyworzeka M, Baran J, Zembala M, Barbasz J, Waligórska A, Dobrucki JW, Mytar B, Szczepanik A, Siedlar M, Drabik G, Urbanowicz B, Zembala M. Interactions of tumour-derived micro(nano)vesicles with human gastric cancer cells. J Transl Med 2015; 13:376. [PMID: 26626416 PMCID: PMC4666152 DOI: 10.1186/s12967-015-0737-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Accepted: 11/20/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Tumour cells release membrane micro(nano)fragments called tumour-derived microvesicles (TMV) that are believed to play an important role in cancer progression. TMV suppress/modify antitumour response of the host, but there is also some evidence for their direct interaction with cancer cells. In cancer patients TMV are present in body fluid and tumour microenvironment. The present study aimed at characterization of whole types/subpopulations, but not only exosomes, of TMV from newly established gastric cancer cell line (called GC1415) and to define their interactions with autologous cells. METHODS TMV were isolated from cell cultures supernatants by centrifugation at 50,000×g and their phenotype was determined by flow cytometry. The size of TMV was analysed by dynamic light scattering and nanoparticle tracking analysis, while morphology by transmission electron microscopy and atomic force microscopy. Interactions of TMV with cancer cells were visualized using fluorescence-activated cell sorter, confocal and atomic force microscopy, biological effects by xenografts in NOD SCID mice. RESULTS Isolated TMV showed expression of CD44H, CD44v6 (hyaluronian receptors), CCR6 (chemokine receptor) and HER-2/neu molecules, exhibited different shapes and sizes (range 60-900 nm, highest frequency of particles with size range of 80-120 nm). TMV attached to autologous cancer cells within 2 h and then were internalized by them at 24 h. CD44H, CD44v6 and CCR6 molecules may play a role in attachment of TMV to cancer cells, while HER-2 associated with CD24 be involved in promoting cancer cells growth. Pre-exposure of cancer cells to TMV resulted in enhancement of tumour growth and cancer cell-induced angiogenesis in NOD SCID mice model. CONCLUSIONS TMV interact directly with cancer cells serving as macro-messengers and molecular cargo transfer between gastric cancer cells resulting in enhancement of tumour growth. TMV should be considered in future as target of anticancer therapy.
Collapse
Affiliation(s)
- Małgorzata Stec
- Department of Clinical Immunology and Transplantology, Jagiellonian University Medical College, Wielicka 265 Str., 30-663, Kraków, Poland.
| | - Rafał Szatanek
- Department of Clinical Immunology and Transplantology, Jagiellonian University Medical College, Wielicka 265 Str., 30-663, Kraków, Poland.
| | - Monika Baj-Krzyworzeka
- Department of Clinical Immunology and Transplantology, Jagiellonian University Medical College, Wielicka 265 Str., 30-663, Kraków, Poland.
| | - Jarosław Baran
- Department of Clinical Immunology and Transplantology, Jagiellonian University Medical College, Wielicka 265 Str., 30-663, Kraków, Poland.
| | - Maria Zembala
- Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Kraków, Poland.
| | - Jakub Barbasz
- Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Kraków, Poland.
| | - Agnieszka Waligórska
- Division of Cell Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
| | - Jurek W Dobrucki
- Division of Cell Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
| | - Bożenna Mytar
- Department of Clinical Immunology and Transplantology, Jagiellonian University Medical College, Wielicka 265 Str., 30-663, Kraków, Poland.
| | - Antoni Szczepanik
- First Department of General and Gastrointestinal Surgery, Jagiellonian University Medical College, Kraków, Poland.
| | - Maciej Siedlar
- Department of Clinical Immunology and Transplantology, Jagiellonian University Medical College, Wielicka 265 Str., 30-663, Kraków, Poland.
| | - Grażyna Drabik
- Department of Clinical Immunology and Transplantology, Jagiellonian University Medical College, Wielicka 265 Str., 30-663, Kraków, Poland.
| | - Barbara Urbanowicz
- Electron Microscopy Laboratory, University Children's Hospital of Cracow, Kraków, Poland.
| | - Marek Zembala
- Department of Clinical Immunology and Transplantology, Jagiellonian University Medical College, Wielicka 265 Str., 30-663, Kraków, Poland.
| |
Collapse
|
|
38
|
Zhang XG, Song BT, Liu FJ, Sun D, Wang KX, Qu H. CCR6 overexpression predicted advanced biological behaviors and poor prognosis in patients with gastric cancer. Clin Transl Oncol 2015; 18:700-7. [DOI: 10.1007/s12094-015-1420-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Accepted: 09/25/2015] [Indexed: 11/30/2022]
|
|
39
|
Boyle ST, Faulkner JW, McColl SR, Kochetkova M. The chemokine receptor CCR6 facilitates the onset of mammary neoplasia in the MMTV-PyMT mouse model via recruitment of tumor-promoting macrophages. Mol Cancer 2015; 14:115. [PMID: 26047945 PMCID: PMC4464622 DOI: 10.1186/s12943-015-0394-1] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Accepted: 05/29/2015] [Indexed: 01/02/2023] Open
Abstract
Background The expression of the chemokine receptor CCR6 has been previously correlated with higher grades and stages of breast cancer and decreased relapse-free survival. Also, its cognate chemokine ligand CCL20 has been reported to induce proliferation of cultured human breast epithelial cells. Methods To establish if CCR6 plays a functional role in mammary tumorigenesis, a bigenic MMTV-PyMT CCR6-null mouse was generated and mammary tumor development was assessed. Levels of tumor-infiltrating immune cells within tumor-bearing mammary glands from MMTV-PyMT Ccr6WT and Ccr6−/− mice were also analyzed. Results Deletion of CCR6 delayed tumor onset, significantly reduced the extent of initial hyperplastic outgrowth, and decreased tumor incidence in PyMT transgenic mice. CCR6 was then shown to promote the recruitment of pro-tumorigenic macrophages to the tumor site, facilitating the onset of neoplasia. Conclusions This study delineated for the first time a role for CCR6 in the development of breast cancer, and demonstrated a critical function for this receptor in maintaining the pro-tumorigenic cancer microenvironment. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0394-1) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Sarah T Boyle
- Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia
| | - Jessica W Faulkner
- Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia
| | - Shaun R McColl
- Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.,Centre for Molecular Pathology, University of Adelaide, Adelaide, South Australia, Australia
| | - Marina Kochetkova
- Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.
| |
Collapse
|
|
40
|
Serum chemokine network correlates with chemotherapy in non-small cell lung cancer. Cancer Lett 2015; 365:57-67. [PMID: 25976768 DOI: 10.1016/j.canlet.2015.05.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Revised: 04/17/2015] [Accepted: 05/05/2015] [Indexed: 10/23/2022]
Abstract
OBJECTIVE Inflammation plays an important role in the microenvironment of lung cancer. The present study aimed to evaluate the association of inflammatory biomarker networks with chemotherapies for patients with non-small cell lung cancer (NSCLC). METHODS The sera of healthy non-smokers (n = 14) and patients with NSCLC (n = 50), 36 with adenocarcinoma and 14 with squamous cell carcinoma, were collected. Healthy patients were untreated, while those with NSCLC were either chemotherapy-naïve or had received one and two courses of chemotherapy. The cytokine concentrations were measured using multiplexed cytokine immunoassays. The clinical informatics was scored with a Digital Evaluation Score System (DESS) to assess the severity of the patients. All patients completed follow-up for up to 2 years. RESULTS Among the 40 mediators measured, 13 significantly differed between patients with lung cancer and healthy controls, while 18 differed between untreated patients and those with stage IV adenocarcinoma who had undergone the first and second chemotherapy courses. The protein network of cytokines in NSCLC after multiple courses of chemotherapy was similar to that of normal persons. MIP-3α is the most crucial biomarker for predicting survival rates in NSCLC patients. CONCLUSIONS Our data identify an NSCLC-specific profile of inflammatory mediators that may be useful for cancer sub-classification, as well as the evaluation of therapeutic effects and overall survival.
Collapse
|
|
41
|
Wang GZ, Cheng X, Li XC, Liu YQ, Wang XQ, Shi X, Wang ZY, Guo YQ, Wen ZS, Huang YC, Zhou GB. Tobacco smoke induces production of chemokine CCL20 to promote lung cancer. Cancer Lett 2015; 363:60-70. [PMID: 25864589 DOI: 10.1016/j.canlet.2015.04.005] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Revised: 03/20/2015] [Accepted: 04/05/2015] [Indexed: 11/29/2022]
Abstract
Tobacco kills nearly 6 million people each year, and 90% of the annual 1.59 million lung cancer deaths worldwide are caused by cigarette smoke. Clinically, a long latency is required for individuals to develop lung cancer since they were first exposed to smoking. In this study, we aimed to identify clinical relevant inflammatory factors that are critical for carcinogenesis by treating normal human lung epithelial cells with tobacco carcinogen nicotine-derived nitrosaminoketone (NNK) for a long period (60 days) and systematic screening in 84 cytokines/chemokines. We found that a chemokine CCL20 was significantly up-regulated by NNK, and in 78/173 (45.1%) patients the expression of CCL20 was higher in tumor samples than their adjacent normal lung tissues. Interestingly, CCL20 was up-regulated in 48/92 (52.2%) smoker and 29/78 (37.2%) nonsmoker patients (p = 0.05), and high CCL20 was associated with poor prognosis. NNK induced the production of CCL20, which promoted lung cancer cell proliferation and migration. In addition, an anti-inflammation drug, dexamethasone, inhibited NNK-induced CCL20 production and suppressed lung cancer in vitro and in vivo. These results indicate that CCL20 is crucial for tobacco smoke-caused lung cancer, and anti-CCL20 could be a rational approach to fight against this deadly disease.
Collapse
Affiliation(s)
- Gui-Zhen Wang
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences & Graduate School of the University of Chinese Academy of Sciences, Beijing 100101, China
| | - Xin Cheng
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences & Graduate School of the University of Chinese Academy of Sciences, Beijing 100101, China
| | - Xin-Chun Li
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences & Graduate School of the University of Chinese Academy of Sciences, Beijing 100101, China
| | - Yong-Qiang Liu
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences & Graduate School of the University of Chinese Academy of Sciences, Beijing 100101, China
| | - Xian-Quan Wang
- Department of Orthopedics, Provincial Hospital Affiliated to Shandong University, 324 Jing Wu Road, Jinan 250021, China
| | - Xu Shi
- Department of Central Laboratory, The First Hospital, Jilin University, Changchun 130032, China
| | - Zai-Yong Wang
- Department of Thoracic Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yong-Qing Guo
- Department of Thoracic Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Zhe-Sheng Wen
- Department of Thoracic Surgery, The Cancer Hospital, Sun Yat-Sen University, Guangzhou 510060, China
| | - Yun-Chao Huang
- Department of Thoracic Surgery, Yunnan Cancer Hospital, Kunming 650106, China
| | - Guang-Biao Zhou
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences & Graduate School of the University of Chinese Academy of Sciences, Beijing 100101, China.
| |
Collapse
|
|
42
|
Remark R, Becker C, Gomez JE, Damotte D, Dieu-Nosjean MC, Sautès-Fridman C, Fridman WH, Powell CA, Altorki NK, Merad M, Gnjatic S. The non-small cell lung cancer immune contexture. A major determinant of tumor characteristics and patient outcome. Am J Respir Crit Care Med 2015; 191:377-90. [PMID: 25369536 DOI: 10.1164/rccm.201409-1671pp] [Citation(s) in RCA: 205] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Solid tumors, beyond mere accumulation of cancer cells, form a complex ecosystem consisting of normal epithelial cells, fibroblasts, blood and lymphatic vessels, structural components, and infiltrating hematopoietic cells including myeloid and lymphoid elements that impact tumor growth, tumor spreading, and clinical outcome. The composition of the immune microenvironment is diverse, including various populations of T cells, B cells, dendritic cells, natural killer cells, myeloid-derived suppressor cells, neutrophils, or macrophages. The immune contexture describes the density, location, and organization of these immune cells within solid tumors. In lung cancer, which is the deadliest type of cancer, and particularly in non-small cell lung cancer, its most prevalent form, reports have described some of the interactions between the tumor and the host. These data, in addition to articles on various types of tumors, provide a greater understanding of the tumor-host microenvironment interaction and stimulate the development of prognostic and predictive biomarkers, the identification of novel target antigens for therapeutic intervention, and the implementation of tools for long-term management of patients with cancer.
Collapse
|
|
43
|
Qiu W, Wang G, Sun X, Ye J, Wei F, Shi X, Lv G. The involvement of cell surface nucleolin in the initiation of CCR6 signaling in human hepatocellular carcinoma. Med Oncol 2015; 32:75. [PMID: 25698534 DOI: 10.1007/s12032-015-0530-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 02/13/2015] [Indexed: 02/07/2023]
Abstract
In recent years, the chemokine CC receptor 6 (CCR6) and its ligand CCL20 were reported to play an essential role in hepatocellular carcinoma (HCC). However, the role of cell surface nucleolin in the CCR6 pathway of HCC is not well featured. Using immunohistochemistry, Western blotting, siRNA, wound healing and transwell assay, we investigated the relationships of cell surface nucleolin and CCR6 signaling in HCC. In the present study, our findings identified that cell surface nucleolin and CCR6 protein were stained in most of HCC tissues (64, 68 %, respectively) and differently expressed in HCC cell lines; meanwhile, both expression has an association with advanced stage, lymph node metastasis and poor 5-year prognosis. According to in vitro assays, we found that the silencing of either cell surface nucleolin or CCR6 inhibited the protein expression of p-ERK, p-AKT, MMP2, MMP9 and ICAM-1 in the CCL20-stimulated HCCLM6 cells. Functional analysis revealed that cell surface nucleolin or CCR6 silencing significantly hampered HCCLM6 cell motility and invasiveness ability, when compared with control. In conclusion, this work suggests that cell surface nucleolin participates in the initiation of CCR6 pathway and biological behaviors of HCC, leading to HCC cell adhesion, migration and invasive behavior. In the clinical practice, cell surface nucleolin and CCR6 are recommended to predict poor prognosis and be used as a useful target for HCC patients.
Collapse
Affiliation(s)
- Wei Qiu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, 71 Xinmin Street, Changchun, 130021, Jilin, China
| | | | | | | | | | | | | |
Collapse
|
|
44
|
Cheng S, Shao Z, Liu X, Guo L, Zhang X, Na Q, Chen X, Ma Y, Zheng J, Song B, Liu J. Interleukin 17A Polymorphism Elevates Gene Expression and Is Associated with Increased Risk of Nonsmall Cell Lung Cancer. DNA Cell Biol 2015; 34:63-8. [PMID: 25289477 DOI: 10.1089/dna.2014.2628] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Affiliation(s)
- Sensen Cheng
- School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, Jinan, China
| | - Zhulin Shao
- School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, Jinan, China
| | - Xiuchun Liu
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, China
| | - Liangjun Guo
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, China
| | - Xia Zhang
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, China
| | - Qinyun Na
- Department of Surgery, Huadong Hospital, Shanxi, China
| | - Xiaofeng Chen
- Department of Surgery, Huadong Hospital, Shanxi, China
| | - Yuan Ma
- School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, Jinan, China
| | - Jinsong Zheng
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, China
| | - Bao Song
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, China
| | - Jie Liu
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, China
| |
Collapse
|
|
45
|
Zhang Z, Zhao X, Zhang T, Wang L, Yang L, Huang L, Li F, Liu J, Yue D, Wang F, Li J, Guan F, Xu Y, Zhang B, Zhang Y. Phenotypic characterization and anti-tumor effects of cytokine-induced killer cells derived from cord blood. Cytotherapy 2015; 17:86-97. [PMID: 25457278 DOI: 10.1016/j.jcyt.2014.09.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Revised: 09/18/2014] [Accepted: 09/25/2014] [Indexed: 12/26/2022]
Abstract
BACKGROUND AIMS Cytokine-induced killer (CIK) cell therapy represents a feasible immunotherapeutic option for treating malignancies. However, the number of anti-tumor lymphocytes cannot be easily obtained from the cancer patients with poor immunity status, and older patients cannot tolerate repeated collection of blood. Cord blood-derived CIK (CB-CIK) cells have shown efficacy in treating the patients with cancer in several clinical trials. This study was conducted to evaluate the biological characteristics and anti-tumor function of CB-CIK cells. METHODS The immunogenicity, chemokine receptors and proliferation of CB-CIK cells were analyzed by flow cytometry. The CIK cells on day 13 were treated with cisplatin and the anti-apoptosis capacity was analyzed. The function of CB-CIK cells against the human cancer was evaluated both in vitro and in vivo. RESULTS Compared with peripheral blood-derived CIK (PB-CIK) cells, CB-CIK cells demonstrated lower immunogenicity and increased proliferation rates. CB-CIK cells also had a higher percentage of main functional fraction CD3(+)CD56(+). The anti-apoptosis ability of CB-CIK cells after treatment with cisplatin was higher than that of PB-CIK cells. Furthermore, CB-CIK cells were effective for secreting interleukin-2 and interferon-γ and a higher percentage of chemokine receptors CCR6 and CCR7. In addition, tumor growth was greatly inhibited by CB-CIK treatment in a nude mouse xenograft model. CONCLUSIONS CB-CIK cells exhibit more efficient anti-tumor activity in in vitro analysis and in the preclinical model and may serve as a potential therapeutic approach for the treatment of cancer.
Collapse
Affiliation(s)
- Zhen Zhang
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xianlan Zhao
- Department of Obstetrics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Tengfei Zhang
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Liping Wang
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Lingzhu Yang
- Department of Obstetrics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Lan Huang
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Feng Li
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jinyan Liu
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; School of Life Science, Zhengzhou University, Zhengzhou, Henan, China
| | - Dongli Yue
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Fei Wang
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; School of Life Science, Zhengzhou University, Zhengzhou, Henan, China
| | - Jieyao Li
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Fangxia Guan
- School of Life Science, Zhengzhou University, Zhengzhou, Henan, China
| | - Yuming Xu
- Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Bin Zhang
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Department of Hematology/Oncology, School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Yi Zhang
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; School of Life Science, Zhengzhou University, Zhengzhou, Henan, China; Key Laboratory of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| |
Collapse
|
|
46
|
The effect of proinflammatory cytokines on IL-17RA expression in NSCLC. Med Oncol 2014; 31:144. [PMID: 25112467 DOI: 10.1007/s12032-014-0144-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Accepted: 07/26/2014] [Indexed: 01/08/2023]
Abstract
Interleukin-17 receptor (IL-17RA) is essential for proinflammatory cytokine IL-17-mediated pathogenesis of various tumors. IL-17RA is upregulated by some proinflammatory cytokines such as IL-21 and IL-15 and downregulated by IL-2, while the effect of IL-1β, IL-6, IL-8, TNF-α on IL-17RA expression in non-small cell lung caner (NSCLC) remains unknown. Our findings revealed that IL-17RA mRNA was increased in NSCLC tissues compared with the corresponding peritumor tissues (P = 0.0039) and high expression of IL-17RA protein in human NSCLC tissues was significantly associated with histological subtype, primary tumor size and clinical stages (P = 0.033, 0.033 and 0.011, respectively). IL-17RA mRNA expression was positively related to IL-1β, IL-6, IL-8, TNF-α mRNA expression (P = 0.013, 0.0001, 0.002 and 0.010 respectively) in NSCLC tissues. Furthermore, IL-1β, IL-6, IL-8, TNF-α upregulated IL-17RA mRNA and protein in A549 and H460 cells (all P < 0.05). It is suggested that IL-1β, IL-6, IL-8, TNF-α promoted IL-17RA expression in NSCLC and they may involve in IL-17RA signaling in NSCLC.
Collapse
|
|
47
|
Zeng W, Chang H, Ma M, Li Y. CCL20/CCR6 promotes the invasion and migration of thyroid cancer cells via NF-kappa B signaling-induced MMP-3 production. Exp Mol Pathol 2014; 97:184-90. [PMID: 24984269 DOI: 10.1016/j.yexmp.2014.06.012] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Accepted: 06/27/2014] [Indexed: 01/01/2023]
Abstract
CCL20, an important member of the CC-chemokine family, is the only ligand that activates CCR6. The levels of CCL20 and CCR6 are elevated in many human cancers, and CCL20/CCR6 interaction participates in the development and progression of cancer. In this present study, we found that CCR6 was overexpressed in thyroid cancer cells. Activation of CCR6 by CCL20 promoted the invasion and migration of human thyroid cancer SW1736 cells, while knockdown of CCR6 repressed the effect of CCL20. Furthermore, CCL20/CCR6 interaction induced the activation of NF-κB, and stimulated the expression and secretion of MMP-3. In addition, BAY117082, a special inhibitor of NF-κB, suppressed the expression and secretion of MMP-3 stimulated by CCL20/CCR6. Together, these results suggest that CCL20/CCR6 enhances thyroid cancer cell invasion and migration. The possible molecular mechanisms involved NF-κB activation and NF-κB-dependent MMP-3 upregulation. Thus, molecular therapies that aim at CCL20 and CCR6 may offer promising intervention strategies for thyroid cancer.
Collapse
Affiliation(s)
- Wei Zeng
- Department of Otolaryngology, First Affiliated Hospital of Henan University of Science and Technology, Luoyang 471003, China
| | - Hao Chang
- Department of Otolaryngology, First Affiliated Hospital of Henan University of Science and Technology, Luoyang 471003, China
| | - Min Ma
- Department of Otolaryngology, First Affiliated Hospital of Henan University of Science and Technology, Luoyang 471003, China
| | - Yanwei Li
- Department of Ophthalmology, First Affiliated Hospital of Henan University of Science and Technology, Luoyang 471003, China.
| |
Collapse
|
|
48
|
Zhang X, Meng A, Wang H, Yan X. High serum macrophage inflammatory protein-3α is associated with the early recurrence or metastasis of non-small cell lung cancer following primary pulmonary resection. Oncol Lett 2014; 8:948-952. [PMID: 25013520 PMCID: PMC4081402 DOI: 10.3892/ol.2014.2229] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2013] [Accepted: 05/23/2014] [Indexed: 01/07/2023] Open
Abstract
The present study sought to characterize the role of macrophage inflammatory protein-3α (MIP-3α) in non-small cell lung cancer (NSCLC) patients with early recurrence or metastasis after primary pulmonary resection. Follow-up examinations were conducted for 203 NSCLC patients with primary pulmonary resection for two years post-operatively, and data was also collected for 20 healthy subjects. Serum MIP-3α levels were determined prior to surgery and at post-operative days (PODs) 30, 90 and 180, and the relevant clinical and operative variables were collected. Serum MIP-3α was measured using a commercially available enzyme-linked immunosorbent assay. There were no significant differences in age, gender and histological type among all groups (P>0.05). Serum MIP-3α levels on POD 180 were significantly higher in the recurrence group than in the non-recurrence group and healthy subjects (P=0.001). There was no significant difference in the serum MIP-3α level at PODs 90 and 180 in the patients with or without adjuvant chemotherapy (P>0.05). The recurrence rate in the high serum MIP-3α level group was 41.67%, much higher than the 23.53% observed in the low level group (P=0.006). The patients with high serum levels of MIP-3α had a significantly shorter overall recurrence-free time compared with those with low levels (P=0.004). Multivariate Cox’s regression analyses showed that only serum MIP-3α level was significant, with a hazard ratio of 1.061, a 95% confidence interval of 1.044–1.078 and a P-value of 0.001. The serum MIP-3α level in the patients with liver and bone metastases were remarkably higher than those with recurrence at other sites. The high post-operative serum MIP-3α levels were associated with an increased risk of post-operative early recurrence or metastasis in the lung cancer patients, specifically in those with bone or liver metastases.
Collapse
Affiliation(s)
- Xiaopeng Zhang
- Graduate School, Hebei Medical University, Shijiazhuang, Hebei, P.R. China ; Department of Thoracic Surgery, Hebei Province General Hospital, Shijiazhuang, Hebei, P.R. China
| | - Aihong Meng
- Respiratory Division, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, P.R. China
| | - Huien Wang
- Department of Thoracic Surgery, Hebei Province General Hospital, Shijiazhuang, Hebei, P.R. China
| | - Xixin Yan
- Graduate School, Hebei Medical University, Shijiazhuang, Hebei, P.R. China ; Respiratory Division, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, P.R. China
| |
Collapse
|
|
49
|
Nandi B, Pai C, Huang Q, Prabhala RH, Munshi NC, Gold JS. CCR6, the sole receptor for the chemokine CCL20, promotes spontaneous intestinal tumorigenesis. PLoS One 2014; 9:e97566. [PMID: 24866282 PMCID: PMC4035256 DOI: 10.1371/journal.pone.0097566] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 04/21/2014] [Indexed: 12/12/2022] Open
Abstract
Interactions between the inflammatory chemokine CCL20 and its receptor CCR6 have been associated with colorectal cancer growth and metastasis, however, a causal role for CCL20 signaling through CCR6 in promoting intestinal carcinogenesis has not been demonstrated in vivo. In this study, we aimed to determine the role of CCL20-CCR6 interactions in spontaneous intestinal tumorigenesis. CCR6-deficient mice were crossed with mice heterozygous for a mutation in the adenomatous polyposis coli (APC) gene (APCMIN/+ mice) to generate APCMIN/+ mice with CCR6 knocked out (CCR6KO-APCMIN/+ mice). CCR6KO-APCMIN/+ mice had diminished spontaneous intestinal tumorigenesis. CCR6KO-APCMIN/+ also had normal sized spleens as compared to the enlarged spleens found in APCMIN/+ mice. Decreased macrophage infiltration into intestinal adenomas and non-tumor epithelium was observed in CCR6KO-APCMIN/+ as compared to APCMIN/+ mice. CCL20 signaling through CCR6 caused increased production of CCL20 by colorectal cancer cell lines. Furthermore, CCL20 had a direct mitogenic effect on colorectal cancer cells. Thus, interactions between CCL20 and CCR6 promote intestinal carcinogenesis. Our results suggest that the intestinal tumorigenesis driven by CCL20-CCR6 interactions may be driven by macrophage recruitment into the intestine as well as proliferation of neoplastic epithelial cells. This interaction could be targeted for the treatment or prevention of malignancy.
Collapse
MESH Headings
- Animals
- Apoptosis
- Blotting, Western
- Cell Proliferation
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/pathology
- Chemokine CCL20/genetics
- Chemokine CCL20/metabolism
- Colonic Neoplasms/genetics
- Colonic Neoplasms/metabolism
- Colonic Neoplasms/pathology
- Female
- Fluorescent Antibody Technique
- Genes, APC
- Humans
- Immunoenzyme Techniques
- Intestinal Neoplasms/etiology
- Intestinal Neoplasms/metabolism
- Intestinal Neoplasms/pathology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- RNA, Messenger/genetics
- Real-Time Polymerase Chain Reaction
- Receptors, CCR6/genetics
- Receptors, CCR6/metabolism
- Receptors, CCR6/physiology
- Reverse Transcriptase Polymerase Chain Reaction
- Tumor Cells, Cultured
Collapse
Affiliation(s)
- Bisweswar Nandi
- Research Service, VA Boston Healthcare System, West Roxbury, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Christine Pai
- Research Service, VA Boston Healthcare System, West Roxbury, Massachusetts, United States of America
| | - Qin Huang
- Harvard Medical School, Boston, Massachusetts, United States of America
- Pathology, Service, VA Boston Healthcare System, West Roxbury, Massachusetts, United States of America
| | - Rao H. Prabhala
- Research Service, VA Boston Healthcare System, West Roxbury, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
- Dana-Farber Cancer Center, Boston, Massachusetts, United States of America
| | - Nikhil C. Munshi
- Harvard Medical School, Boston, Massachusetts, United States of America
- Dana-Farber Cancer Center, Boston, Massachusetts, United States of America
- Medicine Service, VA Boston Healthcare System, West Roxbury, Massachusetts, United States of America
| | - Jason S. Gold
- Harvard Medical School, Boston, Massachusetts, United States of America
- Surgery Service, VA Boston Healthcare System, West Roxbury, Massachusetts, United States of America
- Brigham and Women's Hospital, Boston, Massachusetts, United States of America
- * E-mail:
| |
Collapse
|
|
50
|
Geraghty P, Hardigan A, Foronjy RF. Cigarette smoke activates the proto-oncogene c-src to promote airway inflammation and lung tissue destruction. Am J Respir Cell Mol Biol 2014; 50:559-70. [PMID: 24111605 DOI: 10.1165/rcmb.2013-0258oc] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The diagnosis of chronic obstructive pulmonary disease (COPD) confers a 2-fold increased lung cancer risk even after adjusting for cigarette smoking, suggesting that common pathways are operative in both diseases. Although the role of the tyrosine kinase c-Src is established in lung cancer, less is known about its impact in other lung diseases, such as COPD. This study examined whether c-Src activation by cigarette smoke contributes to the pathogenesis of COPD. Cigarette smoke increased c-Src activity in human small airway epithelial (SAE) cells from healthy donors and in the lungs of exposed mice. Similarly, higher c-Src activation was measured in SAE cells from patients with COPD compared with healthy control subjects. In SAE cells, c-Src silencing or chemical inhibition prevented epidermal growth factor (EGF) receptor signaling in response to cigarette smoke but not EGF stimulation. Further studies showed that cigarette smoke acted through protein kinase C α to trigger c-Src to phosphorylate EGF receptor and thereby to induce mitogen-activated protein kinase responses in these cells. To further investigate the role of c-Src, A/J mice were orally administered the specific Src inhibitor AZD-0530 while they were exposed to cigarette smoke for 2 months. AZD-0530 treatment blocked c-Src activation, decreased macrophage influx, and prevented airspace enlargement in the lungs of cigarette smoke-exposed mice. Moreover, inhibiting Src deterred the cigarette smoke-mediated induction of matrix metalloproteinase-9 and -12 in alveolar macrophages and lung expression of cathepsin K, IL-17, TNF-α, MCP-1, and KC, all key factors in the pathogenesis of COPD. These results indicate that activation of the proto-oncogene c-Src by cigarette smoke promotes processes linked to the development of COPD.
Collapse
|