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Wen C, Tao H, Chen H, Pu W, Yan Q, Zou Y, Su SS, Zhou L, Peng Y, Wang G, Xu T, Zheng X, Wu M, Dai Y. Single-cell RNA sequencing and functional analysis reveal the role of altered glycosylation levels of hepatic macrophages in liver cirrhosis. J Gastroenterol 2025; 60:607-620. [PMID: 39888412 DOI: 10.1007/s00535-025-02218-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 01/14/2025] [Indexed: 02/01/2025]
Abstract
BACKGROUND Liver cirrhosis represents a critical stage of chronic liver disease, characterized by progressive liver damage, cellular dysfunction, and disrupted cell-to-cell interactions. Glycosylation, an essential post-translational modification, significantly influences cellular behavior and disease progression. Its role in cirrhosis at the single-cell level remains unclear, despite its importance. METHODS This study, based on single-cell glycosylation and transcriptome data, compared the expression of differentially expressed genes in liver tissues from cirrhotic and healthy control samples, identifying changes in glycosylation-related genes and their functional pathway enrichment characteristics. Additionally, it analyzed the composition of immune cells and intercellular interaction features, with a focus on the interaction between macrophages and other immune cells and their potential role in immune regulation. RESULTS The analysis revealed significant changes in immune cell composition and glycosylation patterns in cirrhotic livers. Specifically, the number of macrophages increased substantially, while overall glycosylation levels decreased. Enhanced interactions between macrophages and other cell types were observed, highlighting the central role of macrophages in reshaping the immune microenvironment during cirrhosis progression. Gene expression analysis showed a marked upregulation of FUCA1, a gene encoding a glycosylation-related hydrolase. This change was strongly associated with the observed reduction in glycosylation levels. Functional enrichment analysis further revealed that glycosylation-related genes were primarily involved in immune pathways, including antigen processing and presentation, cytokine signaling, and immune activation. CONCLUSIONS Single-cell glycosylation analysis provides crucial insights into immune cell interactions in cirrhosis. Targeting glycosylation pathways in macrophages may offer new treatment strategies for cirrhosis.
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Affiliation(s)
- Chunmei Wen
- School of Medicine, Anhui University of Science & Technology, Huainan, China
| | - Huihui Tao
- School of Medicine, Anhui University of Science & Technology, Huainan, China.
- Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Huainan, China.
| | - Huaizhou Chen
- The Organ Transplantation Department of 924th Hospital of Joint Logistic Support Force of PLA, Guilin, China
| | - Wenjun Pu
- Shenzhen People's Hospital, Shenzhen, Guangdong, China
| | - Qiang Yan
- The Organ Transplantation Department of 924th Hospital of Joint Logistic Support Force of PLA, Guilin, China
| | - Yaoshuang Zou
- The Organ Transplantation Department of 924th Hospital of Joint Logistic Support Force of PLA, Guilin, China
| | - Sheng Sean Su
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Lingling Zhou
- School of Medicine, Anhui University of Science & Technology, Huainan, China
- Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Huainan, China
| | - Yali Peng
- School of Medicine, Anhui University of Science & Technology, Huainan, China
| | - Guoying Wang
- School of Medicine, Anhui University of Science & Technology, Huainan, China
| | - Tiantian Xu
- School of Medicine, Anhui University of Science & Technology, Huainan, China
| | - Xuejia Zheng
- The First Hospital of Anhui University of Science and Technology, Huainan, China
| | - Mengyao Wu
- School of Medicine, Anhui University of Science & Technology, Huainan, China
| | - Yong Dai
- School of Medicine, Anhui University of Science & Technology, Huainan, China.
- Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Huainan, China.
- The Organ Transplantation Department of 924th Hospital of Joint Logistic Support Force of PLA, Guilin, China.
- The First Hospital of Anhui University of Science and Technology, Huainan, China.
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Zhou X, Li R, Lai M, Lai C. Exploring molecular and cellular mechanisms of Pre-Metastatic niche in renal cell carcinoma. Mol Cancer 2025; 24:121. [PMID: 40264130 PMCID: PMC12012986 DOI: 10.1186/s12943-025-02315-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Accepted: 03/25/2025] [Indexed: 04/24/2025] Open
Abstract
Renal cell carcinoma (RCC) is among the most frequently occurring types of cancer, and its metastasis is a major contributor to its elevated mortality. Before the primary tumor metastasizes to secondary or distant organs, it remodels the microenvironment of these sites, creating a pre-metastatic niche (PMN) conducive to the colonization and growth of metastatic tumors. RCC releases a variety of biomolecules that induce angiogenesis, alter vascular permeability, modulate immune cells to create an immunosuppressive microenvironment, affect extracellular matrix remodeling and metabolic reprogramming, and determine the organotropism of metastasis through different signaling pathways. This review summarizes the principal processes and mechanisms underlying the formation of the premetastatic niche in RCC. Additionally, we emphasize the significance and potential of targeting PMNs for the prevention and treatment of tumor metastasis in future therapeutic approaches. Finally, we summarized the currently potential targeted strategies for detecting and treating PMN in RCC and provide a roadmap for further in-depth studies on PMN in RCC.
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Affiliation(s)
- Xiao Zhou
- Department of Pathology, and Department of Pathology Sir Run Run Shaw Hospital, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Science (2019RU042), Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
| | - Ruirui Li
- Institute of Immunology, Department of Respiratory Disease of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
| | - Maode Lai
- Department of Pathology, and Department of Pathology Sir Run Run Shaw Hospital, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Science (2019RU042), Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
| | - Chong Lai
- Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
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3
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Tagore S, Caprio L, Amin AD, Bestak K, Luthria K, D'Souza E, Barrera I, Melms JC, Wu S, Abuzaid S, Wang Y, Jakubikova V, Koch P, Brodtman DZ, Bawa B, Deshmukh SK, Ebel L, Ibarra-Arellano MA, Jaiswal A, Gurjao C, Biermann J, Shaikh N, Ramaradj P, Georgis Y, Lagos GG, Ehrlich MI, Ho P, Walsh ZH, Rogava M, Politis MG, Biswas D, Cottarelli A, Rizvi N, Shu CA, Herzberg B, Anandasabapathy N, Sledge G, Zorn E, Canoll P, Bruce JN, Rizvi NA, Taylor AM, Saqi A, Hibshoosh H, Schwartz GK, Henick BS, Chen F, Schapiro D, Shah P, Izar B. Single-cell and spatial genomic landscape of non-small cell lung cancer brain metastases. Nat Med 2025; 31:1351-1363. [PMID: 40016452 DOI: 10.1038/s41591-025-03530-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 01/19/2025] [Indexed: 03/01/2025]
Abstract
Brain metastases frequently develop in patients with non-small cell lung cancer (NSCLC) and are a common cause of cancer-related deaths, yet our understanding of the underlying human biology is limited. Here we performed multimodal single-nucleus RNA and T cell receptor, single-cell spatial and whole-genome sequencing of brain metastases and primary tumors of patients with treatment-naive NSCLC. Chromosomal instability (CIN) is a distinguishing genomic feature of brain metastases compared with primary tumors, which we validated through integrated analysis of molecular profiling and clinical data in 4,869 independent patients, and a new cohort of 12,275 patients with NSCLC. Unbiased analyses revealed transcriptional neural-like programs that strongly enriched in cancer cells from brain metastases, including a recurring, CINhigh cell subpopulation that preexists in primary tumors but strongly enriched in brain metastases, which was also recovered in matched single-cell spatial transcriptomics. Using multiplexed immunofluorescence in an independent cohort of treatment-naive pairs of primary tumors and brain metastases from the same patients with NSCLC, we validated genomic and tumor-microenvironmental findings and identified a cancer cell population characterized by neural features strongly enriched in brain metastases. This comprehensive analysis provides insights into human NSCLC brain metastasis biology and serves as an important resource for additional discovery.
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Affiliation(s)
- Somnath Tagore
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Department of Systems Biology, Program for Mathematical Genomics, Columbia University, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Lindsay Caprio
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Amit Dipak Amin
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Kresimir Bestak
- Institute for Computational Biomedicine, Faculty of Medicine, University Hospital Heidelberg and Heidelberg University, Heidelberg, Germany
| | - Karan Luthria
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Edridge D'Souza
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Irving Barrera
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Johannes C Melms
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Sharon Wu
- Caris Life Sciences, Phoenix, AZ, USA
| | - Sinan Abuzaid
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Yiping Wang
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Department of Systems Biology, Program for Mathematical Genomics, Columbia University, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Viktoria Jakubikova
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Peter Koch
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - D Zack Brodtman
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Banpreet Bawa
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | | | - Leon Ebel
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Miguel A Ibarra-Arellano
- Institute for Computational Biomedicine, Faculty of Medicine, University Hospital Heidelberg and Heidelberg University, Heidelberg, Germany
| | - Abhinav Jaiswal
- Department of Dermatology, Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, New York, NY, USA
| | - Carino Gurjao
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Department of Systems Biology, Program for Mathematical Genomics, Columbia University, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Jana Biermann
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Department of Systems Biology, Program for Mathematical Genomics, Columbia University, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Neha Shaikh
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Priyanka Ramaradj
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Yohanna Georgis
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Galina G Lagos
- Lifespan Cancer Institute, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Matthew I Ehrlich
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Patricia Ho
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Zachary H Walsh
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Meri Rogava
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Michelle Garlin Politis
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Devanik Biswas
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Azzurra Cottarelli
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Nikhil Rizvi
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Catherine A Shu
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Benjamin Herzberg
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Niroshana Anandasabapathy
- Department of Dermatology, Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, New York, NY, USA
| | | | - Emmanuel Zorn
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Peter Canoll
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Jeffrey N Bruce
- Department of Neurological Surgery, New York Presbyterian/Columbia University Irving Medical Center, New York, NY, USA
| | - Naiyer A Rizvi
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Synthekine Inc., Menlo Park, CA, USA
| | - Alison M Taylor
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Anjali Saqi
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Hanina Hibshoosh
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Gary K Schwartz
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Brian S Henick
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Fei Chen
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Denis Schapiro
- Institute for Computational Biomedicine, Faculty of Medicine, University Hospital Heidelberg and Heidelberg University, Heidelberg, Germany
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
- Translational Spatial Profiling Center (TPSC), Heidelberg, Germany
| | - Parin Shah
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Benjamin Izar
- Division of Hematology/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
- Department of Systems Biology, Program for Mathematical Genomics, Columbia University, New York, NY, USA.
- Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.
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Xiang J, Wang J, Xiao H, Huang C, Wu C, Zhang L, Qian C, Xiang D. Targeting tumor-associated macrophages in colon cancer: mechanisms and therapeutic strategies. Front Immunol 2025; 16:1573917. [PMID: 40191202 PMCID: PMC11968422 DOI: 10.3389/fimmu.2025.1573917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 03/10/2025] [Indexed: 04/09/2025] Open
Abstract
Colon cancer (CC) remains a primary contributor to cancer-related fatalities worldwide, driven by difficulties in early diagnosis and constrained therapeutic options. Recent studies underscore the importance of the tumor microenvironment (TME), notably tumor-associated macrophages (TAMs), in fostering malignancy progression and therapy resistance. Through their inherent plasticity, TAMs facilitate immunosuppression, angiogenic processes, metastatic spread, and drug tolerance. In contrast to M1 macrophages, which promote inflammatory and tumoricidal responses, M2 macrophages support tumor expansion and dissemination by exerting immunosuppressive and pro-angiogenic influences. Consequently, manipulating TAMs has emerged as a potential avenue to enhance treatment effectiveness. This review outlines the origins, polarization states, and functions of TAMs in CC, highlights their role in driving tumor advancement, and surveys ongoing efforts to target these cells for better patient outcomes. Emerging therapeutic strategies aimed at modulating TAM functions - including depletion strategies, reprogramming approaches that shift M2-polarized TAMs toward an M1 phenotype, and inhibition of key signaling pathways sustaining TAM-mediated immunosuppression-are currently under active investigation. These approaches hold promise in overcoming TAM - induced resistance and improving immunotherapeutic efficacy in CC.
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Affiliation(s)
- Jianqin Xiang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Jian Wang
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Huihui Xiao
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Chengchen Huang
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Chunrong Wu
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Lin Zhang
- Department of Gastroenterology, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Chenyuan Qian
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Debing Xiang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China
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5
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Ion G, Bostan M, Hardman WE, Putt McFarland M, Bleotu C, Radu N, Diaconu CC, Mihaila M, Caramihai MD, Hotnog CM. Nutrients Lowering Obesity-Linked Chemokines Blamable for Metastasis. Int J Mol Sci 2025; 26:2275. [PMID: 40076892 PMCID: PMC11899810 DOI: 10.3390/ijms26052275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 02/25/2025] [Accepted: 02/27/2025] [Indexed: 03/14/2025] Open
Abstract
Food intake is an essential contributor to both health and disease. Nutrients contribute to a beneficial metabolic equilibrium at the cellular level, preventing or delaying disease onset. Dietary intake contributes to obesity, and obesity supports further cancer and metastasis. Metastasis, a multifactorial and multistep process, is supported by the systemic inflammation of obesity. Spreading of the cancer cells requires the presence of a plethora of recruiter and regulator molecules. Molecules such as chemokines are provided at high levels by obesity-associated fat depots. Chemokine up-regulation in adipose tissue of obese individuals has been associated with different types of cancers such as breast, prostate, colon, liver, and stomach. Chemokines support all metastasis steps from invasion/migration to intravasation, circulation, extravasation, and ending with colonization. The obesity pool of chemokines supporting these processes includes CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL18, CCL19, CCL20, CXCL1, CXCL5, CXCL 8, CXCL10, and CXCL12. Keeping obesity under control can be beneficial in reducing the levels of pro-inflammatory chemokines and the risk of poor cancer outcome. Nutrients can help, support, and boost cancer treatment effects or jeopardize the treatment. Constituents with anti-inflammatory and anti-obesity properties such as polyphenols, organosulfur components, fatty acids, curcumin, and vitamin E have a proven beneficial effect in lowering obesity and its contribution to metastasis.
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Affiliation(s)
- Gabriela Ion
- Center of Immunology, Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (G.I.); (C.M.H.)
| | - Marinela Bostan
- Center of Immunology, Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (G.I.); (C.M.H.)
- Department of Immunology, ‘Victor Babes’ National Institute of Pathology, 050096 Bucharest, Romania
| | - Wanda Elaine Hardman
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA (M.P.M.)
| | - Margaret Putt McFarland
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA (M.P.M.)
| | - Coralia Bleotu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (C.B.); (C.C.D.)
- Research Institute of the University of Bucharest (ICUB), University of Bucharest, 060023 Bucharest, Romania
- The Academy of Romanian Scientist, 050711 Bucharest, Romania
| | - Nicoleta Radu
- Faculty of Biotechnology, University of Agronomic Sciences and Veterinary Medicine of Bucharest, 011464 Bucharest, Romania;
- Biotechnology Department, National Institute for Chemistry and Petrochemistry R&D of Bucharest, 060021 Bucharest, Romania
| | - Carmen Cristina Diaconu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (C.B.); (C.C.D.)
| | - Mirela Mihaila
- Center of Immunology, Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (G.I.); (C.M.H.)
- Faculty of Pharmacy, Titu Maiorescu University, 040314 Bucharest, Romania
| | - Mihai Dan Caramihai
- Faculty of Automatic Control and Computer Science, National University of Science and Technology Politehnica Bucharest, 060042 Bucharest, Romania;
| | - Camelia Mia Hotnog
- Center of Immunology, Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (G.I.); (C.M.H.)
- Department of Biochemistry and Biophysics, Faculty of Midwives and Nursing, University of Medicine and Pharmacy “Carol Davila” Bucharest, 050474 Bucharest, Romania
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6
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Zou M, Qattan A, Al-Alwan M, Ghebeh H, Binjumah N, Al-Haj L, Khabar KSA, Altaweel A, Almohanna F, Assiri AM, Aboussekhra A, Alzahrani AS, Shi Y. Genome-wide transcriptome analysis and drug target discovery reveal key genes and pathways in thyroid cancer metastasis. Front Endocrinol (Lausanne) 2025; 16:1514264. [PMID: 39996058 PMCID: PMC11847698 DOI: 10.3389/fendo.2025.1514264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Accepted: 01/24/2025] [Indexed: 02/26/2025] Open
Abstract
Introduction Metastasis is the major cause of thyroid cancer morbidity and mortality. However, the mechanisms are still poorly understood. Methods We performed genome-wide transcriptome analysis comparing gene expression profile of metastatic thyroid cancer cells (Met) with primary tumor cells established from transgenic mouse models of papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid cancer (ATC). Results Genes involved in tumor microenvironment (TME), inflammation, and immune escape were significantly overexpressed in Met cells. Notably, IL-6-mediated inflammatory and PD-L1 pathways were highly active in Met cells with increased secretion of pro-inflammatory and pro-metastatic cytokines such as CCL2, CCL11, IL5, IL6, and CXCL5. Furthermore, Met cells showed robust overexpression of Tbxas1, a thromboxane A synthase 1 gene that catalyzes the conversion of prostaglandin H2 to thromboxane A2 (TXA2), a potent inducer of platelet aggregation. Application of aspirin, a TXA2 inhibitor, significantly reduced lung metastases. Mertk, a member of the TAM (Tyro, Axl, Mertk) family of RTKs, was also overexpressed in Met cells, which led to increased MAPK activation, epithelial-mesenchymal transition (EMT), and enrichment of cancer stem cells. Braf-mutant Met cells developed resistance to BRAFV600E inhibitor PLX4720, but remained sensitive to β-catenin inhibitor PKF118-310. Conclusion We have identified several overexpressed genes/pathways in thyroid cancer metastasis, making them attractive therapeutic targets. Given the complexity of metastasis involving multiple pathways (PD-L1, Mertk, IL6, COX-1/Tbxas1-TXA2), simultaneously targeting more than one of these pathways may be warranted to achieve better therapeutic effect for metastatic thyroid cancer.
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Affiliation(s)
- Minjing Zou
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Amal Qattan
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Monther Al-Alwan
- Department of Cell Therapy and Immunobiology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Hazem Ghebeh
- Department of Cell Therapy and Immunobiology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Naif Binjumah
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Latifa Al-Haj
- Department of Molecular Biomedicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Khalid S. A. Khabar
- Department of Molecular Biomedicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Abdulmohsen Altaweel
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Falah Almohanna
- Department of Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Abdullah M. Assiri
- Department of Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Abdelilah Aboussekhra
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Ali S. Alzahrani
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Yufei Shi
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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7
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Xue B, Qualls C, Lanthiez A, Lu QY, Yang J, Lee RP, Neis P, Mao JT. The Effects of a Grape Seed Procyanidin Extract on Cytochrome P450 3A4 Activity and Inflammatory Mediators in the Lungs of Heavy Active and Former Smokers. Int J Mol Sci 2024; 25:13105. [PMID: 39684816 DOI: 10.3390/ijms252313105] [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: 10/30/2024] [Revised: 11/26/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
Grape seed procyanidin extract (GSE) is widely used to promote cardiovascular health and has purported anti-inflammatory properties. Chronic inflammation in the lungs caused by environmental toxins such as tobacco smoking plays a pivotal role in lung cancer development. In a modified phase I lung cancer chemoprevention study conducted in heavy active and former smokers using leucoselect phytosome (LP), a standardized grape seed procyanidin extract complexed with soy phospholipids to enhance bioavailability, three months of LP treatment favorably modulated a variety of surrogate endpoint biomarkers, including markers of cell proliferation. In this correlative study, we further analyzed the effects of LP on cytochrome P450 3A4 (CYP3A4) activities by comparing the endogenous conversions of cortisol and cortisone to 6-beta-hydroxycortisol and 6-beta-hydroxycortisone, respectively, before and after LP treatment and the anti-inflammatory effects of LP in the lung microenvironment of these participants by comparing a profile of inflammatory cytokines and chemokines in matched pre- and post-treatment bronchoalveolar lavage (BAL) fluids. LP treatment did not significantly alter CYP3A4 activity, and three months of LP treatment significantly decreased tumor necrosis factor (TNF), C-C Motif Chemokine Ligand 3 (CCL3) and granzyme B in BAL fluids. Furthermore, post-LP-treatment BAL fluids significantly reduced migration/invasion of various human lung neoplastic cells in vitro. Our findings support the anti-inflammatory effects of GSE/LP in the lung microenvironment and its potential utility for reducing cancerizing forces, as well as driving forces for other common respiratory diseases such as chronic obstructive pulmonary disease and asthma, in the lungs of heavy former and active smokers.
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Affiliation(s)
- Bingye Xue
- Pulmonary, Critical Care and Sleep Section, New Mexico Veterans Administration Health Care System, University of New Mexico, Albuquerque, NM 87108, USA
| | - Clifford Qualls
- Biostatistics, Biomedical Research Institute of New Mexico, New Mexico Veterans Administration Health Care System, University of New Mexico, Albuquerque, NM 87108, USA
| | - Alexander Lanthiez
- Pulmonary and Critical Care Section, Veterans Administration San Diego Healthcare System, University of California San Diego, La Jolla, CA 92161, USA
| | - Qing-Yi Lu
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Jieping Yang
- UCLA Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Ru-Po Lee
- UCLA Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Patricia Neis
- Pulmonary, Critical Care and Sleep Section, New Mexico Veterans Administration Health Care System, University of New Mexico, Albuquerque, NM 87108, USA
| | - Jenny T Mao
- Pulmonary, Critical Care and Sleep Section, New Mexico Veterans Administration Health Care System, University of New Mexico, Albuquerque, NM 87108, USA
- Pulmonary and Critical Care Section, Veterans Administration San Diego Healthcare System, University of California San Diego, La Jolla, CA 92161, USA
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8
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Shen C, Zhu X, Chang H, Li C, Hou M, Chen L, Lu Chen, Zhou Z, Ji M, Xu Z. The rebalancing of the immune system at the maternal-fetal interface ameliorates autism-like behavior in adult offspring. Cell Rep 2024; 43:114787. [PMID: 39321022 DOI: 10.1016/j.celrep.2024.114787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 07/04/2024] [Accepted: 09/06/2024] [Indexed: 09/27/2024] Open
Abstract
Maternal immune activation (MIA) is critical for imparting neuropathology and altered behaviors in offspring; however, maternal-fetal immune cell populations have not been thoroughly investigated in MIA-induced autism spectrum disorders (ASDs). Here, we report the single-cell transcriptional landscape of placental cells in both PBS- and poly(I:C)-induced MIA dams. We observed a decrease in regulatory T (Treg) cells but an increase in the M1 macrophage population at the maternal-fetal interface in MIA dams. Based on the Treg-targeting approach, we investigate an immunoregulatory protein, the helminth-derived heat shock protein 90α (Sjp90α), that induces maternal Treg cells and subsequently rescues the autism-like behaviors in adult offspring. Furthermore, in vivo depletion of maternal macrophages attenuates placental inflammatory reaction and reverses behavioral abnormalities in adult offspring. Notably, Sjp90α induces CD4+ T cell differentiation via scavenger receptor A (SR-A) on the macrophage in vitro. Our findings suggest a maternal Treg-targeted approach to alleviate MIA-induced autism-like behavior in adult offspring.
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Affiliation(s)
- Chunxiang Shen
- State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Pathogen Biology and Immunology, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Xinyi Zhu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Pathogen Biology and Immunology, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Hao Chang
- State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Pathogen Biology and Immunology, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Chen Li
- State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Pathogen Biology and Immunology, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Min Hou
- State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Pathogen Biology and Immunology, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China; Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing, Jiangsu 211166, P.R. China
| | - Lin Chen
- Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing, Jiangsu 211166, P.R. China
| | - Lu Chen
- Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing, Jiangsu 211166, P.R. China
| | - Zikai Zhou
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Guangdong 528400, P.R. China.
| | - Minjun Ji
- State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Pathogen Biology and Immunology, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China; Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing, Jiangsu 211166, P.R. China; NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China.
| | - Zhipeng Xu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Pathogen Biology and Immunology, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China; Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing, Jiangsu 211166, P.R. China; NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China.
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9
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Li X, Cui J, Wang L, Cao C, Liu H. Integrated multi-omics profiling reveals the ZZZ3/CD70 axis is a super-enhancer-driven regulator of diffuse large B-cell lymphoma cell-natural killer cell interactions. Exp Biol Med (Maywood) 2024; 249:10155. [PMID: 39376717 PMCID: PMC11457841 DOI: 10.3389/ebm.2024.10155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 08/27/2024] [Indexed: 10/09/2024] Open
Abstract
Tumor immune microenvironment is crucial for diffuse large B-cell lymphoma (DLBCL) development. However, the mechanisms by which super-enhancers (SEs) regulate the interactions between DLBCL cells and tumor-infiltrating immune cells remains largely unknown. This study aimed to investigate the role of SE-controlled genes in regulating the interactions between DLBCL cells and tumor-infiltrating immune cells. Single-cell RNA-seq, bulk RNA-seq and H3K27ac ChIP-seq data were downloaded from the Heidelberg Open Research Data database and Gene Expression Omnibus database. HOMER algorithm and Seurat package in R were used for bioinformatics analysis. Cell proliferation and lactate dehydrogenase (LDH) release was detected by MTS and LDH release assays, respectively. Interaction between B cell cluster and CD8+ T cell and NK cell cluster was most obviously enhanced in DLBCL, with CD70-CD27, MIF-CD74/CXCR2 complex, MIF-CD74/CD44 complex and CCL3-CCR5 interactions were significantly increased. NK cell sub-cluster showed the strongest interaction with B cell cluster. ZZZ3 upregulated the transcription of CD70 by binding to its SE. Silencing CD70 in DOHH2 cells significantly promoted the proliferation of co-cultured NK92 cells and LDH release from DOHH2 cells, which was counteracted by ZZZ3 overexpression in DOHH2 cells. CD70 silencing combined with PD-L1 blockade promoted LDH release from DOHH2 cells co-cultured with NK92 cells. In conclusion, DLBCL cells inhibited the proliferation and killing of infiltrating NK cells by regulating ZZZ3/CD70 axis. Targeting ZZZ3/CD70 axis combined with PD-L1 blockade is expected to be a promising strategy for DLBCL treatment.
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MESH Headings
- Lymphoma, Large B-Cell, Diffuse/metabolism
- Lymphoma, Large B-Cell, Diffuse/pathology
- Lymphoma, Large B-Cell, Diffuse/genetics
- Humans
- Killer Cells, Natural/metabolism
- Killer Cells, Natural/immunology
- CD27 Ligand/metabolism
- CD27 Ligand/genetics
- Cell Line, Tumor
- Tumor Microenvironment
- Gene Expression Regulation, Neoplastic
- Cell Proliferation
- Multiomics
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10
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Jung H, Paust S. Chemokines in the tumor microenvironment: implications for lung cancer and immunotherapy. Front Immunol 2024; 15:1443366. [PMID: 39114657 PMCID: PMC11304008 DOI: 10.3389/fimmu.2024.1443366] [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: 06/03/2024] [Accepted: 07/01/2024] [Indexed: 08/10/2024] Open
Abstract
The tumor microenvironment (TME) is a complex interconnected network of immune cells, fibroblasts, blood vessels, and extracellular matrix surrounding the tumor. Because of its immunosuppressive nature, the TME can pose a challenge for cancer immunotherapies targeting solid tumors. Chemokines have emerged as a crucial element in enhancing the efficacy of cancer immunotherapy, playing a direct role in immune cell signaling within the TME and facilitating immune cell migration towards cancer cells. However, chemokine ligands and their receptors exhibit context-dependent diversity, necessitating evaluation of their tumor-promoting or inhibitory effects based on tumor type and immune cell characteristics. This review explores the role of chemokines in tumor immunity and metastasis in the context of the TME. We also discuss current chemokine-related advances in cancer immunotherapy research, with a particular focus on lung cancer, a common cancer with a low survival rate and limited immunotherapy options.
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Affiliation(s)
| | - Silke Paust
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States
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11
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Lu T, Shi Y, Wang M, Liu W, Cao Y, Shi L, Ma Q, Liu S. CCR5 promoter polymorphisms associated with nonsmall cell lung cancer. Int J Immunogenet 2024; 51:10-19. [PMID: 37962280 DOI: 10.1111/iji.12644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 09/19/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023]
Abstract
C-C chemokine receptor 5 (CCR5) plays a crucial role in the regulation of immune cell activation and migration as well as the progression of many cancers. We performed an in silico analysis using public data resources and found that the lung cancer patients with higher CCR5 expression had a notably better overall survival than those with lower CCR5 expression patients and CCR5 expression level is positive correlated with the infiltration of immune cells, such as B, CD8+ T and CD4+ T cells, in both lung adenocarcinoma and lung squamous cell cancer. In the present study, we investigated the association between the promoter polymorphism of CCR5 and nonsmall cell lung cancer (NSCLC). A case-control study of 449 NSCLC patients and 516 controls of Chinese Han population was conducted, along with polymorphism detection using a sequencing method. A dual-luciferase reporter assay system was used to analyse the transcriptional activity of CCR5 promoter variations. Our results showed that the frequency of rs1799987-AA was significantly higher in the NSCLC group than in the controls in recessive model (p = .007, OR = 1.66 95% confidence interval [CI]: 1.14-2.40, adjusted by sex and age); the G allele showed a significant associated with NSCLC in dominant model (p = .003, OR = 1.64, 95%CI: 1.18-2.28, adjusted by sex and age). Compared with haplotype H1 rs2227010-rs2734648-rs1799987-rs1799988-rs1800023-rs1800024: A-T-G-T-G-C, haplotype H5: A-G-G-T-G-C increased the risk of NSCLC by over 10-fold (p < .0001, OR = 16.09, 95%CI: 5.37-48.20, adjusted by sex and age) and notably depressed the transcriptional activity of the CCR5 promoter in 293T, A549, H1299 and HeLa cells. In conclusion, CCR5 promoter polymorphisms are significantly associated with NSCLC by affecting the transcriptional activity of the CCR5 promoter.
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Affiliation(s)
- Tianchang Lu
- Department of Immunogenetics, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, China
| | - Yuhan Shi
- College of Agronomy and Biotechnology of Yunnan Agricultural University, Kunming, China
| | - Minyi Wang
- School of Life Science, Yunnan University, Kunming, China
| | - Weipeng Liu
- Institute of Medical Biology, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, China
| | - Yang Cao
- Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Li Shi
- Department of Immunogenetics, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, China
| | - Qianli Ma
- Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Shuyuan Liu
- Department of Immunogenetics, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, China
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12
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Hu D, Lin Z, Li P, Zhang Z, Jiang J, Yang C. Investigation of Potential Crucial Genes and Key Pathways in Keratoconus: An Analysis of Gene Expression Omnibus Data. Biochem Genet 2023; 61:2724-2740. [PMID: 37233843 DOI: 10.1007/s10528-023-10398-6] [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: 01/08/2023] [Accepted: 05/07/2023] [Indexed: 05/27/2023]
Abstract
Keratoconus is one of the most common causes leading to visual impairment in young adult population. The pathogenesis of keratoconus remains poorly understood. The aim of this study was to identify the potential key genes and pathways associated with keratoconus and to further analyze its molecular mechanism. Two RNA-sequencing datasets of keratoconus and paired normal corneal tissues from the Gene Expression Omnibus database were obtained. Differentially expressed genes (DEGs) were identified, and the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted. The protein-protein interaction (PPI) network of the DEGs was established, and the hub genes and significant gene modules of PPI were further constructed. Lastly, the GO and KEGG analyses of the hub gene were performed. In total, 548 common DEGs were identified. GO enrichment analysis showed that the DEGs were primarily associated with regulation of cell adhesion, the response to molecule of bacterial origin, lipopolysaccharide and biotic stimulus, collagen-containing extracellular matrix, extracellular matrix, and structure organization. KEGG pathway analysis showed that these DEGs were mainly involved in the TNF signaling pathway, IL-17 signaling pathway, Rheumatoid arthritis, Cytokine-cytokine receptor interaction. The PPI network was constructed with 146 nodes and 276 edges, and 3 significant modules are selected. Finally, top 10 hub genes were identified from the PPI network. The results revealed that extracellular matrix remodeling and immune inflammatory response could be the key links of keratoconus, TNF, IL6, IL1A, IL1B, CCL3, MMP3, MMP9, MMP1, and TGFB1 may be potential crucial genes, and TNF signaling pathway and IL-17 signaling pathway were the potential pathways accounting for pathogenesis and development of keratoconus.
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Affiliation(s)
- Di Hu
- Department of Ophthalmology, Children's Hospital of Fudan University, No.399 Wanyuan Road, Shanghai, 201102, China
| | - Zenan Lin
- Department of Ophthalmology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, No.100 Haining Road, Shanghai, 200080, China
| | - Pan Li
- Department of Ophthalmology, First Hospital of Xi'an, Institute of Ophthalmology, Key Lab of Ophthalmology, Clinical Center for Ophthalmology, Xi'an, 710002, China
| | - Zhehuan Zhang
- Department of Ophthalmology, Children's Hospital of Fudan University, No.399 Wanyuan Road, Shanghai, 201102, China
| | - Junhong Jiang
- Department of Ophthalmology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, No.100 Haining Road, Shanghai, 200080, China.
| | - Chenhao Yang
- Department of Ophthalmology, Children's Hospital of Fudan University, No.399 Wanyuan Road, Shanghai, 201102, China.
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13
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Alloferon and Zanamivir Show Effective Antiviral Activity against Influenza A Virus (H1N1) Infection In Vitro and In Vivo. Int J Mol Sci 2022; 24:ijms24010678. [PMID: 36614125 PMCID: PMC9820929 DOI: 10.3390/ijms24010678] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/11/2022] [Accepted: 12/15/2022] [Indexed: 01/03/2023] Open
Abstract
The use of vaccines is the most effective and reliable method for the prevention of viral infections. However, research on evaluation of effective therapeutic agents for use in treatment after infection is necessary. Zanamivir was administered through inhalation for treatment of pandemic influenza A/H1N1 in 2009. However, the emergence of drug-resistant strains can occur rapidly. Alloferon, an immunomodulatory drug developed as an NK cell activator, exerts antiviral effects against various viruses, particularly influenza viruses. Therefore, alloferon and zanamivir were administered in combination in an effort to improve the antiviral effect of zanamivir by reducing H1N1 resistance. First, we confirmed that administration of combined treatment would result in effective inhibition of viral proliferation in MDCK and A549 cells infected with H1N1. Production of IL-6 and MIP-1α in these cells and the activity of p38 MAPK and c-Jun that are increased by H1N1 were inhibited by combined treatment. Mice were then infected intranasally with H1N1, and examination of the antiviral efficacy of the alloferon/zanamivir combination was performed. The results showed that combined treatment after infection with H1N1 prevented weight loss, increased the survival rate, and improved lung fibrosis. Combined treatment also resulted in reduced infiltration of neutrophils and macrophages into the lungs. Combined treatment effectively inhibited the activity of p38 MAPK and c-Jun in lung tissue, which was increased by infection with H1N1. Therefore, the combination of alloferon/zanamivir effectively prevents the development of H1N1-mediated inflammation in the lungs by inhibiting the production of inflammatory mediators and migration of inflammatory cells into lung tissue.
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14
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Raghani RM, Ma JA, Zhang Y, Orbach SM, Wang J, Zeinali M, Nagrath S, Kakade S, Xu Q, Podojil JR, Murthy T, Elhofy A, Jeruss JS, Shea LD. Myeloid cell reprogramming alleviates immunosuppression and promotes clearance of metastatic lesions. Front Oncol 2022; 12:1039993. [PMID: 36479083 PMCID: PMC9720131 DOI: 10.3389/fonc.2022.1039993] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 11/02/2022] [Indexed: 11/22/2022] Open
Abstract
Suppressive myeloid cells, including monocyte and neutrophil populations, play a vital role in the metastatic cascade and can inhibit the anti-tumor function of cytotoxic T-cells. Cargo-free polymeric nanoparticles (NPs) have been shown to modulate innate immune cell responses in multiple pathologies of aberrant inflammation. Here, we test the hypothesis that the intravenous administration of drug-free NPs in the 4T1 murine model of metastatic triple-negative breast cancer can reduce metastatic colonization of the lungs, the primary metastatic site, by targeting the pro-tumor immune cell mediators of metastatic progression. In vivo studies demonstrated that NP administration reprograms the immune milieu of the lungs and reduces pulmonary metastases. Single-cell RNA sequencing of the lungs revealed that intravenous NP administration alters myeloid cell phenotype and function, skewing populations toward inflammatory, anti-tumor phenotypes and away from pro-tumor phenotypes. Monocytes, neutrophils, and dendritic cells in the lungs of NP-treated mice upregulate gene pathways associated with IFN signaling, TNF signaling, and antigen presentation. In a T-cell deficient model, NP administration failed to abrogate pulmonary metastases, implicating the vital role of T-cells in the NP-mediated reduction of metastases. NPs delivered as an adjuvant therapy, following surgical resection of the primary tumor, led to clearance of established pulmonary metastases in all treated mice. Collectively, these results demonstrate that the in vivo administration of cargo-free NPs reprograms myeloid cell responses at the lungs and promotes the clearance of pulmonary metastases in a method of action dependent on functional T-cells.
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Affiliation(s)
- Ravi M. Raghani
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
| | - Jeffrey A. Ma
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
| | - Yining Zhang
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, United States
| | - Sophia M. Orbach
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
| | - Jing Wang
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
| | - Mina Zeinali
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, United States
| | - Sunitha Nagrath
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, United States
| | - Sandeep Kakade
- COUR Pharmaceuticals Development Co, Inc, Northbrook, IL, United States
| | - Qichen Xu
- COUR Pharmaceuticals Development Co, Inc, Northbrook, IL, United States
| | - Joseph R. Podojil
- COUR Pharmaceuticals Development Co, Inc, Northbrook, IL, United States
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Tushar Murthy
- COUR Pharmaceuticals Development Co, Inc, Northbrook, IL, United States
| | - Adam Elhofy
- COUR Pharmaceuticals Development Co, Inc, Northbrook, IL, United States
| | - Jacqueline S. Jeruss
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
- Department of Surgery, University of Michigan, Ann Arbor, MI, United States
- Department of Pathology, University of Michigan, Ann Arbor, MI, United States
| | - Lonnie D. Shea
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, United States
- *Correspondence: Lonnie D. Shea,
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15
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Tudorancea IM, Ciorpac M, Stanciu GD, Caratașu C, Săcărescu A, Ignat B, Burlui A, Rezuș E, Creangă I, Alexa-Stratulat T, Tudorancea I, Tamba BI. The Therapeutic Potential of the Endocannabinoid System in Age-Related Diseases. Biomedicines 2022; 10:2492. [PMID: 36289755 PMCID: PMC9599275 DOI: 10.3390/biomedicines10102492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 09/24/2022] [Accepted: 10/03/2022] [Indexed: 11/25/2022] Open
Abstract
The endocannabinoid system (ECS) dynamically regulates many aspects of mammalian physiology. ECS has gained substantial interest since growing evidence suggests that it also plays a major role in several pathophysiological conditions due to its ability to modulate various underlying mechanisms. Furthermore, cannabinoids, as components of the cannabinoid system (CS), have proven beneficial effects such as anti-inflammatory, immunomodulatory, neuromodulatory, antioxidative, and cardioprotective effects. In this comprehensive review, we aimed to describe the complex interaction between CS and most common age-related diseases such as neuro-degenerative, oncological, skeletal, and cardiovascular disorders, together with the potential of various cannabinoids to ameliorate the progression of these disorders. Since chronic inflammation is postulated as the pillar of all the above-mentioned medical conditions, we also discuss in this paper the potential of CS to ameliorate aging-associated immune system dysregulation.
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Affiliation(s)
- Ivona Maria Tudorancea
- Advanced Research and Development Center for Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania
| | - Mitică Ciorpac
- Advanced Research and Development Center for Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania
| | - Gabriela Dumitrița Stanciu
- Advanced Research and Development Center for Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania
| | - Cătălin Caratașu
- Advanced Research and Development Center for Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania
| | - Alina Săcărescu
- Department of Medical Specialties II, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității, 700115 Iași, Romania
- Department of Neurology, Clinical Rehabilitation Hospital, 14 Pantelimon Halipa, 700661 Iași, Romania
| | - Bogdan Ignat
- Department of Neurology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
| | - Alexandra Burlui
- Department of Rheumatology and Rehabilitation, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
- Clinical Rehabilitation Hospital, 700661 Iași, Romania
| | - Elena Rezuș
- Department of Rheumatology and Rehabilitation, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
- Clinical Rehabilitation Hospital, 700661 Iași, Romania
| | - Ioana Creangă
- Advanced Research and Development Center for Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania
- Oncology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
| | - Teodora Alexa-Stratulat
- Oncology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
- Oncology Department, Regional Institute of Oncology, 700483 Iași, Romania
| | - Ionuț Tudorancea
- Department of Morpho-Functional Sciences II, Discipline of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
- Cardiology Clinic “St. Spiridon” County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Bogdan Ionel Tamba
- Advanced Research and Development Center for Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania
- Department of Pharmacology, Clinical Pharmacology and Algesiology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania
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Wang B, Zhang Y, Lou Y, Hu X, Li F. Initial research on the effect and mechanism of Tivozanib on pulsed dye laser induced angiogenesis. Lasers Surg Med 2022; 54:1157-1166. [PMID: 35916102 DOI: 10.1002/lsm.23586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 07/05/2022] [Accepted: 07/07/2022] [Indexed: 11/08/2022]
Abstract
INTRODUCTION Pulsed dye laser (PDL) is the main treatment for port wine stain (PWS), but a considerable number of patients show low clearances. The reason for the poor efficacy is related to PDL-induced angiogenesis. Vascular endothelial growth factor (VEGF) plays an important role in PDL-induced angiogenesis and can activate the tyrosine kinase activity of VEGF receptor (VEGFR) in endothelial cells. It triggers a full range of responses, and then participates in the regulation of angiogenesis. Tivozanib is an inhibitor of VEGFR tyrosine kinase activity, which can block the pro-angiogenic effect of VEGF and reduce vascular permeability. METHOD Different energy densities of PDL were used to irradiate the abdominal skin of rats. According to the general and pathological changes of the irradiated area, the energy density of 8 J/cm2 with smaller scab and stronger vascular effect was selected for follow-up experiments. Divided the rat abdomen skin into four areas, irradiated three of them uniformly with an energy density of 8 J/cm2 , and applied different concentrations of Tivozanib coating agent to the laser irradiation area, and grouped them as follows: (1) vacant group, (2) control group, (3) 0.5% Tivozanib group, (4) 1% Tivozanib group. Camera and dermoscopy were used to observe skin changes. Hematoxylin-eosin staining, immunohistochemical staining, and blood vessels were counted to detect dermal vascular regeneration. Transcriptome sequencing and real-time polymerase chain reaction (PCR) were conducted to elucidate the mechanism and validate the reliability. RESULTS The number of blood vessels in the 0.5% Tivozanib group and 1% Tivozanib group was significantly reduced on the 7, 10, and 14 days compared with the control group. The number of blood vessels in the 1% Tivozanib group was significantly reduced compared with the 0.5% Tivozanib group, indicating that Tivozanib successfully inhibited PDL-induced angiogenesis, and the inhibitory effect of 1% Tivozanib was more significant than that of 0.5% Tivozanib. Transcriptome sequencing results showed a total of 588 significantly differentially expressed genes, including 90 upregulated genes and 498 downregulated genes. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis showed that the significantly differentially expressed genes were mainly enriched in the metabolic pathways which were closely related to angiogenesis. Finally, real-time PCR was used to verify the genes with higher expression differences, the top ranking and closely related to angiogenesis, namely, Cxcl1, Cxcl2, Cxcl3, Cxcl6, Ccl3, Csf3, IL1β, iNOS, Mmp9, Mmp13, Plau, Ets1, Spp1, Nr4a1. The results were consistent with the trend of transcriptome sequencing results, which proved the reliability of this study. CONCLUSION This study explored the inhibitory effect of Tivozanib on PDL-induced angiogenesis, and provided a new idea for the treatment of clinical PWS. Transcriptome sequencing explored the mechanism and provided reliable clues for later in-depth research.
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Affiliation(s)
- Bing Wang
- Department of Dermatology, The Second Hospital of Jilin University, Changchun, P.R. China
| | - Yaqin Zhang
- Department of Dermatology, The Second Hospital of Jilin University, Changchun, P.R. China
| | - Yan Lou
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, P.R. China
| | - Xin Hu
- Department of Microbiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Fuqiu Li
- Department of Dermatology, The Second Hospital of Jilin University, Changchun, P.R. China
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17
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Xue MQ, Wang YL, Wang JC, Wang XD, Wang XJ, Zhang YQ. Comprehensive analysis of the PD-L1 and immune infiltrates of N6-methyladenosine related long non-coding RNAs in bladder cancer. Sci Rep 2022; 12:10082. [PMID: 35710698 PMCID: PMC9203575 DOI: 10.1038/s41598-022-14097-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 06/01/2022] [Indexed: 11/09/2022] Open
Abstract
Bladder cancer (BLCA) is one of the most frequent genitourinary cancers, with a high rate of morbidity and mortality. The connection of m6A-related lncRNAs with PD-L1 and tumor immune microenvironment (TIME) in BLCA prognosis was extensively investigated in this study, which could suggest novel therapeutic targets for further investigation. 30 m6A-associated lncRNAs with predictive values from the TCGA data set were identified with co-expression analysis. Cluster2 was correlated with a poor prognosis, upregulated PD-L1 expression, and higher immune ratings. Cluster2 had larger amounts of resting CD4 memory-activated T cells, M2 macrophages, neutrophils, and NK cells infiltration. "CHEMOKINE SIGNALING PATHWAY" was the most significantly enriched signaling pathway according to GSEA, which may play an important role in the different immune cell infiltrates between cluster1/2. The risk model for m6A-related lncRNAs could be employed in a prognostic model to predict BLCA prognosis, regardless of other clinical features. Collectively, m6A-related lncRNAs were linked to PD-L1 and TIME, which would dynamically affect the number of tumor-infiltrating immune cells. m6A-related lncRNAs may be key mediators of PD-L1 expression and immune cells infiltration and may strongly affect the TIME of BLCA.
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Affiliation(s)
- M Q Xue
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
| | - Y L Wang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China. .,Henan Bioengineering Technology Reseach Center, Zhengzhou, 450010, People's Republic of China.
| | - J C Wang
- Henan Bioengineering Technology Reseach Center, Zhengzhou, 450010, People's Republic of China
| | - X D Wang
- Henan General Hospital, Zhengzhou, 450002, People's Republic of China
| | - X J Wang
- Henan General Hospital, Zhengzhou, 450002, People's Republic of China
| | - Y Q Zhang
- Zhengzhou Technical College, Zhengzhou, 450010, People's Republic of China
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18
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Chang H, Ni Y, Shen C, Li C, He K, Zhu X, Chen L, Chen L, Qiu J, Ji Y, Hou M, Ji M, Xu Z. Peritoneal GATA6 + macrophage drives hepatic immunopathogenesis and maintains the T reg cell niche in the liver. Immunol Suppl 2022; 167:77-93. [PMID: 35689656 DOI: 10.1111/imm.13519] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 04/25/2022] [Indexed: 11/28/2022]
Abstract
The source of macrophages that contribute to human liver disease remains poorly understood. The purpose of this study is to investigate the functional mechanism of peritoneal macrophages in the development of hepatic immunopathology. By performing the natural infection with the blood fluke Schistosoma japonicum (S. japonicum) and the chemically carbon tetrachloride (CCl4 )-induced liver injured mouse model, we identified the peritoneal cavity as an essential source of hepatic macrophages. Here, we show that a large number of F4/80+ macrophages was accumulated in the peritoneal cavity during liver injury. An unknown source population of macrophages, which highly expressed GATA6 that is specific to peritoneal macrophages, was found to exist in the injured livers. Peritoneal macrophage deletion by injection with clodronate-containing liposomes led to an attenuated hepatic pathology and the inflammatory microenvironment, while adoptive transfer of macrophages into the abdominal cavity, by contrast, results in restoring liver pathology. Importantly, there are set genes of monocyte chemoattractant protein (MCP)-1, -2, and -3 that are highly related to recruit GATA6+ macrophages during S. japonicum infection, while administration of bindarit, a selective inhibitor of MCPs synthesis, dramatically decreased the hepatic expression of GATA6+ macrophages and thus attenuated hepatic pathology. Furthermore, in vivo study showed that peritoneal macrophages promote hepatic immunopathology is dependent on the accumulation of regulatory T cells (Tregs) in the liver. Altogether, these data provide the first clear evidence that GATA6+ peritoneal macrophages play critical roles in both the formation of hepatic immunopathology and the accumulation of Tregs cells.
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Affiliation(s)
- Hao Chang
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yangyue Ni
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chunxiang Shen
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chen Li
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Kaiyue He
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xinyi Zhu
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lin Chen
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lu Chen
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jingfan Qiu
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yong Ji
- Department of Cardiothoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Min Hou
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Minjun Ji
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China.,NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhipeng Xu
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China.,NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, Jiangsu, China
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19
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Sheng D, Ma W, Zhang R, Zhou L, Deng Q, Tu J, Chen W, Zhang F, Gao N, Dong M, Wang D, Li F, Liu Y, He X, Duan S, Zhang L, Liu T, Liu S. Ccl3 enhances docetaxel chemosensitivity in breast cancer by triggering proinflammatory macrophage polarization. J Immunother Cancer 2022; 10:jitc-2021-003793. [PMID: 35613826 PMCID: PMC9134178 DOI: 10.1136/jitc-2021-003793] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/14/2022] [Indexed: 11/21/2022] Open
Abstract
Background Although the antitumor efficacy of docetaxel (DTX) has long been attributed to the antimitotic activities, its impact on the tumor microenvironment (TME) has recently gained more attention. Macrophages are a major component of the TME and play a critical role in DTX efficacy; however, the underlying action mechanisms remain unclear. Methods DTX chemotherapeutic efficacy was demonstrated via both macrophage depletion and C–C motif chemokine ligand 3 (Ccl3)-knockout transgenic allograft mouse model. Ccl3-knockdown and Ccl3-overexpressing breast cancer cell allografts were used for the in vivo study. Combination therapy was used to evaluate the effect of Ccl3 induction on DTX chemosensitivity. Vital regulatory molecules and pathways were identified using RNA sequencing. Macrophage phagocytosis of cancer cells and its influence on cancer cell proliferation under DTX treatment were assessed using an in vitro coculture assay. Serum and tumor samples from patients with breast cancer were used to demonstrate the clinical relevance of our study. Results Our study revealed that Ccl3 induced by DTX in macrophages and cancer cells was indispensable for the chemotherapeutic efficacy of DTX. DTX-induced Ccl3 promoted proinflammatory macrophage polarization and subsequently facilitated phagocytosis of breast cancer cells and cancer stem cells. Ccl3 overexpression in cancer cells promoted proinflammatory macrophage polarization to suppress tumor progression and increase DTX chemosensitivity. Mechanistically, DTX induced Ccl3 by relieving the inhibition of cAMP-response element binding protein on Ccl3 via reactive oxygen species accumulation, and Ccl3 then promoted proinflammatory macrophage polarization via activation of the Ccl3–C-C motif chemokine receptor 5–p38/interferon regulatory factor 5 pathway. High CCL3 expression predicted better prognosis, and high CCL3 induction revealed better DTX chemosensitivity in patients with breast cancer. Furthermore, both the Creb inhibitor and recombinant mouse Ccl3 significantly enhanced DTX chemosensitivity. Conclusions Our results indicate that Ccl3 induced by DTX triggers proinflammatory macrophage polarization and subsequently facilitates phagocytosis of cancer cells. Ccl3 induction in combination with DTX may provide a promising therapeutic rationale for increasing DTX chemosensitivity in breast cancer.
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Affiliation(s)
- Dandan Sheng
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College; Fudan University, Shanghai, China
| | - Wei Ma
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College; Fudan University, Shanghai, China
| | - Rui Zhang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College; Fudan University, Shanghai, China
| | - Lei Zhou
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Qiaodan Deng
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College; Fudan University, Shanghai, China
| | - Juchuanli Tu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College; Fudan University, Shanghai, China
| | - Weilong Chen
- Intelligent Pathology Institute and Department of Pathology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Fuchuang Zhang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College; Fudan University, Shanghai, China
| | - Nailong Gao
- Department of Precision Machinery and Precision Instrumentation, University of Science and Technology of China, Hefei, China
| | - Mengxue Dong
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College; Fudan University, Shanghai, China
| | - Dong Wang
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Science, University of Science and Technology of China, Hefei, China
| | - Fengkai Li
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College; Fudan University, Shanghai, China
| | - Yin Liu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xueyan He
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College; Fudan University, Shanghai, China
| | - Shengzhong Duan
- Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lixing Zhang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College; Fudan University, Shanghai, China
| | - Tong Liu
- Department of Breast Surgery, Tumor Hospital of Harbin Medical University, Harbin, Heilongjiang, China .,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College; Fudan University, Shanghai, China .,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
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20
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To SKY, Tang MKS, Tong Y, Zhang J, Chan KKL, Ip PPC, Shi J, Wong AST. A Selective β-Catenin-Metadherin/CEACAM1-CCL3 Axis Mediates Metastatic Heterogeneity upon Tumor-Macrophage Interaction. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2103230. [PMID: 35403834 PMCID: PMC9165500 DOI: 10.1002/advs.202103230] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 01/31/2022] [Indexed: 05/23/2023]
Abstract
Tumor heterogeneity plays a key role in cancer relapse and metastasis, however, the distinct cellular behaviors and kinetics of interactions among different cancer cell subclones and the tumor microenvironment are poorly understood. By profiling an isogenic model that resembles spontaneous human ovarian cancer metastasis with an highly metastatic (HM) and non-metastatic (NM) tumor cell pair, one finds an upregulation of Wnt/β-catenin signaling uniquely in HM. Using humanized immunocompetent mice, one shows for the first time that activated β-catenin acts nonautonomously to modulate the immune microenvironment by enhancing infiltrating tumor-associated macrophages (TAM) at the metastatic site. Single-cell time-lapse microscopy further reveals that upon contact with macrophages, a significant subset of HM, but not NM, becomes polyploid, a phenotype pivotal for tumor aggressiveness and therapy resistance. Moreover, HM, but not NM, polarizes macrophages to a TAM phenotype. Mechanistically, β-catenin upregulates cancer cell surface metadherin, which communicates through CEACAM1 expressed on macrophages to produce CCL3. Tumor xenografts in humanized mice and clinical patient samples both corroborate the relevance of enhanced metastasis, TAM activation, and polyploidy in vivo. The results thus suggest that targeting the β-catenin-metadherin/CEACAM1-CCL3 positive feedback cascade holds great therapeutic potential to disrupt polyploidization of the cancer subclones that drive metastasis.
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Affiliation(s)
- Sally K. Y. To
- School of Biological SciencesThe University of Hong KongPokfulam RoadHong KongChina
| | - Maggie K. S. Tang
- School of Biological SciencesThe University of Hong KongPokfulam RoadHong KongChina
- Laboratory for Synthetic Chemistry and Chemical Biology Limited17W, Hong Kong Science and Technology Parks, New TerritoriesHong KongChina
| | - Yin Tong
- Department of PathologyThe University of Hong KongQueen Mary HospitalPokfulam RoadHong Kong
| | - Jiangwen Zhang
- School of Biological SciencesThe University of Hong KongPokfulam RoadHong KongChina
| | - Karen K. L. Chan
- Department of Obstetrics & GynaecologyThe University of Hong KongQueen Mary HospitalPokfulam RoadHong KongChina
| | - Philip P. C. Ip
- Department of PathologyThe University of Hong KongQueen Mary HospitalPokfulam RoadHong Kong
| | - Jue Shi
- Centre for Quantitative Systems Biology and Department of PhysicsHong Kong Baptist UniversityHong KongChina
| | - Alice S. T. Wong
- School of Biological SciencesThe University of Hong KongPokfulam RoadHong KongChina
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21
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Hourani T, Holden JA, Li W, Lenzo JC, Hadjigol S, O’Brien-Simpson NM. Tumor Associated Macrophages: Origin, Recruitment, Phenotypic Diversity, and Targeting. Front Oncol 2021; 11:788365. [PMID: 34988021 PMCID: PMC8722774 DOI: 10.3389/fonc.2021.788365] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 11/30/2021] [Indexed: 12/20/2022] Open
Abstract
The tumor microenvironment (TME) is known to have a strong influence on tumorigenesis, with various components being involved in tumor suppression and tumor growth. A protumorigenic TME is characterized by an increased infiltration of tumor associated macrophages (TAMs), where their presence is strongly associated with tumor progression, therapy resistance, and poor survival rates. This association between the increased TAMs and poor therapeutic outcomes are stemming an increasing interest in investigating TAMs as a potential therapeutic target in cancer treatment. Prominent mechanisms in targeting TAMs include: blocking recruitment, stimulating repolarization, and depletion methods. For enhancing targeting specificity multiple nanomaterials are currently being explored for the precise delivery of chemotherapeutic cargo, including the conjugation with TAM-targeting peptides. In this paper, we provide a focused literature review of macrophage biology in relation to their role in tumorigenesis. First, we discuss the origin, recruitment mechanisms, and phenotypic diversity of TAMs based on recent investigations in the literature. Then the paper provides a detailed review on the current methods of targeting TAMs, including the use of nanomaterials as novel cancer therapeutics.
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Affiliation(s)
| | | | | | | | | | - Neil M. O’Brien-Simpson
- Antimicrobial, Cancer Therapeutics and Vaccines (ACTV) Research Group, Melbourne Dental School, Centre for Oral Health Research, Royal Dental Hospital, The University of Melbourne, Melbourne, VIC, Australia
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22
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Thomas JR, Appios A, Zhao X, Dutkiewicz R, Donde M, Lee CYC, Naidu P, Lee C, Cerveira J, Liu B, Ginhoux F, Burton G, Hamilton RS, Moffett A, Sharkey A, McGovern N. Phenotypic and functional characterization of first-trimester human placental macrophages, Hofbauer cells. J Exp Med 2021; 218:211477. [PMID: 33075123 PMCID: PMC7579740 DOI: 10.1084/jem.20200891] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 07/30/2020] [Accepted: 09/11/2020] [Indexed: 12/31/2022] Open
Abstract
Hofbauer cells (HBCs) are a population of macrophages found in high abundance within the stroma of the first-trimester human placenta. HBCs are the only fetal immune cell population within the stroma of healthy placenta. However, the functional properties of these cells are poorly described. Aligning with their predicted origin via primitive hematopoiesis, we find that HBCs are transcriptionally similar to yolk sac macrophages. Phenotypically, HBCs can be identified as HLA-DR-FOLR2+ macrophages. We identify a number of factors that HBCs secrete (including OPN and MMP-9) that could affect placental angiogenesis and remodeling. We determine that HBCs have the capacity to play a defensive role, where they are responsive to Toll-like receptor stimulation and are microbicidal. Finally, we also identify a population of placenta-associated maternal macrophages (PAMM1a) that adhere to the placental surface and express factors, such as fibronectin, that may aid in repair.
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Affiliation(s)
- Jake R Thomas
- Department of Pathology, University of Cambridge, Cambridge, UK.,Centre for Trophoblast Research, Departments of Physiology and Neuroscience, University of Cambridge, Cambridge, UK
| | - Anna Appios
- Department of Pathology, University of Cambridge, Cambridge, UK.,Centre for Trophoblast Research, Departments of Physiology and Neuroscience, University of Cambridge, Cambridge, UK
| | - Xiaohui Zhao
- Centre for Trophoblast Research, Departments of Physiology and Neuroscience, University of Cambridge, Cambridge, UK
| | | | - Maria Donde
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - Colin Y C Lee
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - Praveena Naidu
- Department of Pathology, University of Cambridge, Cambridge, UK.,Centre for Trophoblast Research, Departments of Physiology and Neuroscience, University of Cambridge, Cambridge, UK
| | - Christopher Lee
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore.,School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
| | - Joana Cerveira
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - Bing Liu
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China.,State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing, China.,State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin, China
| | - Florent Ginhoux
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore.,School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.,Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China.,Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
| | - Graham Burton
- Centre for Trophoblast Research, Departments of Physiology and Neuroscience, University of Cambridge, Cambridge, UK
| | - Russell S Hamilton
- Centre for Trophoblast Research, Departments of Physiology and Neuroscience, University of Cambridge, Cambridge, UK.,Department of Genetics, University of Cambridge, Cambridge, UK
| | - Ashley Moffett
- Department of Pathology, University of Cambridge, Cambridge, UK.,Centre for Trophoblast Research, Departments of Physiology and Neuroscience, University of Cambridge, Cambridge, UK
| | - Andrew Sharkey
- Department of Pathology, University of Cambridge, Cambridge, UK.,Centre for Trophoblast Research, Departments of Physiology and Neuroscience, University of Cambridge, Cambridge, UK
| | - Naomi McGovern
- Department of Pathology, University of Cambridge, Cambridge, UK.,Centre for Trophoblast Research, Departments of Physiology and Neuroscience, University of Cambridge, Cambridge, UK
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23
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Alluri SR, Higashi Y, Kil KE. PET Imaging Radiotracers of Chemokine Receptors. Molecules 2021; 26:molecules26175174. [PMID: 34500609 PMCID: PMC8434599 DOI: 10.3390/molecules26175174] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/24/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022] Open
Abstract
Chemokines and chemokine receptors have been recognized as critical signal components that maintain the physiological functions of various cells, particularly the immune cells. The signals of chemokines/chemokine receptors guide various leukocytes to respond to inflammatory reactions and infectious agents. Many chemokine receptors play supportive roles in the differentiation, proliferation, angiogenesis, and metastasis of diverse tumor cells. In addition, the signaling functions of a few chemokine receptors are associated with cardiac, pulmonary, and brain disorders. Over the years, numerous promising molecules ranging from small molecules to short peptides and antibodies have been developed to study the role of chemokine receptors in healthy states and diseased states. These drug-like candidates are in turn exploited as radiolabeled probes for the imaging of chemokine receptors using noninvasive in vivo imaging, such as positron emission tomography (PET). Recent advances in the development of radiotracers for various chemokine receptors, particularly of CXCR4, CCR2, and CCR5, shed new light on chemokine-related cancer and cardiovascular research and the subsequent drug development. Here, we present the recent progress in PET radiotracer development for imaging of various chemokine receptors.
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Affiliation(s)
- Santosh R. Alluri
- University of Missouri Research Reactor, University of Missouri, Columbia, MO 65211, USA;
| | - Yusuke Higashi
- Department of Medicine, Tulane University, New Orleans, LA 70112, USA;
| | - Kun-Eek Kil
- University of Missouri Research Reactor, University of Missouri, Columbia, MO 65211, USA;
- Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO 65211, USA
- Correspondence: ; Tel.: +1-(573)-884-7885
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24
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Ouyang Y, Qiu Y, Liu Y, Zhu R, Chen Y, El-Seedi HR, Chen X, Zhao C. Cancer-fighting potentials of algal polysaccharides as nutraceuticals. Food Res Int 2021; 147:110522. [PMID: 34399500 DOI: 10.1016/j.foodres.2021.110522] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 05/31/2021] [Accepted: 06/09/2021] [Indexed: 01/03/2023]
Abstract
Cancer has been listed as one of the world's five incurable diseases by the World Health Organization and causes tens of thousands of deaths every year. Unfortunately, anticancer agents either show limited efficacy or show serious side effects. The algae possess high nutritional value and their polysaccharides have a variety of biological activities, especially anti-cancer and immunomodulatory properties. Algal polysaccharides exert anti-cancer effects by inducing apoptosis, cell cycle arrest, anti-angiogenesis, and regulating intestinal flora and immune function. Algal polysaccharides can be combined with nanoparticles and other drugs to reduce the side effects caused by chemotherapy and increase the anticancer effects. This review shows the signal pathways related to the anti-cancer mechanisms of algal polysaccharides, including their influence on intestinal flora and immune regulation, the application of nanoparticles, and the effects on combination therapy and clinical trials of cancer treatments.
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Affiliation(s)
- Yuezhen Ouyang
- Engineering Research Centre of Fujian-Taiwan Special Marine Food Processing and Nutrition, Ministry of Education, Fuzhou, China; College of Food Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Yinghui Qiu
- Engineering Research Centre of Fujian-Taiwan Special Marine Food Processing and Nutrition, Ministry of Education, Fuzhou, China; College of Food Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Yuning Liu
- Engineering Research Centre of Fujian-Taiwan Special Marine Food Processing and Nutrition, Ministry of Education, Fuzhou, China; College of Food Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Ruiyu Zhu
- School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou 310023, China
| | - Yihan Chen
- Engineering Research Centre of Fujian-Taiwan Special Marine Food Processing and Nutrition, Ministry of Education, Fuzhou, China; College of Food Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Hesham R El-Seedi
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China; Pharmacognosy Group, Department of Pharmaceutical Biosciences, BMC, Uppsala University, SE-751 23 Uppsala, Sweden
| | - Xinhua Chen
- Key Laboratory of Marine Biotechnology of Fujian Province, Institute of Oceanology, Fujian Agriculture and Forestry University, Fuzhou 350002, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai 519000, China
| | - Chao Zhao
- Engineering Research Centre of Fujian-Taiwan Special Marine Food Processing and Nutrition, Ministry of Education, Fuzhou, China; College of Food Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China; Key Laboratory of Marine Biotechnology of Fujian Province, Institute of Oceanology, Fujian Agriculture and Forestry University, Fuzhou 350002, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai 519000, China.
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25
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Huang Q, Liu J, Wu S, Zhang X, Xiao Z, Liu Z, Du W. Spi-B Promotes the Recruitment of Tumor-Associated Macrophages via Enhancing CCL4 Expression in Lung Cancer. Front Oncol 2021; 11:659131. [PMID: 34141615 PMCID: PMC8205110 DOI: 10.3389/fonc.2021.659131] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 05/03/2021] [Indexed: 01/14/2023] Open
Abstract
Tumor immune escape plays a critical role in malignant tumor progression and leads to the failure of anticancer immunotherapy. Spi-B, a lymphocyte lineage-specific Ets transcription factor, participates in mesenchymal invasion and favors metastasis in human lung cancer. However, the mechanism through which Spi-B regulates the tumor immune environment has not been elucidated. In this study, we demonstrated that Spi-B enhanced the infiltration of tumor-associated macrophages (TAMs) in the tumor microenvironment using subcutaneous mouse models and clinical samples of human lung cancer. Spi-B overexpression increased the expression of TAM polarization- and recruitment-related genes, including CCL4. Moreover, deleting CCL4 inhibited the ability of Spi-B promoting macrophage infiltration. These data suggest that Spi-B promotes the recruitment of TAMs to the tumor microenvironment via upregulating CCL4 expression, which contributes to the progression of lung cancer.
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Affiliation(s)
- Qiumin Huang
- Department of Immunology, Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, China
| | - Junrong Liu
- Department of Immunology, Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, China
| | - Shuainan Wu
- Department of Immunology, Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, China
| | - Xuexi Zhang
- Department of Immunology, Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, China
| | - Zengtuan Xiao
- Department of Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Zhe Liu
- Department of Immunology, Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, Tianjin Medical University, Tianjin, China.,Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Tianjin, China
| | - Wei Du
- Department of Immunology, Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, Tianjin Medical University, Tianjin, China
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26
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Abbott RC, Verdon DJ, Gracey FM, Hughes-Parry HE, Iliopoulos M, Watson KA, Mulazzani M, Luong K, D'Arcy C, Sullivan LC, Kiefel BR, Cross RS, Jenkins MR. Novel high-affinity EGFRvIII-specific chimeric antigen receptor T cells effectively eliminate human glioblastoma. Clin Transl Immunology 2021; 10:e1283. [PMID: 33976881 PMCID: PMC8106904 DOI: 10.1002/cti2.1283] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 03/23/2021] [Accepted: 04/11/2021] [Indexed: 01/01/2023] Open
Abstract
Objectives The increasing success of Chimeric Antigen Receptor (CAR) T cell therapy in haematological malignancies is reinvigorating its application in many other cancer types and with renewed focus on its application to solid tumors. We present a novel CAR against glioblastoma, an aggressive, malignant glioma, with a dismal survival rate for which treatment options have remained unchanged for over a decade. Methods We use the human Retained Display (ReD) antibody platform (Myrio Therapeutics) to identify a novel single‐chain variable fragment (scFv) that recognises epidermal growth factor receptor mutant variant III (EGFRvIII), a common and tumor‐specific mutation found in glioblastoma. We use both in vitro functional assays and an in vivo orthotopic xenograft model of glioblastoma to examine the function of our novel CAR, called GCT02, targeted using murine CAR T cells. Results Our EGFRvIII‐specific scFv was found to be of much higher affinity than reported comparators reverse‐engineered from monoclonal antibodies. Despite the higher affinity, GCT02 CAR T cells kill equivalently but secrete lower amounts of cytokine. In addition, GCT02‐CAR T cells also mediate rapid and complete tumor elimination in vivo. Conclusion We present a novel EGFRvIII‐specific CAR, with effective antitumor functions both in in vitro and in a xenograft model of human glioblastoma.
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Affiliation(s)
- Rebecca C Abbott
- Immunology Division The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia.,The Department of Medical Biology The University of Melbourne Parkville VIC Australia
| | - Daniel J Verdon
- Immunology Division The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
| | | | - Hannah E Hughes-Parry
- Immunology Division The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia.,The Department of Medical Biology The University of Melbourne Parkville VIC Australia
| | - Melinda Iliopoulos
- Immunology Division The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
| | - Katherine A Watson
- Immunology Division The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
| | - Matthias Mulazzani
- Immunology Division The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
| | - Kylie Luong
- Immunology Division The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
| | - Colleen D'Arcy
- Department of Anatomical Pathology Royal Children's Hospital Parkville VIC Australia
| | - Lucy C Sullivan
- Department of Microbiology and Immunology Peter Doherty Institute The University of Melbourne Parkville VIC Australia
| | | | - Ryan S Cross
- Immunology Division The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
| | - Misty R Jenkins
- Immunology Division The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia.,The Department of Medical Biology The University of Melbourne Parkville VIC Australia.,Institute for Molecular Science La Trobe University Bundoora VIC Australia
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27
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Ackun-Farmmer MA, Soto CA, Lesch ML, Byun D, Yang L, Calvi LM, Benoit DSW, Frisch BJ. Reduction of leukemic burden via bone-targeted nanoparticle delivery of an inhibitor of C-chemokine (C-C motif) ligand 3 (CCL3) signaling. FASEB J 2021; 35:e21402. [PMID: 33724567 PMCID: PMC8594422 DOI: 10.1096/fj.202000938rr] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 12/13/2022]
Abstract
Leukemias are challenging diseases to treat due, in part, to interactions between leukemia cells and the bone marrow microenvironment (BMME) that contribute significantly to disease progression. Studies have shown that leukemic cells secrete C-chemokine (C-C motif) ligand 3 (CCL3), to disrupt the BMME resulting in loss of hematopoiesis and support of leukemic cell survival and proliferation. In this study, a murine model of blast crisis chronic myelogenous leukemia (bcCML) that expresses the translocation products BCR/ABL and Nup98/HoxA9 was used to determine the role of CCL3 in BMME regulation. Leukemic cells derived from CCL3-/- mice were shown to minimally engraft in a normal BMME, thereby demonstrating that CCL3 signaling was necessary to recapitulate bcCML disease. Further analysis showed disruption in hematopoiesis within the BMME in the bcCML model. To rescue the altered BMME, therapeutic inhibition of CCL3 signaling was investigated using bone-targeted nanoparticles (NP) to deliver Maraviroc, an inhibitor of C-C chemokine receptor type 5 (CCR5), a CCL3 receptor. NP-mediated Maraviroc delivery partially restored the BMME, significantly reduced leukemic burden, and improved survival. Overall, our results demonstrate that inhibiting CCL3 via CCR5 antagonism is a potential therapeutic approach to restore normal hematopoiesis as well as reduce leukemic burden within the BMME.
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Affiliation(s)
- Marian A. Ackun-Farmmer
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA
- Department of Orthopaedics and Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
| | - Celia A. Soto
- Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, NY, USA
| | - Maggie L. Lesch
- Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, NY, USA
| | - Daniel Byun
- Department of Orthopaedics and Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
| | - Lila Yang
- New York Institute of Technology College of Osteopathic Medicine, New York, NY, USA
| | - Laura M. Calvi
- Department of Orthopaedics and Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Medicine Endocrine Division, University of Rochester Medical Center, Rochester, NY, USA
- Wilmot Cancer Institute, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA
| | - Danielle S. W. Benoit
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA
- Department of Orthopaedics and Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Materials Science Program, University of Rochester, Rochester, NY, USA
- Department of Chemical Engineering, University of Rochester, Rochester, NY, USA
| | - Benjamin J. Frisch
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA
- Department of Orthopaedics and Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, NY, USA
- Wilmot Cancer Institute, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA
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28
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Yang Y, Yang L, Wang Y. [Immunotherapy for Lung Cancer: Mechanisms of Resistance and Response Strategy]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2021; 24:112-123. [PMID: 33626853 PMCID: PMC7936078 DOI: 10.3779/j.issn.1009-3419.2021.101.02] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Inhibition of immune checkpoints is at the forefront of immunotherapy for lung cancer. However, a high percentage of lung cancer patients do not respond to these immunotherpy or their responses are transient, indicating the existence of immune resistance. Emerging evidence suggested that the interactions between cancer cells and immune system were continuous and dynamic. Here, we review how a range of cancer-cell-autonomous characteristics, tumor-microenvironment factors, and host-related influences account for heterogenous responses. Furthermore, with the identification of new targets of immunotherapy and development of immune-based combination therapy, we elucidate the methods might useful to overcome resistance.
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Affiliation(s)
- Yaning Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lu Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yan Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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29
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Anti-proliferative and anti-migratory properties of coffee diterpenes kahweol acetate and cafestol in human renal cancer cells. Sci Rep 2021; 11:675. [PMID: 33436830 PMCID: PMC7804192 DOI: 10.1038/s41598-020-80302-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 12/18/2020] [Indexed: 02/06/2023] Open
Abstract
Despite improvements in systemic therapy options for renal cancer, it remains one of the most drug-resistant malignancies. Interestingly, reports have shown that kahweol and cafestol, natural diterpenes extracted from coffee beans, exhibit anti-cancer activity. However, the multiple potential pharmacological actions of both have yet to be fully understood. This study therefore investigated the effects of kahweol acetate and cafestol on human renal cancer ACHN and Caki-1 cells. Accordingly, the combination of kahweol acetate and cafestol administration synergistically inhibited cell proliferation and migration by inducing apoptosis and inhibiting epithelial-mesenchymal transition. Mechanistic dissection revealed that kahweol acetate and cafestol inhibited Akt and ERK phosphorylation. Moreover, kahweol acetate and cafestol downregulated the expression of not only C-C chemokine receptors 2, 5, and 6 but also programmed death-ligand 1, indicating their effects on the tumor microenvironment. Thus, kahweol acetate and cafestol may be novel therapeutic candidates for renal cancer considering that they exert multiple pharmacological effects.
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30
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Xie D, Luo X. Identification of four methylation-driven genes as candidate biomarkers for monitoring single-walled carbon nanotube-induced malignant transformation of the lung. Toxicol Appl Pharmacol 2020; 412:115391. [PMID: 33387576 DOI: 10.1016/j.taap.2020.115391] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/24/2020] [Accepted: 12/28/2020] [Indexed: 01/15/2023]
Abstract
Long-term exposure to carbon nanotubes (CNTs) has been reported to induce malignant transformation. This study aimed to screen candidate biomarkers for monitoring occupational workers to prevent the development of lung cancer. mRNA (GSE56104) and methylation (GSE153246) profiles of lung epithelial BEAS-2B cells exposed to malignant transformation dose of single-walled CNTs or control medium were downloaded from Gene Expression Omnibus database. A total of 1513 differentially expressed genes (DEGs) and 912 differentially methylated genes (DMGs) were identified using LIMMA method. The weighted correlation network analysis identified blue and turquoise modules were associated with malignant transformation of BEAS-2B cells, 124 DMGs of which were overlapped with DEGs. The mRNA and methylation levels of four methylation-driven DEGs were validated in both lung adenocarcinoma (LUAD) and squamous cell carcinomas (LUSC) of The Cancer Genome Atlas dataset and they were associated with overall survival of LUAD patients. Downregulation of PXMP4 and MCOLN2, while upregulation of MET was confirmed in both LUSC and LUAD via Human Protein Atlas analysis. PXMP4 and MET protein levels were also supported in the proteomic analysis of LUAD. Receiver operating characteristic (ROC) curve analysis showed the combination of four genes may be the optimal biomarker for predicting lung cancer, with the area under ROC curve >0.9. Function analysis revealed BARX2 may interact with CCND1 to regulate cell cycle; MET and PXMP4/MCOLN2 may positively correlate with CCR5/IL-6 or GATA3/HLA-DPB1/HLA-DPA1 to involve immune regulation. In conclusion, these four methylation-driven genes may be candidate prognostic and diagnostic biomarkers for single-walled CNT-related lung cancer.
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Affiliation(s)
- Dongli Xie
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, China
| | - Xiaogang Luo
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, China.
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31
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Kadomoto S, Izumi K, Mizokami A. The CCL20-CCR6 Axis in Cancer Progression. Int J Mol Sci 2020; 21:ijms21155186. [PMID: 32707869 PMCID: PMC7432448 DOI: 10.3390/ijms21155186] [Citation(s) in RCA: 163] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/15/2020] [Accepted: 07/16/2020] [Indexed: 12/14/2022] Open
Abstract
Chemokines, which are basic proteins that exert their effects via G protein-coupled receptors and a subset of the cytokine family, are mediators deeply involved in leukocyte migration during an inflammatory reaction. Chemokine (C-C motif) ligand 20 (CCL20), also known as macrophage inflammatory protein (MIP)-3α, liver activation regulated chemokine (LARC), and Exodus-1, is a small protein that is physiologically expressed in the liver, colon, and skin, is involved in tissue inflammation and homeostasis, and has a specific receptor C-C chemokine receptor 6 (CCR6). The CCL20-CCR6 axis has long been known to be involved in inflammatory and infectious diseases, such as rheumatoid arthritis and human immunodeficiency virus infections. Recently, however, reports have shown that the CCL20-CCR6 axis is associated with several cancers, including hepatocellular carcinoma, colorectal cancer, breast cancer, pancreatic cancer, cervical cancer, and kidney cancer. The CCL20-CCR6 axis promotes cancer progression directly by enhancing migration and proliferation of cancer cells and indirectly by remodeling the tumor microenvironment through immune cell control. The present article reviewed the role of the CCL20-CCR6 axis in cancer progression and its potential as a therapeutic target.
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Affiliation(s)
| | - Kouji Izumi
- Correspondence: ; Tel.: +81-76-265-2393; Fax: +81-76-234-4263
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32
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Gibson JT, Norris KE, Wald G, Buchta Rosean CM, Thomas LJ, Boi SK, Bertrand LA, Bing M, Gordetsky JB, Deshane J, Li P, Brown JA, Nepple KG, Norian LA. Obesity induces limited changes to systemic and local immune profiles in treatment-naive human clear cell renal cell carcinoma. PLoS One 2020; 15:e0233795. [PMID: 32469992 PMCID: PMC7259552 DOI: 10.1371/journal.pone.0233795] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 05/12/2020] [Indexed: 02/07/2023] Open
Abstract
Understanding the effects of obesity on the immune profile of renal cell carcinoma (RCC) patients is critical, given the rising use of immunotherapies to treat advanced disease and recent reports of differential cancer immunotherapy outcomes with obesity. Here, we evaluated multiple immune parameters at the genetic, soluble protein, and cellular levels in peripheral blood and renal tumors from treatment-naive clear cell RCC (ccRCC) subjects (n = 69), to better understand the effects of host obesity (Body Mass Index "BMI" ≥ 30 kg/m2) in the absence of immunotherapy. Tumor-free donors (n = 38) with or without obesity were used as controls. In our ccRCC cohort, increasing BMI was associated with decreased percentages of circulating activated PD-1+CD8+ T cells, CD14+CD16neg classical monocytes, and Foxp3+ regulatory T cells (Tregs). Only CD14+CD16neg classical monocytes and Tregs were reduced when obesity was examined as a categorical variable. Obesity did not alter the percentages of circulating IFNγ+ CD8 T cells or IFNγ+, IL-4+, or IL-17A+ CD4 T cells in ccRCC subjects. Of 38 plasma proteins analyzed, six (CCL3, IL-1β, IL-1RA, IL-10, IL-17, and TNFα) were upregulated specifically in ccRCC subjects with obesity versus tumor-free controls with obesity. IGFBP-1 was uniquely decreased in ccRCC subjects with obesity versus non-obese ccRCC subjects. Immunogenetic profiling of ccRCC tumors revealed that 93% of examined genes were equivalently expressed and no changes in cell type scores were found in stage-matched tumors from obesity category II/III versus normal weight (BMI ≥ 35 kg/m2 versus 18.5-24.9 kg/m2, respectively) subjects. Intratumoral PLGF and VEGF-A proteins were elevated in ccRCC subjects with obesity. Thus, in ccRCC patients with localized disease, obesity is not associated with widespread detrimental alterations in systemic or intratumoral immune profiles. The effects of combined obesity and immunotherapy administration on immune parameters remains to be determined.
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Affiliation(s)
- Justin T. Gibson
- Graduate Biomedical Sciences, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Katlyn E. Norris
- School of Health Professions Honors Undergraduate Research Program, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Gal Wald
- Department of Urology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of America
| | - Claire M. Buchta Rosean
- Department of Urology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of America
| | - Lewis J. Thomas
- Department of Urology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of America
| | - Shannon K. Boi
- Graduate Biomedical Sciences, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Laura A. Bertrand
- Department of Urology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of America
| | - Megan Bing
- Department of Urology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of America
| | - Jennifer B. Gordetsky
- Departments of Pathology and Urology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Jessy Deshane
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Peng Li
- Department of Acute, Chronic, and Continuing Care, School of Nursing, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - James A. Brown
- Department of Urology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of America
- Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa, United States of America
| | - Kenneth G. Nepple
- Department of Urology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of America
- Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa, United States of America
| | - Lyse A. Norian
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- * E-mail:
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33
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Liu S, Zhou X, Peng X, Li M, Ren B, Cheng G, Cheng L. Porphyromonas gingivalis Promotes Immunoevasion of Oral Cancer by Protecting Cancer from Macrophage Attack. THE JOURNAL OF IMMUNOLOGY 2020; 205:282-289. [PMID: 32471882 DOI: 10.4049/jimmunol.1901138] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 04/21/2020] [Indexed: 02/05/2023]
Abstract
The relationship of Porphyromonas gingivalis and oral squamous cell carcinoma (OSCC) has been studied for several years. Previous studies have focused on the direct effect of P. gingivalis on the activities of primary epithelial cells and OSCC cells. However, the immune system is responsible for mediating cancer development, whether P. gingivalis can affect oral cancer immunity has seldom been explored to date. In this study, we investigated the role of P. gingivalis in the immunoevasion of OSCC. We evaluated the effect of P. gingivalis on the phagocytosis of Cal-27 cells (OSCC cell line) by bone marrow-derived macrophages in vitro and studied the effect of P. gingivalis on the growth of OSCC and the polarization of tumor-associated macrophages in vivo. We found that P. gingivalis was able to inhibit the phagocytosis of Cal-27 cells by macrophages, and membrane-component molecules of P. gingivalis, such as proteins, were speculated to be the effector components. In addition, sustained infection with antibiotics-inactivated P. gingivalis promoted OSCC growth in mice and induced the polarization of macrophages into M2 tumor-associated macrophages, which mainly display protumor properties. Transcriptome analysis and quantitative RT-PCR revealed that P. gingivalis infection upregulated the expression of genes encoding protumor molecules in Cal-27 cells (suprabasin, IL-1R2, and CD47) and in macrophages (IL-1α, CCL-3, and CCL-5). Our in vitro and in vivo data suggest that P. gingivalis can promote immunoevasion of oral cancer by protecting cancer from macrophage attack. To our knowledge, the present study reveals a novel mechanism by which P. gingivalis promotes OSCC development.
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Affiliation(s)
- Shiyu Liu
- State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, China.,Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, China.,Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu 610041, China
| | - Xian Peng
- State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, China.,National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu 610041, China
| | - Mingyun Li
- State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, China.,National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu 610041, China
| | - Biao Ren
- State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, China.,National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu 610041, China
| | - Guo Cheng
- Laboratory of Molecular Translational Medicine, Centre for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610017, China
| | - Lei Cheng
- State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, China; .,Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu 610041, China
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34
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Noh KH, Jeong AJ, Lee H, Lee SH, Yi E, Chang PS, Kwak C, Ye SK. Crosstalk Between Prostate Cancer Cells and Tumor-Associated Fibroblasts Enhances the Malignancy by Inhibiting the Tumor Suppressor PLZF. Cancers (Basel) 2020; 12:cancers12051083. [PMID: 32349303 PMCID: PMC7281005 DOI: 10.3390/cancers12051083] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 04/20/2020] [Indexed: 02/07/2023] Open
Abstract
Although prostate cancer is clinically manageable during the early stages of progression, metastatic progression severely compromises the prognosis and leads to mortality. Constitutive activation of STAT3 has been connected to prostate cancer malignancy, and abolishing the STAT3 activity may diminish tumor growth and metastasis. However, its suppressor genes and pathways have not been well established. In this study, we show that promyelocytic leukemia zinc finger (PLZF) has a putative tumor-suppressor function in prostate cancer by inhibiting phosphorylation of STAT3. Compared with a benign prostate, high-grade prostate cancer patient tissue was negatively correlated with PLZF expression. PLZF depletion accelerated proliferation and survival, migration, and invasion in human prostate cancer cells. Mechanistically, we demonstrated a novel role of PLZF as the transcriptional regulator of the tyrosine phosphatase SHP-1 that inhibits the oncogenic JAKs–STAT3 pathway. These results suggest that the collapse of PLZF expression by the CCL3 derived from fibroblasts accelerates the cell migration and invasion properties of prostate cancer cells. Our results suggest that increasing PLZF could be an attractive strategy for suppressing prostate cancer metastasis as well as for tumor growth.
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Affiliation(s)
- Kum Hee Noh
- Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea; (K.H.N.); (A.J.J.); (H.L.); (S.-H.L.); (E.Y.)
- Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul 03080, Korea
| | - Ae Jin Jeong
- Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea; (K.H.N.); (A.J.J.); (H.L.); (S.-H.L.); (E.Y.)
- Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul 03080, Korea
| | - Haeri Lee
- Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea; (K.H.N.); (A.J.J.); (H.L.); (S.-H.L.); (E.Y.)
- Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul 03080, Korea
| | - Song-Hee Lee
- Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea; (K.H.N.); (A.J.J.); (H.L.); (S.-H.L.); (E.Y.)
- Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul 03080, Korea
| | - Eunhee Yi
- Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea; (K.H.N.); (A.J.J.); (H.L.); (S.-H.L.); (E.Y.)
| | - Pahn-Shick Chang
- Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Korea;
- Center for Food and Bioconvergence, Seoul National University, Seoul 08826, Korea
- Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Korea
| | - Cheol Kwak
- Department of Urology, Seoul National University Hospital, Seoul 03080, Korea;
- Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Sang-Kyu Ye
- Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea; (K.H.N.); (A.J.J.); (H.L.); (S.-H.L.); (E.Y.)
- Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul 03080, Korea
- Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea
- Neuro-Immune Information Storage Network Research Center, Seoul National University College of Medicine, Seoul 03080, Korea
- Correspondence: ; Tel.: +82-2740-8281
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35
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Luo A, Meng M, Wang G, Han R, Zhang Y, Jing X, Zhao L, Gu S, Zhao X. Myeloid-Derived Suppressor Cells Recruited by Chemokine (C-C Motif) Ligand 3 Promote the Progression of Breast Cancer via Phosphoinositide 3-Kinase-Protein Kinase B-Mammalian Target of Rapamycin Signaling. J Breast Cancer 2020; 23:141-161. [PMID: 32395374 PMCID: PMC7192746 DOI: 10.4048/jbc.2020.23.e26] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 04/05/2020] [Indexed: 12/19/2022] Open
Abstract
Purpose Numerous studies have shown that the frequency of myeloid-derived suppressor cells (MDSCs) is associated with tumor progression, metastasis, and recurrence. Chemokine (C-C motif) ligand 3 (CCL3) may be secreted by tumor cells and attract MDSCs into the tumor microenvironment. In the present study, we aimed to explore the molecular mechanisms whereby CCL3 is involved in the interaction of breast cancer cells and MDSCs. Methods The expression of CCL3 and its receptors was investigated using real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. The cell counting Kit-8, wound healing, and transwell assays were performed to study cell growth, migration, and invasion. Cell cycling, apoptosis, and the frequency of MDSCs were investigated through flow cytometry. Transwell assays were used for co-culture and chemotaxis detection. Markers of the epithelial-mesenchymal transition (EMT) were determined with western blotting. The role of CCL3 in vivo was studied via tumor xenograft experiments. Results CCL3 promoted cell proliferation, migration, invasion, and cycling, and inhibited apoptosis of breast cancer cells in vitro. Blocking CCL3 in vivo inhibited tumor growth and metastases. The frequency of MDSCs in patients with breast cancer was higher than that in healthy donors. Additionally, MDSCs might be recruited by CCL3. Co-culture with MDSCs activated the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway and promoted the EMT in breast cancer cells, and their proliferation, migration, and invasion significantly increased. These changes were not observed when breast cancer cells with CCL3 knockdown were co-cultured with MDSCs. Conclusion CCL3 promoted the growth of breast cancer cells, and MDSCs recruited by CCL3 interacted with these cells and then activated the PI3K-Akt-mTOR pathway, which led to EMT and promoted the migration and invasion of the cells.
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Affiliation(s)
- Anqi Luo
- Department of Nuclear medicine, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Min Meng
- Department of Oncology, Shandong Provincial Hospital Affiliated with Shandong University, Jinan, China
| | - Guanying Wang
- Department of Oncology, First Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, China
| | - Rui Han
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yujiao Zhang
- Department of Oncology, First Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, China
| | - Xin Jing
- Department of Oncology, First Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, China
| | - Lin Zhao
- Department of Oncology, First Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, China
| | - Shanzhi Gu
- Department of Forensic Medicine, Medical School of Xi'an Jiaotong University, Xi'an, China
| | - Xinhan Zhao
- Department of Oncology, First Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, China
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36
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The expanding landscape of inflammatory cells affecting cancer therapy. Nat Biomed Eng 2020; 4:489-498. [PMID: 32203281 DOI: 10.1038/s41551-020-0524-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 02/04/2020] [Indexed: 12/12/2022]
Abstract
Tumour-infiltrating myeloid cells (TIMCs) are critical regulators of cancer growth. The different phenotypes, functions and therapeutic effects of these phagocytes have, however, been difficult to study. With the advent of single-cell-based technologies, a new 'worldview' is emerging: the classification of TIMCs into subtypes that are conserved across patients and across species. As the landscape of TIMCs is beginning to be understood, it opens up questions about the function of each TIMC subtype and its drugability. In this Perspective, we outline the current map of TIMC populations in cancer and their known and presumed functions, and discuss their therapeutic implications and the biological research questions that they give rise to. The answers should be particularly relevant for bioengineers, materials scientists and the chemical and pharmaceutical communities developing the next generation of cancer therapies.
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37
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Ntanasis-Stathopoulos I, Fotiou D, Terpos E. CCL3 Signaling in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1231:13-21. [PMID: 32060842 DOI: 10.1007/978-3-030-36667-4_2] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Within the tumor microenvironment, chemokines play a key role in immune cell trafficking regulation and immune landscape formulation. CCL3 or macrophage inflammatory protein-1α (MIP-1α), an important chemokine implicated in both immune surveillance and tolerance, has emerged as a prognostic biomarker in both solid and hematological malignancies. CCL3 exerts both antitumor and pro-tumor behavior which is context dependent highlighting the complexity of the underlying interrelated signaling cascades. Current CCL3-directed therapeutic approaches are investigational and further optimization is required to increase efficacy and minimize adverse events.
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Affiliation(s)
- Ioannis Ntanasis-Stathopoulos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Despoina Fotiou
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Evangelos Terpos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.
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38
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Terashima Y, Toda E, Itakura M, Otsuji M, Yoshinaga S, Okumura K, Shand FHW, Komohara Y, Takeda M, Kokubo K, Chen MC, Yokoi S, Rokutan H, Kofuku Y, Ohnishi K, Ohira M, Iizasa T, Nakano H, Okabe T, Kojima H, Shimizu A, Kanegasaki S, Zhang MR, Shimada I, Nagase H, Terasawa H, Matsushima K. Targeting FROUNT with disulfiram suppresses macrophage accumulation and its tumor-promoting properties. Nat Commun 2020; 11:609. [PMID: 32001710 PMCID: PMC6992764 DOI: 10.1038/s41467-020-14338-5] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Accepted: 12/20/2019] [Indexed: 12/15/2022] Open
Abstract
Tumor-associated macrophages affect tumor progression and resistance to immune checkpoint therapy. Here, we identify the chemokine signal regulator FROUNT as a target to control tumor-associated macrophages. The low level FROUNT expression in patients with cancer correlates with better clinical outcomes. Frount-deficiency markedly reduces tumor progression and decreases macrophage tumor-promoting activity. FROUNT is highly expressed in macrophages, and its myeloid-specific deletion impairs tumor growth. Further, the anti-alcoholism drug disulfiram (DSF) acts as a potent inhibitor of FROUNT. DSF interferes with FROUNT-chemokine receptor interactions via direct binding to a specific site of the chemokine receptor-binding domain of FROUNT, leading to inhibition of macrophage responses. DSF monotherapy reduces tumor progression and decreases macrophage tumor-promoting activity, as seen in the case of Frount-deficiency. Moreover, co-treatment with DSF and an immune checkpoint antibody synergistically inhibits tumor growth. Thus, inhibition of FROUNT by DSF represents a promising strategy for macrophage-targeted cancer therapy. The cytoplasmic protein FROUNT can bind to chemokine receptors and enhance chemokine signalling. Here, the authors show that inhibiting FROUNT in macrophages either by knockdown of the gene or using the anti-alcoholism drug disulfiram, results in a reduction in tumour growth.
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Affiliation(s)
- Yuya Terashima
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Chiba, 278-0022, Japan. .,Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan. .,Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Chiba, 278-0022, Japan.
| | - Etsuko Toda
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Chiba, 278-0022, Japan.,Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.,Department of Analytic Human Pathology, Nippon Medical School, Tokyo, 113-8602, Japan.,Department of Analytic Human Pathology, Nippon Medical School, Tokyo, 113-8602, Japan
| | - Meiji Itakura
- Department of Thoracic Disease, Chiba Cancer Center, Chiba, 260-8717, Japan.,Chiba Cancer Center Research Institute, Chiba, 260-8717, Japan.,Chiba Cancer Center Research Institute, Chiba, 260-8717, Japan
| | - Mikiya Otsuji
- Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.,Department of Anesthesiology, Tokyo Teishin Hospital, Tokyo, 102-8798, Japan.,Department of Anesthesiology, Tokyo Teishin Hospital, Tokyo, 102-8798, Japan
| | - Sosuke Yoshinaga
- Department of Structural BioImaging, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan
| | | | - Francis H W Shand
- Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Yoshihiro Komohara
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan
| | - Mitsuhiro Takeda
- Department of Structural BioImaging, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan
| | - Kana Kokubo
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Chiba, 278-0022, Japan.,Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.,Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Chiba, 278-0022, Japan
| | - Ming-Chen Chen
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Chiba, 278-0022, Japan.,Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.,Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Chiba, 278-0022, Japan
| | - Sana Yokoi
- Chiba Cancer Center Research Institute, Chiba, 260-8717, Japan
| | - Hirofumi Rokutan
- Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Yutaka Kofuku
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Koji Ohnishi
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan
| | - Miki Ohira
- Chiba Cancer Center Research Institute, Chiba, 260-8717, Japan
| | - Toshihiko Iizasa
- Department of Thoracic Disease, Chiba Cancer Center, Chiba, 260-8717, Japan
| | - Hirofumi Nakano
- Drug Discovery Initiative, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Takayoshi Okabe
- Drug Discovery Initiative, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Hirotatsu Kojima
- Drug Discovery Initiative, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Akira Shimizu
- Department of Analytic Human Pathology, Nippon Medical School, Tokyo, 113-8602, Japan
| | - Shiro Kanegasaki
- Research Institute, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan
| | - Ming-Rong Zhang
- Department of Radiopharmaceutics Development, National Institutes for Quantum and Radiological Science and Technology, Chiba, 263-8555, Japan
| | - Ichio Shimada
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Hiroki Nagase
- Chiba Cancer Center Research Institute, Chiba, 260-8717, Japan
| | - Hiroaki Terasawa
- Department of Structural BioImaging, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan
| | - Kouji Matsushima
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Chiba, 278-0022, Japan.,Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.,Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Chiba, 278-0022, Japan
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Kodama T, Koma YI, Arai N, Kido A, Urakawa N, Nishio M, Shigeoka M, Yokozaki H. CCL3-CCR5 axis contributes to progression of esophageal squamous cell carcinoma by promoting cell migration and invasion via Akt and ERK pathways. J Transl Med 2020; 100:1140-1157. [PMID: 32457351 PMCID: PMC7438203 DOI: 10.1038/s41374-020-0441-4] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 05/08/2020] [Accepted: 05/08/2020] [Indexed: 01/25/2023] Open
Abstract
Tumor-associated macrophages (TAMs) contribute to the progression and mortality of various malignancies. We reported that high numbers of infiltrating TAMs were significantly associated with tumor progression and poor prognosis in esophageal squamous cell carcinoma (ESCC). In our previous investigation of TAMs' actions in ESCC, we compared gene expression profiles between peripheral blood monocyte (PBMo)-derived macrophages and TAM-like macrophages stimulated with conditioned media of ESCC cell lines. Among the upregulated genes in the TAM-like macrophages, we focused on CC chemokine ligand 3 (CCL3), which was reported to contribute to tumor progression in several malignancies. Herein, we observed that not only TAMs but also ESCC cell lines expressed CCL3. A CCL3 receptor, CC chemokine receptor 5 (CCR5) was expressed in the ESCC cell lines. Treating the ESCC cell lines with recombinant human (rh)CCL3 induced the phosphorylations of Akt and ERK, which were suppressed by CCR5 knockdown. Migration and invasion of ESCC cells were promoted by treatment with rhCCL3 and co-culture with TAMs. TAMs/rhCCL3-promoted cell migration and invasion were suppressed by inhibition of the CCL3-CCR5 axis, PI3K/Akt, and MEK/ERK pathways. Treatment with rhCCL3 upregulated MMP2 and VEGFA expressions in ESCC cell lines. Our immunohistochemical analysis of 68 resected ESCC cases showed that high expression of CCL3 and/or CCR5 in ESCC tissues was associated with poor prognosis. High CCR5 expression was associated with deeper invasion, presence of vascular invasion, higher pathological stage, higher numbers of infiltrating CD204+ TAMs, and higher microvascular density. High expression of both CCL3 and CCR5 was an independent prognostic factor for disease-free survival. These results suggest that CCL3 derived from both TAMs and cancer cells contributes to the progression and poor prognosis of ESCC by promoting cell migration and invasion via the binding of CCR5 and the phosphorylations of Akt and ERK. The CCL3-CCR5 axis could become the target of new therapies against ESCC.
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Affiliation(s)
- Takayuki Kodama
- grid.31432.370000 0001 1092 3077Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yu-ichiro Koma
- grid.31432.370000 0001 1092 3077Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Noriaki Arai
- grid.31432.370000 0001 1092 3077Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Aya Kido
- grid.31432.370000 0001 1092 3077Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan ,grid.257022.00000 0000 8711 3200Department of Molecular Pathology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Naoki Urakawa
- grid.31432.370000 0001 1092 3077Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan ,grid.31432.370000 0001 1092 3077Division of Gastro-intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Mari Nishio
- grid.31432.370000 0001 1092 3077Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Manabu Shigeoka
- grid.31432.370000 0001 1092 3077Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiroshi Yokozaki
- grid.31432.370000 0001 1092 3077Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
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40
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Cai D, Xu Y, Ding R, Qiu K, Zhang R, Wang H, Huang L, Xie X, Yan H, Deng Y, Lin X, Shao J, Luo X, Duan C. Extensive serum biomarker analysis in patients with non-small-cell lung carcinoma. Cytokine 2019; 126:154868. [PMID: 31629110 DOI: 10.1016/j.cyto.2019.154868] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 07/21/2019] [Accepted: 09/28/2019] [Indexed: 01/16/2023]
Abstract
Lung cancer is a common malignant disease, nearly 2.09 million new patients occurred last year. Approximately 85% of the patients are classified as non-small-cell lung cancer (NSCLC). It is therefore important to identify new diagnostic and prognostic biomarkers for the early detection of this disease. The presented study identifies biomarkers in the serum of NSCLC patients. The expression of 274 cytokines was measured by a novel antibody array methodology and ELISA was applied to validate the array results. The levels of MIP-1 α, IL-8, MIP-1 β, Resistin, GDF-15, HGF, CA125, FLRG, VCAM-1, DKK-3, sTNF-R1, CTACK, Acrp30, CXCL-16 and LYVE-1 were significantly higher in serum from NSCLC patients, while the level of TIMP-2 and IGFBP-6 were lower. More importantly, the validation supported the result of the antibody array. The result of the antibody array indicates that these cytokines might be novel auxiliary biomarkers in the diagnosis and prognosis of NSCLC.
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Affiliation(s)
- Donghao Cai
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Ying Xu
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Rui Ding
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Kaifeng Qiu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Department of Pharmacy, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Ruihua Zhang
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Han Wang
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Lisi Huang
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Xiaoying Xie
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Haiyan Yan
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Yawen Deng
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Xianghua Lin
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Jing Shao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Medical Research Center, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Xiaohong Luo
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China
| | - Chaohui Duan
- Laboratory of Clinical, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China.
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Wang W, Chu HY, Zhong ZM, Qi X, Cheng R, Qin RJ, Liang J, Zhu XF, Zeng MS, Sun CZ. Platelet-secreted CCL3 and its receptor CCR5 promote invasive and migratory abilities of anaplastic thyroid carcinoma cells via MMP-1. Cell Signal 2019; 63:109363. [PMID: 31344439 DOI: 10.1016/j.cellsig.2019.109363] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 07/19/2019] [Accepted: 07/19/2019] [Indexed: 01/28/2023]
Abstract
Platelet counts have been reported to be closely related to distant metastasis of many malignant tumors. Our previous study showed that elevated peripheral blood platelet counts may be an adverse prognostic factor of anaplastic thyroid carcinoma (ATC) patients, indicating that platelets may promote ATC progression. In the present study, we aimed to identify the role of platelets in ATC cell invasion and migration and to explore the underlying mechanisms. We found that platelets can promote the invasive and migratory of ATC cells, which may be related to the interaction between activated platelet-secreted chemokine (C-C motif) ligand 3 (CCL3) and its receptor CCR5. The interaction was shown to induce the upregulation of matrix metalloproteinase (MMP)-1 via NF-κB pathway. These findings could provide a new idea for the research of targeted platelets to inhibit tumor metastasis.
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Affiliation(s)
- Wei Wang
- Department of Head and Neck Surgery Section II, the Third Affiliated Hospital of Kunming Medical University, 519 Kunzhou Road, Kunming, China; Department of Oncology, Chuxiong people's Hospital, 318 Lucheng South Road, Chuxiong, China
| | - Hong-Ying Chu
- Department of Head and Neck Surgery Section II, the Third Affiliated Hospital of Kunming Medical University, 519 Kunzhou Road, Kunming, China
| | - Zhao-Ming Zhong
- Department of Head and Neck Surgery Section II, the Third Affiliated Hospital of Kunming Medical University, 519 Kunzhou Road, Kunming, China; Department of Medical Oncology, the First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming, China
| | - Xiao Qi
- Department of Head and Neck Surgery Section II, the Third Affiliated Hospital of Kunming Medical University, 519 Kunzhou Road, Kunming, China
| | - Rui Cheng
- Department of Head and Neck Surgery Section II, the Third Affiliated Hospital of Kunming Medical University, 519 Kunzhou Road, Kunming, China
| | - Ru-Jia Qin
- Department of Head and Neck Surgery Section II, the Third Affiliated Hospital of Kunming Medical University, 519 Kunzhou Road, Kunming, China
| | - Jin Liang
- Department of Medical Oncology, the First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming, China
| | - Xiao-Feng Zhu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, China
| | - Mu-Sheng Zeng
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, China.
| | - Chuan-Zheng Sun
- Department of Head and Neck Surgery Section II, the Third Affiliated Hospital of Kunming Medical University, 519 Kunzhou Road, Kunming, China.
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Nishikawa G, Kawada K, Nakagawa J, Toda K, Ogawa R, Inamoto S, Mizuno R, Itatani Y, Sakai Y. Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression via CCR5. Cell Death Dis 2019; 10:264. [PMID: 30890699 PMCID: PMC6424976 DOI: 10.1038/s41419-019-1508-2] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 02/21/2019] [Accepted: 03/05/2019] [Indexed: 12/14/2022]
Abstract
Mesenchymal stem cells (MSCs) are recruited from BM to the stroma of developing tumors, where they serve as critical components of the tumor microenvironment by secreting growth factors, cytokines, and chemokines. The role of MSCs in colorectal cancer (CRC) progression was controversial. In this study, we found that C-C chemokine receptor type 5 (CCR5) ligands (i.e., C-C motif chemokine ligand 3 (CCL3), CCL4, and CCL5) were highly produced from MSCs using a chemokine array screening with conditioned media from the cultured human MSCs. A relatively strong CCR5 expression could be detected within the cytoplasm of several CRC cell lines. Regarding the effect of MSC, we found that the xenografts in which CCR5-overexpressing HCT116 cells were inoculated into immunocompromised mice were highly promoted in vivo by a mixture with MSCs. Notably, the CCR5 inhibitor, maraviroc, significantly abolished the MSC-induced tumor growth in vivo. In human clinical specimens (n = 89), 20 cases (29%) were high for CCR5, whereas 69 cases (71%) were low. Statistical analyses indicated that CCR5 expression in primary CRC was associated with CRC patients’ prognosis. Especially, stage III/IV patients with CCR5-high CRCs exhibited a significantly poorer prognosis than those with CCR5-low CRCs. Furthermore, we investigated the effects of preoperative serum CCR5 ligands on patients’ prognosis (n = 114), and found that CRC patients with high serum levels of CCL3 and CCL4 exhibited a poorer prognosis compared to those with low levels of CCL3 and CCL4, while there was no association between CCL5 and prognosis. These results suggest that the inhibition of MSC–CRC interaction by a CCR5 inhibitor could provide the possibility of a novel therapeutic strategy for CRC, and that serum levels of CCL3 and CCL4 could be predictive biomarkers for the prognosis of CRC patients.
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Affiliation(s)
- Gen Nishikawa
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kenji Kawada
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
| | - Jun Nakagawa
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kosuke Toda
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ryotaro Ogawa
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Susumu Inamoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Rei Mizuno
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshiro Itatani
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshiharu Sakai
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Pulmonary and pleural toxicity of potassium octatitanate fibers, rutile titanium dioxide nanoparticles, and MWCNT-7 in male Fischer 344 rats. Arch Toxicol 2019; 93:909-920. [DOI: 10.1007/s00204-019-02410-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Accepted: 02/06/2019] [Indexed: 01/06/2023]
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Mukaida N, Nosaka T, Nakamoto Y, Baba T. Lung Macrophages: Multifunctional Regulator Cells for Metastatic Cells. Int J Mol Sci 2018; 20:116. [PMID: 30597969 PMCID: PMC6337639 DOI: 10.3390/ijms20010116] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 12/21/2018] [Accepted: 12/24/2018] [Indexed: 12/29/2022] Open
Abstract
Metastasis is responsible for most of the cancer-associated deaths and proceeds through multiple steps. Several lines of evidence have established an indispensable involvement of macrophages present at the primary tumor sites in various steps of metastasis, from primary tumor growth to its intravasation into circulation. The lungs encompass a large, dense vascular area and, therefore, are vulnerable to metastasis, particularly, hematogenous ones arising from various types of neoplasms. Lung tissues constitutively contain several types of tissue-resident macrophages and circulating monocytes to counteract potentially harmful exogenous materials, which directly reach through the airway. Recent advances have provided an insight into the ontogenetic, phenotypic, and functional heterogeneity of these lung macrophage and monocyte populations, under resting and inflammatory conditions. In this review, we discuss the ontogeny, trafficking dynamics, and functions of these pulmonary macrophages and monocytes and their potential roles in lung metastasis and measures to combat lung metastasis by targeting these populations.
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Affiliation(s)
- Naofumi Mukaida
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
| | - Takuto Nosaka
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Yoshida-gun, Fukui 910-1193, Japan.
| | - Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Yoshida-gun, Fukui 910-1193, Japan.
| | - Tomohisa Baba
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
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45
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Argyle D, Kitamura T. Targeting Macrophage-Recruiting Chemokines as a Novel Therapeutic Strategy to Prevent the Progression of Solid Tumors. Front Immunol 2018; 9:2629. [PMID: 30483271 PMCID: PMC6243037 DOI: 10.3389/fimmu.2018.02629] [Citation(s) in RCA: 143] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 10/25/2018] [Indexed: 12/28/2022] Open
Abstract
Solid tumors are initiated by genetic mutations in non-hematopoietic cells and progress into invasive malignant tumors. This tumor progression often culminates in metastatic disease that is largely refractory to current therapeutic modalities and thus dramatically reduces survival of tumor patients. As solid tumors account for more than 80% of cancer-related deaths, it is necessary to develop novel therapeutic strategies to treat the diseases. An attractive strategy is to target macrophages in both primary tumors [known as tumor-associated macrophages (TAMs)] and metastatic tumors [called metastasis-associated macrophages (MAMs)]. TAMs and MAMs are abundant in most solid tumors and can promote tumor metastasis. Several studies in various models of solid tumors suggest that the accumulation of TAMs, MAMs, and their progenitor cells is regulated by chemokine ligands released by tumor and stromal cells. Consequently, these macrophage-recruiting chemokines could be potential therapeutic targets to prevent malignant tumor development through disruption of the accumulation of pro-metastatic macrophages. This review will discuss the role of chemokine ligands and their receptors in TAM and MAM accumulation in primary and secondary tumor sites, and finally discuss the therapeutic potential of inhibitors against these macrophage-recruiting chemokines.
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Affiliation(s)
- David Argyle
- Royal (Dick) School of Veterinary Studies and the Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Takanori Kitamura
- Royal (Dick) School of Veterinary Studies and the Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
- MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
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46
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Staversky RJ, Byun DK, Georger MA, Zaffuto BJ, Goodman A, Becker MW, Calvi LM, Frisch BJ. The Chemokine CCL3 Regulates Myeloid Differentiation and Hematopoietic Stem Cell Numbers. Sci Rep 2018; 8:14691. [PMID: 30279500 PMCID: PMC6168534 DOI: 10.1038/s41598-018-32978-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 09/17/2018] [Indexed: 12/21/2022] Open
Abstract
The chemokine CCL3 is frequently overexpressed in malignancies and overexpression leads to microenvironmental dysfunction. In murine models of chronic myelogenous leukemia (CML), CCL3 is critical for the maintenance of a leukemia stem cell population, and leukemia progression. With CCL3 implicated as a potentially viable therapeutic target, it is important to carefully characterize its role in normal hematopoietic homeostasis. CCL3−/− mice were used to evaluate the role of CCL3 in regulating hematopoietic stem and progenitor cell (HSPC) populations. CCL3−/− mice had loss of mature myeloid populations, while myeloid progenitors and HSPCs were increased, and microenvironmental populations were unchanged. These data show that CCL3 promotes myeloid lineage differentiation and the size of the HSPC pool independent of the supportive bone marrow microenvironment. Our results demonstrate a previously unrecognized role of CCL3 in the maintenance of homeostatic hematopoiesis that should be evaluated when targeting CCL3 signaling for the treatment of hematologic malignancy.
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Affiliation(s)
- Rhonda J Staversky
- Department of Medicine Hematology/Oncology Division University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Daniel K Byun
- Department of Medicine Hematology/Oncology Division University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Mary A Georger
- Department of Medicine Endocrine Division University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Brandon J Zaffuto
- Department of Medicine Endocrine Division University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Alexandra Goodman
- Department of Medicine Hematology/Oncology Division University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Michael W Becker
- Department of Medicine Hematology/Oncology Division University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.,Wilmot Cancer Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Laura M Calvi
- Department of Medicine Hematology/Oncology Division University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.,Department of Medicine Endocrine Division University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.,Wilmot Cancer Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.,Center for musculoskeletal research, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Benjamin J Frisch
- Department of Medicine Hematology/Oncology Division University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. .,Wilmot Cancer Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. .,Center for musculoskeletal research, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
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Validation of Housekeeping Genes as Reference for Reverse-Transcription-qPCR Analysis in Busulfan-Injured Microvascular Endothelial Cells. BIOMED RESEARCH INTERNATIONAL 2018; 2018:4953806. [PMID: 30386793 PMCID: PMC6189687 DOI: 10.1155/2018/4953806] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 09/10/2018] [Accepted: 09/17/2018] [Indexed: 12/17/2022]
Abstract
Endothelial cells (ECs) could express some important cytokines and signal molecules which play a key role in normal hematopoiesis and repopulation. Busulfan-induced vascular endothelial injury is an important feature after hematopoietic stem cell transplantation (HSCT). But the molecular mechanism of how the injured ECs affect hematopoietic reconstruction is still unknown. It is possibly through modulation of the change of some gene expression. RT-qPCR is one of the most popular methods used to accurately determine gene expression levels, based on stable reference gene (RG) selection from housekeeping genes. So our aim is to select stable RGs for more accurate measures of mRNA levels during Busulfan-induced vascular endothelial injury. In this study, 14 RGs were selected to investigate their expression stability in ECs during 72 hours of EC injury treated with Busulfan. Our results revealed extreme variation in RG stability compared by five statistical algorithms. ywhaz and alas1 were recognized as the two idlest RGs on account of the final ranking, while the two most usually used RGs (gapdh and actb) were not the most stable RGs. Next, these data were verified by testing signalling pathway genes ctnnb1, robo4, and notch1 based on the above four genes ywha, alas1, gapdh, and actb. It shows that the normalization of mRNA expression data using unstable RGs greatly affects gene fold change, which means the reliability of the biological conclusions is questionable. Based on the best RGs used, we also found that robo4 is significantly overexpressed in Busulfan-impaired ECs. In conclusion, our data reaffirms the importance of RGs selection for the valid analysis of gene expression in Busulfan-impaired ECs. And it also provides very useful guidance and basis for more accurate differential expression gene screening and future expanding biomolecule study of different drugs such as cyclophosphamide and fludarabine-injured ECs.
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48
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Ruytinx P, Proost P, Van Damme J, Struyf S. Chemokine-Induced Macrophage Polarization in Inflammatory Conditions. Front Immunol 2018; 9:1930. [PMID: 30245686 PMCID: PMC6137099 DOI: 10.3389/fimmu.2018.01930] [Citation(s) in RCA: 316] [Impact Index Per Article: 45.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 08/06/2018] [Indexed: 12/15/2022] Open
Abstract
Macrophages represent a heterogeneous cell population and are known to display a remarkable plasticity. In response to distinct micro-environmental stimuli, e.g., tumor stroma vs. infected tissue, they polarize into different cell subtypes. Originally, two subpopulations were defined: classically activated macrophages or M1, and alternatively activated macrophages or M2. Nowadays, the M1/M2 classification is considered as an oversimplified approach that does not adequately cover the total spectrum of macrophage phenotypes observed in vivo. Especially in pathological circumstances, macrophages behave as plastic cells modifying their expression and transcription profile along a continuous spectrum with M1 and M2 phenotypes as extremes. Here, we focus on the effect of chemokines on macrophage differentiation and polarization in physiological and pathological conditions. In particular, we discuss chemokine-induced macrophage polarization in inflammatory diseases, including obesity, cancer, and atherosclerosis.
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Affiliation(s)
- Pieter Ruytinx
- Laboratory of Molecular Immunology, Department of Microbiology and Immunology, REGA Institute KU Leuven, Leuven, Belgium
| | - Paul Proost
- Laboratory of Molecular Immunology, Department of Microbiology and Immunology, REGA Institute KU Leuven, Leuven, Belgium
| | - Jo Van Damme
- Laboratory of Molecular Immunology, Department of Microbiology and Immunology, REGA Institute KU Leuven, Leuven, Belgium
| | - Sofie Struyf
- Laboratory of Molecular Immunology, Department of Microbiology and Immunology, REGA Institute KU Leuven, Leuven, Belgium
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Kwee BJ, Budina E, Najibi AJ, Mooney DJ. CD4 T-cells regulate angiogenesis and myogenesis. Biomaterials 2018; 178:109-121. [PMID: 29920403 PMCID: PMC6090550 DOI: 10.1016/j.biomaterials.2018.06.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 06/01/2018] [Accepted: 06/05/2018] [Indexed: 12/13/2022]
Abstract
Ischemic diseases, such as peripheral artery disease, affect millions of people worldwide. While CD4+ T-cells regulate angiogenesis and myogenesis, it is not understood how the phenotype of these adaptive immune cells regulate these regenerative processes. The secreted factors from different types of CD4+ T-cells (Th1, Th2, Th17, and Treg) were utilized in a series of in vitro assays and delivered from an injectable alginate biomaterial into a murine model of ischemia to study their effects on vascular and skeletal muscle regeneration. Conditioned medium from Th2 and Th17 T-cells enhanced angiogenesis in vitro and in vivo, in part by directly stimulating endothelial sprouting. Th1 conditioned medium induced vascular regression in vitro and provided no benefit to angiogenesis in vivo. Th1, Th2, and Th17 conditioned medium, to varying extents, enhanced muscle precursor cell proliferation and inhibited their differentiation in vitro, and prolonged early stages of muscle regeneration in vivo. Treg conditioned medium had a moderate or no effect on these processes in vitro and no discernible effect in vivo. These findings suggest that Th2 and Th17 T-cells may enhance angiogenesis and myogenesis in ischemic injuries, which may be useful in the design of immunomodulatory biomaterials to treat these diseases.
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Affiliation(s)
- Brian J Kwee
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA; Wyss Institute Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA
| | - Erica Budina
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA
| | - Alexander J Najibi
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA; Wyss Institute Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA
| | - David J Mooney
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA; Wyss Institute Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.
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50
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Xue N, Lin JH, Xing S, Liu D, Li SB, Lai YZ, Wang XP, Mao MJ, Zhong Q, Zeng MS, Liu WL. Plasma Macrophage Migration Inhibitory Factor and CCL3 as Potential Biomarkers for Distinguishing Patients with Nasopharyngeal Carcinoma from High-Risk Individuals Who Have Positive Epstein-Barr Virus Capsid Antigen-Specific IgA. Cancer Res Treat 2018; 51:378-390. [PMID: 29807404 PMCID: PMC6333976 DOI: 10.4143/crt.2018.070] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 05/28/2018] [Indexed: 12/26/2022] Open
Abstract
Purpose The purpose of this study was to identify novel plasma biomarkers for distinguishing nasopharyngeal carcinoma (NPC) patients from healthy individuals who have positive Epstein-Barr virus (EBV) viral capsid antigen (VCA-IgA). Materials and Methods One hundred seventy-four plasma cytokines were analyzed by a Cytokine Array in eight healthy individuals with positive EBV VCA-IgA and eight patients with NPC. Real-time polymerase chain reaction, Western blotting, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry were employed to detect the expression levels of macrophage migration inhibitory factor (MIF) and CC chemokine ligand 3 (CCL3) in NPC cell lines and tumor tissues. Plasma MIF and CCL3 were measured by ELISA in 138 NPC patients, 127 EBV VCA-IgA negative (VN) and 100 EBV VCA-IgA positive healthy donors (VP). Plasma EBV VCA-IgA was determined by immunoenzymatic techniques. Results Thirty-four of the 174 cytokines varied significantly between the VP and NPC group. Plasma MIF and CCL3 were significantly elevated in NPC patients compared with VN and VP. Combination of MIF and CCL3 could be used for the differential diagnosis of NPC from VN cohort (area under the curve [AUC], 0.913; sensitivity, 90.00%; specificity, 80.30%), and combination of MIF, CCL3, and VCA-IgA could be used for the differential diagnosis of NPC from VP cohort (AUC, 0.920; sensitivity, 90.00%; specificity, 84.00%), from (VN+VP) cohort (AUC, 0.961; sensitivity, 90.00%; specificity, 92.00%). Overexpressions of MIF and CCL3 were observed in NPC plasma, NPC cell lines and NPC tissues. Conclusion Plasma MIF, CCL3, and VCA-IgA combination significantly improves the diagnostic specificity of NPC in high-risk individuals.
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Affiliation(s)
- Ning Xue
- Department of Clinical Laboratory, Affiliated Tumor Hospital of Zhengzhou University, Henan Tumor Hospital, Zhengzhou, China.,Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Jian-Hua Lin
- Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Shan Xing
- Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Dan Liu
- Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Shi-Bing Li
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yan-Zhen Lai
- Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xue-Ping Wang
- Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Min-Jie Mao
- Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Qian Zhong
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Mu-Sheng Zeng
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Wan-Li Liu
- Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, Guangzhou, China
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