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Walsh RM, Ambrose J, Jack JL, Eades AE, Bye BA, Tannus Ruckert M, Messaggio F, Olou AA, Chalise P, Pei D, VanSaun MN. Depletion of tumor-derived CXCL5 improves T cell infiltration and anti-PD-1 therapy response in an obese model of pancreatic cancer. J Immunother Cancer 2025; 13:e010057. [PMID: 40121029 PMCID: PMC11931939 DOI: 10.1136/jitc-2024-010057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 03/10/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND CXCR1/2 inhibitors are being implemented with immunotherapies in PDAC clinical trials. CXC-ligands are a family of cytokines responsible for stimulating these receptors; while typically secreted by activated immune cells, fibroblasts, and even adipocytes, they are also secreted by immune-evasive cancer cells. CXC-ligand release is known to occur in response to inflammatory stimuli. Adipose tissue is an endocrine organ and a source of inflammatory signaling peptides. Importantly, adipose-derived cytokines and chemokines are implicated as potential drivers of tumor cell immune evasion; cumulatively, these findings suggest that targeting CXC-ligands may be beneficial in the context of obesity. METHODS RNA-sequencing of human PDAC cell lines was used to assess influences of adipose conditioned media on the cancer cell transcriptome. The adipose-induced secretome of PDAC cells was validated with ELISA for induction of CXCL5 secretion. Human tissue data from CPTAC was used to correlate IL-1β and TNF expression with both CXCL5 mRNA and protein levels. CRISPR-Cas9 was used to knockout CXCL5 from a murine PDAC KPC cell line to assess orthotopic tumor studies in syngeneic, diet-induced obese mice. Flow cytometry and immunohistochemistry were used to compare the immune profiles between tumors with or without CXCL5. Mice-bearing CXCL5 competent or deficient tumors were monitored for differential tumor size in response to anti-PD-1 immune checkpoint blockade therapy. RESULTS Human adipose tissue conditioned media stimulates CXCL5 secretion from PDAC cells via either IL-1β or TNF; neutralization of both is required to significantly block the release of CXCL5 from tumor cells. Ablation of CXCL5 from tumors promoted an enriched immune phenotype with an unanticipatedly increased number of exhausted CD8 T cells. Application of anti-PD-1 treatment to control tumors failed to alter tumor growth, yet treatment of CXCL5-deficient tumors showed response by significantly diminished tumor mass. CONCLUSIONS In summary, our findings show that both TNF and IL-1β can stimulate CXCL5 release from PDAC cells in vitro, which correlates with expression in patient data. CXCL5 depletion in vivo alone is sufficient to promote T cell infiltration into tumors, increasing efficacy and requiring checkpoint blockade inhibition to alleviate tumor burden.
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Affiliation(s)
| | | | | | | | | | | | - Fanuel Messaggio
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | | | - Prabhakar Chalise
- Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
- The University of Kansas Cancer Center, Kansas City, Kansas, USA
| | - Dong Pei
- Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
- The University of Kansas Cancer Center, Kansas City, Kansas, USA
| | - Michael N VanSaun
- Cancer Biology, KUMC, Kansas City, Kansas, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
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Schaefer AS, Nibali L, Zoheir N, Moutsopoulos NM, Loos BG. Genetic risk variants implicate impaired maintenance and repair of periodontal tissues as causal for periodontitis-A synthesis of recent findings. Periodontol 2000 2025. [PMID: 39953674 DOI: 10.1111/prd.12622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 12/18/2024] [Accepted: 12/29/2024] [Indexed: 02/17/2025]
Abstract
Periodontitis is a complex inflammatory disease in which the host genome, in conjunction with extrinsic factors, determines susceptibility and progression. Genetic predisposition is the strongest risk factor in the first decades of life. As people age, chronic exposure to the periodontal microbiome puts a strain on the proper maintenance of barrier function. This review summarizes our current knowledge on genetic risk factors implicated in periodontitis, derived (i) from hypothesis-free systematic whole genome-profiling studies (genome-wide association studies [GWAS] and quantitative trait loci [QTL] mapping studies), and independently validated through further unbiased approaches; (ii) from monogenic and oligogenic forms of periodontitis; and (iii) from syndromic forms of periodontitis. The genes include, but are not limited to, SIGLEC5, PLG, ROBO2, ABCA1, PF4, and CTSC. Notably, CTSC and PLG gene mutations were also identified in non-syndromic and syndromic forms of prepubertal and early-onset periodontitis. The functions of the identified genes in this review suggest that the pathways affected by the periodontitis-associated gene variants converge in functions involved in the maintenance and repair of structural integrity of the periodontal tissues. Particularly, these genes play a role in the healing of inflamed and ulcerated periodontal tissues, including roles in fibrinolysis, extrusion of cellular debris, extracellular matrix remodeling and angiogenesis. Syndromes that include periodontitis in their phenotype indicate that neutrophils play an important role in the regulation of inflammation in the periodontium. The established genetic susceptibility genes therefore collectively provide new insights into the molecular mechanisms and plausible causal factors underlying periodontitis.
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Affiliation(s)
- Arne S Schaefer
- Department of Periodontology, Oral Medicine and Oral Surgery, Institute for Dental and Craniofacial Sciences, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Luigi Nibali
- Periodontology Unit, Faculty of Dentistry, Oral and Craniofacial Sciences, Centre for Host Microbiome Interactions, King's College London, London, UK
| | - Noha Zoheir
- Periodontology Unit, Faculty of Dentistry, Oral and Craniofacial Sciences, Centre for Host Microbiome Interactions, King's College London, London, UK
| | - Niki M Moutsopoulos
- Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
| | - Bruno G Loos
- Department of Periodontology, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
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Guo M, Sheng W, Yuan X, Wang X. Neutrophils as promising therapeutic targets in pancreatic cancer liver metastasis. Int Immunopharmacol 2024; 140:112888. [PMID: 39133956 DOI: 10.1016/j.intimp.2024.112888] [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: 04/02/2024] [Revised: 08/01/2024] [Accepted: 08/04/2024] [Indexed: 09/01/2024]
Abstract
Pancreatic cancer is characterized by an extremely poor prognosis and presents significant treatment challenges. Liver metastasis is the leading cause of death in patients with pancreatic cancer. Recent studies have highlighted the significant impact of neutrophils on tumor occurrence and progression, as well as their crucial role in the pancreatic cancer tumor microenvironment. Neutrophil infiltration plays a critical role in the progression and prognosis of pancreatic cancer. Neutrophils contribute to pancreatic cancer liver metastasis through various mechanisms, including angiogenesis, immune suppression, immune evasion, and epithelial-mesenchymal transition (EMT). Therefore, targeting neutrophils holds promise as an important therapeutic strategy for inhibiting pancreatic cancer liver metastasis. This article provides a summary of research findings on the involvement of neutrophils in pancreatic cancer liver metastasis and analyzes their potential as therapeutic targets. This research may provide new insights for the treatment of pancreatic cancer and improve the prognosis of patients with this disease.
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Affiliation(s)
- Minjie Guo
- Department of Thoracic Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Wanying Sheng
- Department of Thoracic Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Xiao Yuan
- Cancer Institute of Jiangsu University, Zhenjiang, China.
| | - Xu Wang
- Department of Thoracic Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
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Wang T, Sheng J, Wang X, Zhu M, Li S, Shen Y, Wu B. CXCL5 Promotes the Malignant Phenotype of Pancreatic Cancer and Is Associated With Immune Infiltration. Clin Med Insights Oncol 2024; 18:11795549241271691. [PMID: 39211563 PMCID: PMC11359438 DOI: 10.1177/11795549241271691] [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: 11/18/2023] [Accepted: 06/27/2024] [Indexed: 09/04/2024] Open
Abstract
Background The significance of CXCL5 in pancreatic cancer is unclear, although it has been implicated in the malignant process of many different types of cancer. Research on the impact of CXCL5 on immune cell infiltration and the malignant phenotype of pancreatic cancer is needed. This study aimed to examine the connection between CXCL5 expression and immune cell infiltration and the malignant phenotype of pancreatic cancer. Methods Tissue samples and clinical information were collected from 90 patients with pancreatic cancer. Tumour tissues and adjacent tissues were made into a tissue microarray and stained for immunohistochemistry analysis. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis were performed to measure the expression level of CXCL5. CXCL5-overexpressing/CXCL5-knockdown cell lines were constructed via transfection for cytological experiments. CCK-8, cell apoptosis, cell cycle, cell invasion, and cell colony formation assays were used to detect the effect of CXCL5 on the malignant phenotype of pancreatic cancer cells. Finally, a mouse model of pancreatic cancer was constructed for in vivo verification. Results Compared with control cells, pancreatic cancer cells overexpressing CXCL5 exhibited increased proliferation, migration, and invasion but decreased apoptosis. Conversely, knockdown of CXCL5 did not enhance the malignant phenotype of pancreatic cancer cells. Spearman correlation analysis indicated that there was a significant negative correlation between CXCL5 levels and the CD8 IRS. However, there was a significant positive correlation between FOXP3 IRS and CXCL5 levels. Conclusions CXCL5 is highly expressed in pancreatic cancer and promotes the malignant phenotype of pancreatic cancer cells. CXCL5 is associated with immunosuppressive FOXP3 + T-cell infiltration, which facilitates the formation of an immunosuppressive microenvironment (with low CD8 + T-cell infiltration).
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Affiliation(s)
- Tao Wang
- Graduate School, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Jian Sheng
- Department of Science and Education, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Xiaoguang Wang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Minyuan Zhu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Shijun Li
- Graduate School, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yiyu Shen
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Bin Wu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
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López-Gil JC, García-Silva S, Ruiz-Cañas L, Navarro D, Palencia-Campos A, Giráldez-Trujillo A, Earl J, Dorado J, Gómez-López G, Monfort-Vengut A, Alcalá S, Gaida MM, García-Mulero S, Cabezas-Sáinz P, Batres-Ramos S, Barreto E, Sánchez-Tomero P, Vallespinós M, Ambler L, Lin ML, Aicher A, García García de Paredes A, de la Pinta C, Sanjuanbenito A, Ruz-Caracuel I, Rodríguez-Garrote M, Guerra C, Carrato A, de Cárcer G, Sánchez L, Nombela-Arrieta C, Espinet E, Sanchez-Arevalo Lobo VJ, Heeschen C, Sainz B. The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells. Gut 2024; 73:1489-1508. [PMID: 38754953 PMCID: PMC11347225 DOI: 10.1136/gutjnl-2023-330995] [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: 08/25/2023] [Accepted: 04/11/2024] [Indexed: 05/18/2024]
Abstract
OBJECTIVE Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies. DESIGN We used the KPC mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) and primary tumour cell lines to investigate putative CSC populations. Transcriptomic analyses were conducted to pinpoint new genes involved in immune evasion. Overexpressing and knockout cell lines were established with lentiviral vectors. Subsequent in vitro coculture assays, in vivo mouse and zebrafish tumorigenesis studies, and in silico database approaches were performed. RESULTS Using the KPC mouse model, we functionally confirmed a population of cells marked by EpCAM, Sca-1 and CD133 as authentic CSCs and investigated their transcriptional profile. Immune evasion signatures/genes, notably the gene peptidoglycan recognition protein 1 (PGLYRP1), were significantly overexpressed in these CSCs. Modulating PGLYRP1 impacted CSC immune evasion, affecting their resistance to macrophage-mediated and T-cell-mediated killing and their tumourigenesis in immunocompetent mice. Mechanistically, tumour necrosis factor alpha (TNFα)-regulated PGLYRP1 expression interferes with the immune tumour microenvironment (TME) landscape, promoting myeloid cell-derived immunosuppression and activated T-cell death. Importantly, these findings were not only replicated in human models, but clinically, secreted PGLYRP1 levels were significantly elevated in patients with PDAC. CONCLUSIONS This study establishes PGLYRP1 as a novel CSC-associated marker crucial for immune evasion, particularly against macrophage phagocytosis and T-cell killing, presenting it as a promising target for PDAC immunotherapy.
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Affiliation(s)
- Juan Carlos López-Gil
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Department of Biochemistry, Autónoma University of Madrid (UAM), Madrid, Spain
| | - Susana García-Silva
- Microenvironment and Metastasis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Laura Ruiz-Cañas
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Biobanco Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Diego Navarro
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Department of Biochemistry, Autónoma University of Madrid (UAM), Madrid, Spain
| | - Adrián Palencia-Campos
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Antonio Giráldez-Trujillo
- Grupo de Oncología Cutánea, Servicio de Anatomía Patológica, Hospiral Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
| | - Julie Earl
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain
| | - Jorge Dorado
- Stem Cells and Cancer Group, Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Gonzalo Gómez-López
- Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Ana Monfort-Vengut
- Cell Cycle and Cancer Biomarkers Laboratory, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
| | - Sonia Alcalá
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
- Department of Biochemistry, Autónoma University of Madrid (UAM), Madrid, Spain
| | - Matthias M Gaida
- Institute of Pathology, JGU-Mainz, University Medical Center Mainz, Mainz, Germany
- TRON, JGU-Mainz, Translational Oncology at the University Medical Center, Mainz, Germany
- Research Center for Immunotherapy, JGU-Mainz, University Medical Center Mainz, Mainz, Germany
| | - Sandra García-Mulero
- Department of Pathology and Experimental Therapy, Universidad de Barcelona Facultad de Medicina y Ciencias de La Salud, Barcelona, Spain
- Molecular Mechanisms and Experimental Therapy in Oncology Program (Oncobell), IDIBELL, Barcelona, Spain
| | - Pablo Cabezas-Sáinz
- Department of Zoology, Genetics and Physical Anthropology, Veterinary Faculty, Universidade de Santiago de Compostela, Lugo, Spain
| | - Sandra Batres-Ramos
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Emma Barreto
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain
- School of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Spain
| | - Patricia Sánchez-Tomero
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Mireia Vallespinós
- Stem Cells and Cancer Group, Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Leah Ambler
- Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Meng-Lay Lin
- Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Alexandra Aicher
- Precision Immunotherapy, Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Ana García García de Paredes
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Gastroenterology and Hepatology, Hospital Universitario Ramon y Cajal, Madrid, Spain
| | | | - Alfonso Sanjuanbenito
- Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain
- Pancreatic and Biliopancreatic Surgery Unit, Hospital Universitario Ramon y Cajal, Madrid, Spain
| | - Ignacio Ruz-Caracuel
- Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain
- Ramon y Cajal University Hospital Anatomy Pathology Service, Madrid, Spain
- Molecular Pathology of Cancer Group, Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Mercedes Rodríguez-Garrote
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain
- Medical Oncology Service, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Carmen Guerra
- Experimental Oncology Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Alfredo Carrato
- Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain
- Medical Oncology Service, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Guillermo de Cárcer
- Cell Cycle and Cancer Biomarkers Laboratory, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
| | - Laura Sánchez
- Department of Zoology, Genetics and Physical Anthropology, Veterinary Faculty, Universidade de Santiago de Compostela, Lugo, Spain
| | - César Nombela-Arrieta
- Department of Medical Oncology and Hematology, University and University Hospital Zurich, Zürich, Switzerland
| | - Elisa Espinet
- Department of Pathology and Experimental Therapy, Universidad de Barcelona Facultad de Medicina y Ciencias de La Salud, Barcelona, Spain
- Molecular Mechanisms and Experimental Therapy in Oncology Program (Oncobell), IDIBELL, Barcelona, Spain
| | - Víctor Javier Sanchez-Arevalo Lobo
- Grupo de Oncología Cutánea, Servicio de Anatomía Patológica, Hospiral Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
- Grupo de Oncología Molecular, Instituto de Investigaciones Biosanitarias, Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, Spain
| | - Christopher Heeschen
- Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute - FPO - IRCCS, Candiolo (TO), Italy
| | - Bruno Sainz
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain
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Jia Y, Zhang F, Meng X, Andreev D, Lyu P, Zhang W, Lai C, Schett G, Bozec A. Osteocytes support bone metastasis of melanoma cells by CXCL5. Cancer Lett 2024; 590:216866. [PMID: 38589005 DOI: 10.1016/j.canlet.2024.216866] [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: 12/13/2023] [Revised: 03/18/2024] [Accepted: 04/03/2024] [Indexed: 04/10/2024]
Abstract
Bone metastasis is a common complication of certain cancers such as melanoma. The spreading of cancer cells into the bone is supported by changes in the bone marrow environment. The specific role of osteocytes in this process is yet to be defined. By RNA-seq and chemokines screening we show that osteocytes release the chemokine CXCL5 when they are exposed to melanoma cells. Osteocytes-mediated CXCL5 secretion enhanced the migratory and invasive behaviour of melanoma cells. When the expression of the CXCL5 receptor, CXCR2, was down-regulated in melanoma cells in vitro, we observed a significant decrease in melanoma cell migration in response to osteocytes. Furthermore, melanoma cells with down-regulated CXCR2 expression showed less bone metastasis and less bone loss in the bone metastasis model in vivo. Furthermore, when simultaneously down-regulating CXCL5 in osteocytes and CXCR2 in melanoma cells, melanoma progression was abrogated in vivo. In summary, these data suggest a significant role of osteocytes in bone metastasis of melanoma, which is mediated through the CXCL5-CXCR2 pathway.
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Affiliation(s)
- Yewei Jia
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Fulin Zhang
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Xianyi Meng
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Darja Andreev
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Pang Lyu
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Wenshuo Zhang
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Chaobo Lai
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Georg Schett
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Aline Bozec
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
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Sun C, Liu C, Liu X, Wu Z, Luo J, Liu R, Wang Y, Lu M, Wang Q, Guo M, Tang Y, Li X, Zheng J. Causal relationship between circulating cytokines and follicular lymphoma: a two-sample Mendelian randomization study. Am J Cancer Res 2024; 14:1577-1593. [PMID: 38726270 PMCID: PMC11076242 DOI: 10.62347/jckd6973] [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: 02/07/2024] [Accepted: 03/27/2024] [Indexed: 05/12/2024] Open
Abstract
Follicular lymphoma (FL), derived from germinal centre (GC) B cells, is a kind of systemic neoplasm. Even though FL is indolent, it remains an incurable haematology Neoplasm. Accumulating evidence has suggested that the circulating cytokine is associated with the development of FL, yet the causal relationship between FL and circulating cytokines remains undetermined. Therefore, we conducted a two-sample Mendelian randomization (MR) to confirm the causal link between FL and levels of circulating cytokines with the use of summary data on circulating cytokines and FL. All these data from genome-wide association study were derived from the Genome-wide pQTL mapping which contains 14,824 individuals. FL data were acquired exclusively from FinnGen, where 218,792 individuals (522 cases vs. 218,270 controls) were involved. Various statistical methods, including the inverse variance weighted method (IVW), weighted median (WME), simple model, weighted model (WM) and MR-Egger, were used to evaluate the potential causal connection between circulating cytokines and FL. Sensitivity analysis, which involves the examination of the heterogeneity, pleiotropy, and leave-one-out method, was also performed to ensure more trustworthy results. A bidirectional MR test was performed to evaluate the direction of causal association between circulating cytokines and FL. Combining all the steps of MR analysis, we revealed four causal cytokines: C-X-C motif chemokine ligand 5 (CXCL5), interleukin-15 receptor A (IL15RA), interleukin-20 (IL20), and neurotrophin-3 (NT-3). The risk of FL may be inversely linked to CXCL5 (OR=0.73, CI: 0.545-0.979, P=0.036), IL-15RA (OR=0.669, CI: 0.451-0.993, P=0.046), and IL-20 (OR=0.565, CI: 0.325-0.981, P=0.043) but positively linked to NT-3 (OR=1.872, CI: 1.063-3.297, P=0.03). In addition, in our study, no causal effect of FL on cytokines was demonstrated and no significant heterogeneity and pleiotropy were found. Our research revealed the causal relationship between cytokines and FL, along with both the anti-protective effect of CXCL5, IL-15RA, and IL-20 and the protective effect of neurotrophin-3 on FL. These findings aim to provide new clues regarding the pathogenesis of FL and to extend the potential of circulating cytokines to therapeutic interventions.
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Affiliation(s)
- Chen Sun
- Department of Pathology, Changhai Hospital, Navy Medical UniversityShanghai, China
- National Key Laboratory of Immunity and Inflammation and Institute of Immunology, Navy Medical UniversityShanghai, China
| | - Chengling Liu
- Center of Burns and Plastic Surgery and Dermatology, The 924th Hospital of Joint Logistics Support Force of The PLAGuilin, Guangxi, China
- National Key Laboratory of Immunity and Inflammation and Institute of Immunology, Navy Medical UniversityShanghai, China
| | - Xingchen Liu
- Department of Pathology, Changhai Hospital, Navy Medical UniversityShanghai, China
- National Key Laboratory of Immunity and Inflammation and Institute of Immunology, Navy Medical UniversityShanghai, China
| | - Zhaoruncheng Wu
- National Key Laboratory of Immunity and Inflammation and Institute of Immunology, Navy Medical UniversityShanghai, China
- School of Biomedical Engineering, Southern Medical UniversityGuangzhou, Guangdong, China
| | - Jianhua Luo
- National Key Laboratory of Immunity and Inflammation and Institute of Immunology, Navy Medical UniversityShanghai, China
| | - Ruolan Liu
- Department of Pathology, Changhai Hospital, Navy Medical UniversityShanghai, China
- National Key Laboratory of Immunity and Inflammation and Institute of Immunology, Navy Medical UniversityShanghai, China
| | - Yuanyuan Wang
- National Key Laboratory of Immunity and Inflammation and Institute of Immunology, Navy Medical UniversityShanghai, China
| | - Mengyu Lu
- Department of Pathology, Changhai Hospital, Navy Medical UniversityShanghai, China
- National Key Laboratory of Immunity and Inflammation and Institute of Immunology, Navy Medical UniversityShanghai, China
| | - Quanxing Wang
- National Key Laboratory of Immunity and Inflammation and Institute of Immunology, Navy Medical UniversityShanghai, China
| | - Meng Guo
- National Key Laboratory of Immunity and Inflammation and Institute of Immunology, Navy Medical UniversityShanghai, China
| | - Yi Tang
- Department of Plastic Surgery, Changhai Hospital, Navy Medical UniversityShanghai, China
| | - Xueying Li
- Department of Pathology, Changhai Hospital, Navy Medical UniversityShanghai, China
| | - Jianming Zheng
- Department of Pathology, Changhai Hospital, Navy Medical UniversityShanghai, China
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8
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Zhang J, Wang C, Yu Y. Comprehensive analyses and experimental verification of NETs and an EMT gene signature for prognostic prediction, immunotherapy, and chemotherapy in pancreatic adenocarcinoma. ENVIRONMENTAL TOXICOLOGY 2024; 39:2006-2023. [PMID: 38088494 DOI: 10.1002/tox.24082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 11/22/2023] [Accepted: 11/28/2023] [Indexed: 03/09/2024]
Abstract
Pancreatic adenocarcinoma (PAAD) is an aggressive malignancy with high mortality and poor prognosis. Neutrophil extracellular traps (NETs) and the epithelial-mesenchymal transition (EMT) significantly influence on the progression of various cancers. However, the underlying relevance of NETs- and EMT-associated genes on the outcomes of patients with PAAD remains to be elucidated. Transcriptome RNA sequencing data, together with clinical information and single-cell sequencing data of PAAD were collected from public databases. In the TCGA-PAAD cohort, ssGSEA was used to calculate NET and EMT scores. WGCNA was used to determine the key gene modules. A risk model with eight NET- and EMT-related genes (NERGs) was established using LASSO and multivariate Cox regression analysis. Patients in the reduced risk (RR) group showed better prognostic values compared with those in the elevated risk (ER) group. The prognostic model exhibited reliable and robust prediction when validated using an external database. The distributions of risk genes were explored in a single-cell sequencing data set. Immune infiltration, immune cycle, and immune checkpoints were compared between the RR and ER groups. Moreover, potential chemotherapeutic drugs were examined. DCBLD2 was identified as a key gene in PAAD cell lines by qRT-PCR, and was highly expressed in PAAD tissues. GSEA demonstrated that DCBLD2 induced the EMT. Transwell assays and western blotting showed that cell invasion and EMT induction were significantly reduced after DCBLD2 knockdown. Collectively, we constructed a prognosis model based on a NET and EMT gene signature, providing a valuable perspective for the prognostic evaluation and management of PAAD patient.
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Affiliation(s)
- Jing Zhang
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, International Campus, Zhejiang University, Haining, China
| | - Chaochen Wang
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, International Campus, Zhejiang University, Haining, China
| | - Yaqun Yu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, China
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9
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Song N, Cui K, Zeng L, Li M, Fan Y, Shi P, Wang Z, Su W, Wang H. Advance in the role of chemokines/chemokine receptors in carcinogenesis: Focus on pancreatic cancer. Eur J Pharmacol 2024; 967:176357. [PMID: 38309677 DOI: 10.1016/j.ejphar.2024.176357] [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: 09/13/2023] [Revised: 01/17/2024] [Accepted: 01/23/2024] [Indexed: 02/05/2024]
Abstract
The chemokines/chemokine receptors pathway significantly influences cell migration, particularly in recruiting immune cells to the tumor microenvironment (TME), impacting tumor progression and treatment outcomes. Emerging research emphasizes the involvement of chemokines in drug resistance across various tumor therapies, including immunotherapy, chemotherapy, and targeted therapy. This review focuses on the role of chemokines/chemokine receptors in pancreatic cancer (PC) development, highlighting their impact on TME remodeling, immunotherapy, and relevant signaling pathways. The unique immunosuppressive microenvironment formed by the interaction of tumor cells, stromal cells and immune cells plays an important role in the tumor proliferation, invasion, migration and therapeutic resistance. Chemokines/chemokine receptors, such as chemokine ligand (CCL) 2, CCL3, CCL5, CCL20, CCL21, C-X-C motif chemokine ligand (CXCL) 1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL16, CXCL17, and C-X3-C motif chemokine ligand (CX3CL)1, derived mainly from leukocyte cells, cancer-related fibroblasts (CAFs), pancreatic stellate cells (PSCs), and tumor-associated macrophages (TAMs), contribute to PC progression and treatment resistance. Chemokines recruit myeloid-derived suppressor cells (MDSC), regulatory T cells (Tregs), and M2 macrophages, inhibiting the anti-tumor activity of immune cells. Simultaneously, they enhance pathways like epithelial-mesenchymal transition (EMT), Akt serine/threonine kinase (AKT), extracellular regulated protein kinases (ERK) 1/2, and nuclear factor kappa-B (NF-κB), etc., elevating the risk of PC metastasis and compromising the efficacy of radiotherapy, chemotherapy, and anti-PD-1/PD-L1 immunotherapy. Notably, the CCLx-CCR2 and CXCLx-CXCR2/4 axis emerge as potential therapeutic targets in PC. This review integrates recent findings on chemokines and receptors in PC treatment, offering valuable insights for innovative therapeutic approaches.
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Affiliation(s)
- Na Song
- Department of Pathology, Xinxiang Key Laboratory of Precision Medicine, The First Affiliated Hospital of Xinxiang Medical University, China; Department of Pathology, Xinxiang Medical University, Xinxiang, 453000, China
| | - Kai Cui
- Department of Pathology, Xinxiang Medical University, Xinxiang, 453000, China
| | - Liqun Zeng
- Department of Pathology, Xinxiang Medical University, Xinxiang, 453000, China
| | - Mengxiao Li
- Department of Pathology, Xinxiang Key Laboratory of Precision Medicine, The First Affiliated Hospital of Xinxiang Medical University, China
| | - Yanwu Fan
- Department of Pathology, Xinxiang Medical University, Xinxiang, 453000, China
| | - Pingyu Shi
- Department of Pathology, Xinxiang Medical University, Xinxiang, 453000, China
| | - Ziwei Wang
- Department of Pathology, Xinxiang Medical University, Xinxiang, 453000, China
| | - Wei Su
- Department of Pathology, Xinxiang Key Laboratory of Precision Medicine, The First Affiliated Hospital of Xinxiang Medical University, China.
| | - Haijun Wang
- Department of Pathology, Xinxiang Key Laboratory of Precision Medicine, The First Affiliated Hospital of Xinxiang Medical University, China; Department of Pathology, Xinxiang Medical University, Xinxiang, 453000, China.
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10
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Imanishi M, Inoue T, Fukushima K, Yamashita R, Nakayama R, Nojima M, Kondo K, Gomi Y, Tsunematsu H, Goto K, Miyamoto L, Funamoto M, Denda M, Ishizawa K, Otaka A, Fujino H, Ikeda Y, Tsuchiya K. CA9 and PRELID2; hypoxia-responsive potential therapeutic targets for pancreatic ductal adenocarcinoma as per bioinformatics analyses. J Pharmacol Sci 2023; 153:232-242. [PMID: 37973221 DOI: 10.1016/j.jphs.2023.10.003] [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: 05/28/2023] [Revised: 09/25/2023] [Accepted: 10/13/2023] [Indexed: 11/19/2023] Open
Abstract
A strong hypoxic environment has been observed in pancreatic ductal adenocarcinoma (PDAC) cells, which contributes to drug resistance, tumor progression, and metastasis. Therefore, we performed bioinformatics analyses to investigate potential targets for the treatment of PDAC. To identify potential genes as effective PDAC treatment targets, we selected all genes whose expression level was related to worse overall survival (OS) in The Cancer Genome Atlas (TCGA) database and selected only the genes that matched with the genes upregulated due to hypoxia in pancreatic cancer cells in the dataset obtained from the Gene Expression Omnibus (GEO) database. Although the extracted 107 hypoxia-responsive genes included the genes that were slightly enriched in angiogenic factors, TCGA data analysis revealed that the expression level of endothelial cell (EC) markers did not affect OS. Finally, we selected CA9 and PRELID2 as potential targets for PDAC treatment and elucidated that a CA9 inhibitor, U-104, suppressed pancreatic cancer cell growth more effectively than 5-fluorouracil (5-FU) and PRELID2 siRNA treatment suppressed the cell growth stronger than CA9 siRNA treatment. Thus, we elucidated that specific inhibition of PRELID2 as well as CA9, extracted via exhaustive bioinformatic analyses of clinical datasets, could be a more effective strategy for PDAC treatment.
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Affiliation(s)
- Masaki Imanishi
- Department of Medical Pharmacology, Graduate School of Biomedical Sciences, Tokushima University, Japan.
| | - Takahisa Inoue
- Department of Medical Pharmacology, Graduate School of Biomedical Sciences, Tokushima University, Japan; Department of Pharmacy, Tokushima University Hospital, Japan
| | - Keijo Fukushima
- Department of Pharmacology for Life Sciences, Graduate School of Biomedical Sciences, Tokushima University, Japan.
| | - Ryosuke Yamashita
- Department of Medical Pharmacology, Graduate School of Biomedical Sciences, Tokushima University, Japan
| | - Ryo Nakayama
- Department of Medical Pharmacology, Graduate School of Biomedical Sciences, Tokushima University, Japan
| | - Masataka Nojima
- Department of Medical Pharmacology, Graduate School of Biomedical Sciences, Tokushima University, Japan
| | - Kosuke Kondo
- Department of Medical Pharmacology, Graduate School of Biomedical Sciences, Tokushima University, Japan
| | - Yoshiki Gomi
- Department of Medical Pharmacology, Graduate School of Biomedical Sciences, Tokushima University, Japan
| | - Honoka Tsunematsu
- Department of Medical Pharmacology, Graduate School of Biomedical Sciences, Tokushima University, Japan
| | - Kohei Goto
- Department of Medical Pharmacology, Graduate School of Biomedical Sciences, Tokushima University, Japan
| | - Licht Miyamoto
- Laboratory of Pharmacology and Food Science, Department of Nutrition and Life Science, Faculty of Health and Medical Sciences, Kanagawa Institute of Technology, Japan
| | - Masafumi Funamoto
- Department of Pharmacology, Graduate School of Biomedical Sciences, Tokushima University, Japan
| | - Masaya Denda
- Department of Bioorganic Synthetic Chemistry, Graduate School of Biomedical Sciences, Tokushima University, Japan
| | - Keisuke Ishizawa
- Department of Pharmacy, Tokushima University Hospital, Japan; Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University, Japan; Clinical Research Center for Developmental Therapeutics, Tokushima University Hospital, Japan
| | - Akira Otaka
- Department of Bioorganic Synthetic Chemistry, Graduate School of Biomedical Sciences, Tokushima University, Japan
| | - Hiromichi Fujino
- Department of Pharmacology for Life Sciences, Graduate School of Biomedical Sciences, Tokushima University, Japan
| | - Yasumasa Ikeda
- Department of Pharmacology, Graduate School of Biomedical Sciences, Tokushima University, Japan
| | - Koichiro Tsuchiya
- Department of Medical Pharmacology, Graduate School of Biomedical Sciences, Tokushima University, Japan
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11
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Karan D, Wick J, Dubey S, Kumar-Sinha C, Siddiqui J, Kunju LP, Iczkowski KA, Chinnaiyan AM. Racial differences in serum chemokines in prostate cancer patients. Cancer 2023; 129:3783-3789. [PMID: 37698493 DOI: 10.1002/cncr.35012] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 06/15/2023] [Accepted: 06/20/2023] [Indexed: 09/13/2023]
Abstract
BACKGROUND This study aimed to understand the differential levels of inflammatory chemokines in association with higher prostate cancer incidence and mortality in African American (AA) men than in Caucasians (CA). METHODS The authors used a chemokine assay to simultaneously measure 40 chemokines and cytokines levels in the serum of preoperative prostate cancer patients and healthy controls of AA and CA races. Selected chemokines (CXCL2, CXCL5, and CCL23) serum level was validated in 211 serum samples from prostate cancer patients and healthy controls. Differential expression of CXCL5 and CCL23 was analyzed using immunohistochemistry in a representative cohort of prostate tumor tissues of AA and CA races. RESULTS Race-specific comparisons from 211 serum samples showed significantly higher levels of CXCL2 (control: 3104.0 pg/mL vs. cancer: 2451.0 pg/mL) and CXCL5 (control: 5189.0 pg/mL vs. cancer: 5459.0 pg/mL) in AA men than in CAs (CXCL2; control: 1155.0 pg/mL vs. cancer: 889.3 pg/mL, and CXCL5; control: 1183.0 pg/mL vs. cancer: 977.5 pg/mL). CCL23 differed significantly within and between the races with a lower level in AA cancer cases (454.5 vs. 966.6 pg/mL) than healthy controls (740.5 vs. 1263.0 pg/mL). Patient age, prostate-specific antigen, or Gleason scores were not significantly associated with these chemokines. Immunostaining for CXCL5 and CCL23 in a representative cohort of archival prostate tissues displayed significantly higher CXCL5 in prostate tumors than in adjacent benign tissues, whereas CCL23 was nondetectable in most of the analyzed tumor tissues. CONCLUSION Lower levels of CCL23 in AA prostate cancer patient sera and tumor tissues and high CXCL2 and CXCL5 may contribute to aggressive prostate cancer, as often seen in AA men. The disproportionate levels of serum chemokines associated with race warrant further exploration to improve equitability in precision oncology to benefit prostate cancer patients.
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Affiliation(s)
- Dev Karan
- Department of Pathology, MCW Cancer Center and Prostate Cancer Center of Excellence, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Jo Wick
- Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Seema Dubey
- Department of Pathology, MCW Cancer Center and Prostate Cancer Center of Excellence, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Chandan Kumar-Sinha
- Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Javed Siddiqui
- Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Lakshmi P Kunju
- Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Kenneth A Iczkowski
- Department of Pathology, MCW Cancer Center and Prostate Cancer Center of Excellence, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Arul M Chinnaiyan
- Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
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12
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Walsh RM, Ambrose J, Jack JL, Eades AE, Bye B, Ruckert MT, Olou AA, Messaggio F, Chalise P, Pei D, VanSaun MN. Adipose-Tumor Crosstalk contributes to CXCL5 Mediated Immune Evasion in PDAC. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.15.553432. [PMID: 37645755 PMCID: PMC10461999 DOI: 10.1101/2023.08.15.553432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Background CXCR1/2 inhibitors are being implemented with immunotherapies in PDAC clinical trials. Cytokines responsible for stimulating these receptors include CXCL ligands, typically secreted by activated immune cells, fibroblasts, and even adipocytes. Obesity has been linked to poor patient outcome and altered anti-tumor immunity. Adipose-derived cytokines and chemokines have been implicated as potential drivers of tumor cell immune evasion, suggesting a possibility of susceptibility to targeting specifically in the context of obesity. Methods RNA-sequencing of human PDAC cell lines was used to assess differential influences on the cancer cell transcriptome after treatment with conditioned media from peri-pancreatic adipose tissue of lean and obese PDAC patients. The adipose-induced secretome of PDAC cells was then assessed by cytokine arrays and ELISAs. Lentiviral transduction and CRISPR-Cas9 was used to knock out CXCL5 from a murine PDAC cell line for orthotopic tumor studies in diet-induced obese, syngeneic mice. Flow cytometry was used to define the immune profiles of tumors. Anti-PD-1 immune checkpoint blockade therapy was administered to alleviate T cell exhaustion and invoke an immune response, while the mice were monitored at endpoint for differences in tumor size. Results The chemokine CXCL5 was secreted in response to stimulation of PDAC cells with human adipose conditioned media (hAT-CM). PDAC CXCL5 secretion was induced by either IL-1β or TNF, but neutralization of both was required to limit secretion. Ablation of CXCL5 from tumors promoted an immune phenotype susceptible to PD-1 inhibitor therapy. While application of anti-PD-1 treatment to control tumors failed to alter tumor growth, knockout CXCL5 tumors were diminished. Conclusions In summary, our findings show that known adipokines TNF and IL-1β can stimulate CXCL5 release from PDAC cells in vitro. In vivo , CXCL5 depletion alone is sufficient to promote T cell infiltration into tumors in an obese setting, but requires checkpoint blockade inhibition to alleviate tumor burden. DATA AVAILABILITY STATEMENT Raw and processed RNAseq data will be further described in the GEO accession database ( awaiting approval from GEO for PRJ number ). Additional raw data is included in the supplemental material and available upon reasonable request. WHAT IS ALREADY KNOWN ON THIS TOPIC Obesity is linked to a worsened patient outcome and immunogenic tumor profile in PDAC. CXCR1/2 inhibitors have begun to be implemented in combination with immune checkpoint blockade therapies to promote T cell infiltration under the premise of targeting the myeloid rich TME. WHAT THIS STUDY ADDS Using in vitro/ex vivo cell and tissue culture-based assays with in vivo mouse models we have identified that adipose derived IL-1β and TNF can promote tumor secretion of CXCL5 which acts as a critical deterrent to CD8 T cell tumor infiltration, but loss of CXCL5 also leads to a more immune suppressive myeloid profile. HOW THIS STUDY MIGHT AFFECT RESEARCH PRACTICE OR POLICY This study highlights a mechanism and emphasizes the efficacy of single CXCR1/2 ligand targeting that could be beneficial to overcoming tumor immune-evasion even in the obese PDAC patient population.
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13
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Wu YN, Su X, Wang XQ, Liu NN, Xu ZW. The roles of phospholipase C-β related signals in the proliferation, metastasis and angiogenesis of malignant tumors, and the corresponding protective measures. Front Oncol 2023; 13:1231875. [PMID: 37576896 PMCID: PMC10419273 DOI: 10.3389/fonc.2023.1231875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 07/13/2023] [Indexed: 08/15/2023] Open
Abstract
PLC-β is widely distributed in eukaryotic cells and is the key enzyme in phosphatidylinositol signal transduction pathway. The cellular functions regulated by its four subtypes (PLC-β1, PLC-β2, PLC-β3, PLC-β4) play an important role in maintaining homeostasis of organism. PLC-β and its related signals can promote or inhibit the occurrence and development of cancer by affecting the growth, differentiation and metastasis of cells, while targeted intervention of PLC-β1-PI3K-AKT, PLC-β2/CD133, CXCR2-NHERF1-PLC-β3, Gαq-PLC-β4-PKC-MAPK and so on can provide new strategies for the precise prevention and treatment of malignant tumors. This paper reviews the mechanism of PLC-β in various tumor cells from four aspects: proliferation and differentiation, invasion and metastasis, angiogenesis and protective measures.
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Affiliation(s)
- Yu-Nuo Wu
- Department of Clinical Medical, the First Clinical Medical College of Anhui Medical University, Hefei, Anhui, China
| | - Xing Su
- Department of Clinical Medical, the First Clinical Medical College of Anhui Medical University, Hefei, Anhui, China
| | - Xue-Qin Wang
- Department of Clinical Medical, the First Clinical Medical College of Anhui Medical University, Hefei, Anhui, China
| | - Na-Na Liu
- Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Zhou-Wei Xu
- Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui, China
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14
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Gibellini L, Borella R, Santacroce E, Serattini E, Boraldi F, Quaglino D, Aramini B, De Biasi S, Cossarizza A. Circulating and Tumor-Associated Neutrophils in the Era of Immune Checkpoint Inhibitors: Dynamics, Phenotypes, Metabolism, and Functions. Cancers (Basel) 2023; 15:3327. [PMID: 37444436 DOI: 10.3390/cancers15133327] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/16/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Neutrophils are the most abundant myeloid cells in the blood and are a considerable immunological component of the tumor microenvironment. However, their functional importance has often been ignored, as they have always been considered a mono-dimensional population of terminally differentiated, short-living cells. During the last decade, the use of cutting-edge, single-cell technologies has revolutionized the classical view of these cells, unmasking their phenotypic and functional heterogeneity. In this review, we summarize the emerging concepts in the field of neutrophils in cancer, by reviewing the recent literature on the heterogeneity of both circulating neutrophils and tumor-associated neutrophils, as well as their possible significance in tumor prognosis and resistance to immune checkpoint inhibitors.
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Affiliation(s)
- Lara Gibellini
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Rebecca Borella
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Elena Santacroce
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Eugenia Serattini
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Federica Boraldi
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Daniela Quaglino
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Beatrice Aramini
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences (DIMEC), University Hospital GB Morgagni-L Pierantoni, 47121 Forlì, Italy
| | - Sara De Biasi
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Andrea Cossarizza
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, 41121 Modena, Italy
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15
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Prajapati DR, Molczyk C, Purohit A, Saxena S, Sturgeon R, Dave BJ, Kumar S, Batra SK, Singh RK. Small molecule antagonist of CXCR2 and CXCR1 inhibits tumor growth, angiogenesis, and metastasis in pancreatic cancer. Cancer Lett 2023; 563:216185. [PMID: 37062329 PMCID: PMC10218365 DOI: 10.1016/j.canlet.2023.216185] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/06/2023] [Accepted: 04/11/2023] [Indexed: 04/18/2023]
Abstract
Pancreatic cancer (PC) has a poor prognosis, and current therapeutic strategies are ineffective in advanced diseases. We and others have shown the aberrant expression of CXCR2 and its ligands in PC development and progression. Our objective for this study was to evaluate the therapeutic utility of CXCR2/1 targeting using an small molecule antagonist, SCH-479833, in different PC preclinical murine models (syngeneic or xenogeneic). Our results demonstrate that CXCR2/1 antagonist had both antitumor and anti-metastatic effects in PC. CXCR2/1 antagonist treatment inhibited tumor cell proliferation, migration, angiogenesis, and recruitment of neutrophils, while it increased apoptosis. Treatment with the antagonist enhanced fibrosis, tumor necrosis, and extramedullary hematopoiesis. Together, these findings suggest that selectively targeting CXCR2/1 with small molecule inhibitors is a promising therapeutic approach for inhibiting PC growth, angiogenesis, and metastasis.
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Affiliation(s)
- Dipakkumar R Prajapati
- Department of Pathology and Microbiology, 985950, Nebraska Medical Center, Omaha, NE, 68198-5900, United States
| | - Caitlin Molczyk
- Department of Pathology and Microbiology, 985950, Nebraska Medical Center, Omaha, NE, 68198-5900, United States
| | - Abhilasha Purohit
- Department of Pathology and Microbiology, 985950, Nebraska Medical Center, Omaha, NE, 68198-5900, United States
| | - Sugandha Saxena
- Department of Pathology and Microbiology, 985950, Nebraska Medical Center, Omaha, NE, 68198-5900, United States
| | - Reegan Sturgeon
- Department of Pathology and Microbiology, 985950, Nebraska Medical Center, Omaha, NE, 68198-5900, United States
| | - Bhavana J Dave
- Department of Pathology and Microbiology, 985950, Nebraska Medical Center, Omaha, NE, 68198-5900, United States
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5845, United States
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5845, United States
| | - Rakesh K Singh
- Department of Pathology and Microbiology, 985950, Nebraska Medical Center, Omaha, NE, 68198-5900, United States.
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Wu Z, Wu Y, Liu Z, Song Y, Ge L, Du T, Liu Y, Liu L, Liu C, Ma L. L1CAM deployed perivascular tumor niche promotes vessel wall invasion of tumor thrombus and metastasis of renal cell carcinoma. Cell Death Discov 2023; 9:112. [PMID: 37015905 PMCID: PMC10073121 DOI: 10.1038/s41420-023-01410-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/21/2023] [Accepted: 03/23/2023] [Indexed: 04/06/2023] Open
Abstract
The survival of tumor cells in the bloodstream, and vasculature adhesion at metastatic sites are crucial for tumor metastasis. Perivascular invasion aids tumor cell self-renewal, survival, and formation of metastases by facilitating readily available oxygen, nutrients, and endothelial-derived paracrine factors. Renal cell carcinoma (RCC) is among the most prevalent tumors of the urinary system, and the formation of venous tumor thrombus (VTT) is a characteristic feature of RCC. We observed high expression of L1CAM in the VTT with vessel wall invasion. L1CAM promotes the adhesion, migration, and invasion ability of RCC and enhances metastasis by interacting with ITGA5, which elicits activation of signaling downstream of integrin α5β1. L1CAM promotes ADAM17 transcription to facilitate transmembrane ectodomain cleavage and release of soluble L1CAM. In response to soluble L1CAM, vascular endothelial cells release several cytokines and chemokines. Endothelial-derived CXCL5 and its receptor CXCR2 promote the migration and intravasation of RCC toward endothelial cells suggesting that crosstalk between endothelial cells and tumor cells has a direct guiding role in driving the metastatic spread of RCC. LICAM plays a crucial role in the invasive ability of RCC, and regulation of L1CAM expression may contribute therapeutically to preventing RCC progression.
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Affiliation(s)
- Zonglong Wu
- Department of Urology, Peking University Third Hospital, Beijing, 100191, P.R. China
| | - Yaqian Wu
- Department of Urology, Peking University Third Hospital, Beijing, 100191, P.R. China
| | - Zhuo Liu
- Department of Urology, Peking University Third Hospital, Beijing, 100191, P.R. China
| | - Yimeng Song
- Department of Urology, Peking University Third Hospital, Beijing, 100191, P.R. China
| | - Liyuan Ge
- Department of Urology, Peking University Third Hospital, Beijing, 100191, P.R. China
| | - Tan Du
- Department of Urology, Peking University Third Hospital, Beijing, 100191, P.R. China
| | - Yunchong Liu
- Department of Urology, Peking University Third Hospital, Beijing, 100191, P.R. China
| | - Li Liu
- School of Nursing, Beijing University of Chinese Medicine, Beijing, 100191, P.R. China
| | - Cheng Liu
- Department of Urology, Peking University Third Hospital, Beijing, 100191, P.R. China.
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, P.R. China.
| | - Lulin Ma
- Department of Urology, Peking University Third Hospital, Beijing, 100191, P.R. China.
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Xie Y, Kuang W, Wang D, Yuan K, Yang P. Expanding role of CXCR2 and therapeutic potential of CXCR2 antagonists in inflammatory diseases and cancers. Eur J Med Chem 2023; 250:115175. [PMID: 36780833 DOI: 10.1016/j.ejmech.2023.115175] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/23/2023] [Accepted: 01/31/2023] [Indexed: 02/10/2023]
Abstract
C-X-C motif chemokine receptor 2 (CXCR2) is G protein-coupled receptor (GPCR) and plays important roles in various inflammatory diseases and cancers, including chronic obstructive pulmonary disease (COPD), atherosclerosis, asthma, and pancreatic cancer. Upregulation of CXCR2 is closely associated with the migration of neutrophils and monocytes. To date, many small-molecule CXCR2 antagonists have entered clinical trials, showing favorable safety and therapeutic effects. Hence, we provide an overview containing the discovery history, protein structure, signaling pathways, biological functions, structure-activity relationships and clinical significance of CXCR2 antagonists in inflammatory diseases and cancers. According to the latest development and recent clinical progress of CXCR2 small molecule antagonists, we speculated that CXCR2 can be used as a biomarker and a new target for diabetes and that CXCR2 antagonists may also attenuate lung injury in coronavirus disease 2019 (COVID-19).
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Affiliation(s)
- Yishi Xie
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing, 211198, China
| | - Wenbin Kuang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing, 211198, China
| | - Dawei Wang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing, 211198, China
| | - Kai Yuan
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing, 211198, China
| | - Peng Yang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing, 211198, China.
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18
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Wang ZZ, Li XT, Li QJ, Zhou JX. Targeting CXCL5 in Pancreatic Cancer Cells Inhibits Cancer Xenograft Growth by Reducing Proliferation and Inhibiting EMT Progression. Dig Dis Sci 2023; 68:841-851. [PMID: 35650416 DOI: 10.1007/s10620-022-07529-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 04/18/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Pancreatic cancer (PC) is the most lethal malignant tumor, with average survival period of about 10 months. C-X-C ligand 5 (CXCL5), an important chemokine for immune cell accumulation in tumor tissues, has been reported to be involved in a variety of human cancers. However, the exact role of CXCL5 in PC progression has not been well defined. METHODS The expression of CXCL5 in PC was analyzed based on online databases and clinical specimens immunohistochemical staining, and Western blotting of CXCL5 in PC cell lines and patient samples. The correlation between CXCL5 expression and prognosis in PC was explored. The role of CXCL5 in PC was investigated through in vitro and in vivo experiments. RESULTS The expression of CXCL5 was significantly increased in PC tissues compared with that in pancreas tissues, and CXCL5 high expression predicts poor prognosis in PC patients. Further analyses demonstrated that overexpression of CXCL5 in PC cells was positively related to higher proliferation rate, higher migration ability, and higher EMT markers including SNAI2 and TWIST1 of tumor cells in vitro. Consistently, the knockdown of CXCL5 in PC cells harmed the proliferation rate, migration ability, and expression of EMT indexes of tumor cells in vitro. Importantly, knockdown of CXCL5 inhibited the growth of xenograft tumors in vivo. CONCLUSION CXCL5 high expression predicts poor prognosis in PC patients. CXCL5 promotes PC cell growth and EMT process. Inhibition of CXCL5 may be a potential therapeutic approach for PC.
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Affiliation(s)
- Zheng-Zheng Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Xiao-Ting Li
- Department of Obstetrics and Gynecology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, China
| | - Qing-Jun Li
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Jin-Xue Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China.
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Mir MA, Bashir M, Ishfaq. Role of the CXCL8–CXCR1/2 Axis in Cancer and Inflammatory Diseases. CYTOKINE AND CHEMOKINE NETWORKS IN CANCER 2023:291-329. [DOI: 10.1007/978-981-99-4657-0_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Lv G, Zhang L, Gao L, Cui J, Liu Z, Sun B, Wang G, Tang Q. The application of single-cell sequencing in pancreatic neoplasm: analysis, diagnosis and treatment. Br J Cancer 2023; 128:206-218. [PMID: 36307645 PMCID: PMC9902442 DOI: 10.1038/s41416-022-02023-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 10/11/2022] [Accepted: 10/12/2022] [Indexed: 02/08/2023] Open
Abstract
Pancreatic neoplasms, including pancreatic ductal adenocarcinoma (PDAC), intraductal papillary mucinous neoplasm (IPMN) and pancreatic cystic neoplasms (PCNs), are the most puzzling diseases. Numerous studies have not brought significant improvements in prognosis and diagnosis, especially in PDAC. One important reason is that previous studies only focused on differences between patients and healthy individuals but ignored intratumoral heterogeneity. In recent years, single-cell sequencing techniques, represented by single-cell RNA sequencing (scRNA-seq), have emerged by which researchers can analyse each cell in tumours instead of their average levels. Herein, we summarise the new current knowledge of single-cell sequencing in pancreatic neoplasms with respect to techniques, tumour heterogeneities and treatments.
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Affiliation(s)
- Gaoyuan Lv
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, 150000, Harbin, Heilongjiang Province, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Liang Zhang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, 150000, Harbin, Heilongjiang Province, China
| | - Lei Gao
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, 150000, Harbin, Heilongjiang Province, China
| | - Jitao Cui
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, 150000, Harbin, Heilongjiang Province, China
| | - Ziying Liu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, 150000, Harbin, Heilongjiang Province, China
| | - Bei Sun
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, 150000, Harbin, Heilongjiang Province, China
| | - Gang Wang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, 150000, Harbin, Heilongjiang Province, China.
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Qiushi Tang
- Chinese Journal of Practical Surgery, Chinese Medical University, Shenyang, China.
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21
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A Cuproptosis-Related lncRNAs Signature Could Accurately Predict Prognosis in Patients with Clear Cell Renal Cell Carcinoma. Anal Cell Pathol (Amst) 2022; 2022:4673514. [PMID: 36588797 PMCID: PMC9800904 DOI: 10.1155/2022/4673514] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 11/28/2022] [Accepted: 12/03/2022] [Indexed: 12/24/2022] Open
Abstract
Background Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancers. As cuproptosis, a new cell death mechanism proposed recently, differs from all other known mechanisms regulating cell death, we aimed to create prognostic markers using cuproptosis-related long non-coding ribonucleic acids (RNAs; lncRNAs) and elucidate the molecular mechanism. Methods Data from transcriptome RNA sequencing of ccRCC samples and the relevant clinical data were downloaded from The Cancer Genome Atlas, and Pearson's correlation analysis was implemented to obtain the cuproptosis-related lncRNAs. Then, univariate Cox, multivariate Cox, and Least Absolute Shrinkage and Selection Operator Cox analyses were performed to construct the risk signatures. The cuproptosis-related lncRNAs predictive signature was evaluated with receiver operating characteristic curves and subgroup analysis. Finally, Gene Set Enrichment Analysis (GSEA), single-sample GSEA (ssGSEA), tumor immune microenvironment (TIME), and immune checkpoints were performed to explore the relationship between immunity and patient prognosis. Results Five cuproptosis-related lncRNAs, including FOXD2-AS1, LINC00460, AC091212.1, AC007365.1, and AC026401.3, were used to construct the signature. In the training and test sets, low-risk groups (as identified by a risk score lower than the median) demonstrated a better prognosis with an area under the curve for 1-, 3-, and 5-year survival being 0.793, 0.716, and 0.719, respectively. GSEA analysis suggested significant enrichment of the tricarboxylic acid cycle and metabolism-related pathways in the low-risk group. Besides, both ssGSEA and TIME suggested that the high-risk group exhibited more active immune infiltration. Conclusion We proposed a cuproptosis-related lncRNAs signature, which had the potential for prognoses and prediction. Our findings might contribute to elucidating potential genomic biomarkers and targets for future therapies in the cuproptosis-related signaling pathways.
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22
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Gautam SK, Basu S, Aithal A, Dwivedi NV, Gulati M, Jain M. Regulation of pancreatic cancer therapy resistance by chemokines. Semin Cancer Biol 2022; 86:69-80. [PMID: 36064086 PMCID: PMC10370390 DOI: 10.1016/j.semcancer.2022.08.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 08/24/2022] [Accepted: 08/25/2022] [Indexed: 12/12/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by high resistance and poor response to chemotherapy. In addition, the poorly immunogenic pancreatic tumors constitute an immunosuppressive tumor microenvironment (TME) that render immunotherapy-based approaches ineffective. Understanding the mechanisms of therapy resistance, identifying new targets, and developing effective strategies to overcome resistance can significantly impact the management of PDAC patients. Chemokines are small soluble factors that are significantly deregulated during PDAC pathogenesis, contributing to tumor growth, metastasis, immune cell trafficking, and therapy resistance. Thus far, different chemokine pathways have been explored as therapeutic targets in PDAC, with some promising results in recent clinical trials. Particularly, immunotherapies such as immune check point blockade therapies and CAR-T cell therapies have shown promising results when combined with chemokine targeted therapies. Considering the emerging pathological and clinical significance of chemokines in PDAC, we reviewed major chemokine-regulated pathways leading to therapy resistance and the ongoing endeavors to target chemokine signaling in PDAC. This review discusses the role of chemokines in regulating therapy resistance in PDAC and highlights the continuing efforts to target chemokine-regulated pathways to improve the efficacy of various treatment modalities.
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Affiliation(s)
- Shailendra K Gautam
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Soumi Basu
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Abhijit Aithal
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Nidhi V Dwivedi
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Mansi Gulati
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
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23
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Jiang W, Li X, Xiang C, Zhou W. Neutrophils in pancreatic cancer: Potential therapeutic targets. Front Oncol 2022; 12:1025805. [PMID: 36324574 PMCID: PMC9618950 DOI: 10.3389/fonc.2022.1025805] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 09/28/2022] [Indexed: 08/30/2023] Open
Abstract
Pancreatic cancer is a digestive system malignancy and poses a high mortality worldwide. Traditionally, neutrophils have been thought to play a role in acute inflammation. In contrast, their importance during tumor diseases has been less well studied. Generally, neutrophils are recruited into the tumor microenvironment and exert inflammation and tumor-promoting effects. As an essential part of the tumor microenvironment, neutrophils play diverse roles in pancreatic cancer, such as angiogenesis, progression, metastasis and immunosuppression. Additionally, neutrophils can be a new potential therapeutic target in cancer. Inhibitors of cytokines, chemokines and neutrophil extracellular traps can exert antitumor effects. In this review, we describe the role of neutrophils in the development and progression of pancreatic cancer, discuss their potential as therapeutic targets, and aim to provide ideas for improving the prognosis of patients with this malignant tumor disease.
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Affiliation(s)
- Wenkai Jiang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Xin Li
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Caifei Xiang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Wence Zhou
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
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Tirado‐Cabrera I, Martin‐Guerrero E, Heredero‐Jimenez S, Ardura JA, Gortázar AR. PTH1R translocation to primary cilia in mechanically-stimulated ostecytes prevents osteoclast formation via regulation of CXCL5 and IL-6 secretion. J Cell Physiol 2022; 237:3927-3943. [PMID: 35933642 PMCID: PMC9804361 DOI: 10.1002/jcp.30849] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 07/12/2022] [Accepted: 07/22/2022] [Indexed: 01/05/2023]
Abstract
Osteocytes respond to mechanical forces controlling osteoblast and osteoclast function. Mechanical stimulation decreases osteocyte apoptosis and promotes bone formation. Primary cilia have been described as potential mechanosensors in bone cells. Certain osteogenic responses induced by fluid flow (FF) in vitro are decreased by primary cilia inhibition in MLO-Y4 osteocytes. The parathyroid hormone (PTH) receptor type 1 (PTH1R) modulates osteoblast, osteoclast, and osteocyte effects upon activation by PTH or PTH-related protein (PTHrP) in osteoblastic cells. Moreover, some actions of PTH1R seem to be triggered directly by mechanical stimulation. We hypothesize that PTH1R forms a signaling complex in the primary cilium that is essential for mechanotransduction in osteocytes and affects osteocyte-osteoclast communication. MLO-Y4 osteocytes were stimulated by FF or PTHrP (1-37). PTH1R and primary cilia signaling were abrogated using PTH1R or primary cilia specific siRNAs or inhibitors, respectively. Conditioned media obtained from mechanically- or PTHrP-stimulated MLO-Y4 cells inhibited the migration of preosteoclastic cells and osteoclast differentiation. Redistribution of PTH1R along the entire cilium was observed in mechanically stimulated MLO-Y4 osteocytic cells. Preincubation of MLO-Y4 cells with the Gli-1 antagonist, the adenylate cyclase inhibitor (SQ22536), or with the phospholipase C inhibitor (U73122), affected the migration of osteoclast precursors and osteoclastogenesis. Proteomic analysis and neutralizing experiments showed that FF and PTH1R activation control osteoclast function through the modulation of C-X-C Motif Chemokine Ligand 5 (CXCL5) and interleukin-6 (IL-6) secretion in osteocytes. These novel findings indicate that both primary cilium and PTH1R are necessary in osteocytes for proper communication with osteoclasts and show that mechanical stimulation inhibits osteoclast recruitment and differentiation through CXCL5, while PTH1R activation regulate these processes via IL-6.
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Affiliation(s)
- Irene Tirado‐Cabrera
- Bone Physiopathology Laboratory, Applied Molecular Medicine Institute (IMMA), Universidad San Pablo‐CEU, CEU UniversitiesCampus MonteprincipeAlcorcónSpain,Department of Basic Medical Sciences, School of Medicine, Universidad San Pablo‐CEU, CEU UniversitiesCampus MonteprincipeAlcorcónMadridSpain
| | - Eduardo Martin‐Guerrero
- Bone Physiopathology Laboratory, Applied Molecular Medicine Institute (IMMA), Universidad San Pablo‐CEU, CEU UniversitiesCampus MonteprincipeAlcorcónSpain
| | - Sara Heredero‐Jimenez
- Bone Physiopathology Laboratory, Applied Molecular Medicine Institute (IMMA), Universidad San Pablo‐CEU, CEU UniversitiesCampus MonteprincipeAlcorcónSpain
| | - Juan A. Ardura
- Bone Physiopathology Laboratory, Applied Molecular Medicine Institute (IMMA), Universidad San Pablo‐CEU, CEU UniversitiesCampus MonteprincipeAlcorcónSpain,Department of Basic Medical Sciences, School of Medicine, Universidad San Pablo‐CEU, CEU UniversitiesCampus MonteprincipeAlcorcónMadridSpain
| | - Arancha R. Gortázar
- Bone Physiopathology Laboratory, Applied Molecular Medicine Institute (IMMA), Universidad San Pablo‐CEU, CEU UniversitiesCampus MonteprincipeAlcorcónSpain,Department of Basic Medical Sciences, School of Medicine, Universidad San Pablo‐CEU, CEU UniversitiesCampus MonteprincipeAlcorcónMadridSpain
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25
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He C, Zhang G, Lu Y, Zhou J, Ren Z. DDX17 modulates the expression and alternative splicing of genes involved in apoptosis and proliferation in lung adenocarcinoma cells. PeerJ 2022; 10:e13895. [PMID: 36164607 PMCID: PMC9508879 DOI: 10.7717/peerj.13895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 07/22/2022] [Indexed: 01/19/2023] Open
Abstract
Background The DEAD-box RNA-binding protein (RBP) DDX17 has been found to be involved in the tumorigenesis of many types of cancers. However, the role of DDX17 in lung adenocarcinoma (LUAD) remains unclear. Methods We silenced DDX17 expression in A549 LUAD cells by small interfering RNA (siRNA). Cell proliferation and apoptosis assays were performed to explore the functions of DDX17. Knockdown of DDX17 by siRNA significantly inhibited proliferation and induced apoptosis in A549 cells. We used high-throughput RNA sequencing (RNA-seq) to identify differentially expressed genes (DEGs) and alternative splicing (AS) events in DDX17 knockdown LUAD cells. Results DDX17 knockdown increased the expression levels of proapoptotic genes and decreased those of proproliferative genes. Moreover, the DDX17-regulated AS events in A549 cells revealed by computational analysis using ABLas software were strongly validated by quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and were also validated by analysis of The Cancer Genome Atlas (TCGA)-LUAD dataset. These findings suggest that DDX17 may function as an oncogene by regulating both the expression and AS of proliferation- and apoptosis-associated genes in LUAD cells. Our findings may offer new insights into understanding the molecular mechanisms of LUAD and provide a new therapeutic direction for LUAD.
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Affiliation(s)
- Cheng He
- Department of Thoracic Oncology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui, China,Department of Thoracic Oncology, Anhui Provincial Cancer Hospital, Hefei, Anhui, China
| | - Gan Zhang
- Department of Thoracic Surgery, Anhui Provincial Cancer Hospital, Hefei, Anhui, China
| | - Yanhong Lu
- Department of Thoracic Surgery, Anhui Provincial Cancer Hospital, Hefei, Anhui, China
| | - Jingyue Zhou
- Department of Thoracic Surgery, Anhui Provincial Cancer Hospital, Hefei, Anhui, China
| | - Zixue Ren
- Department of Thoracic Surgery, Anhui Provincial Cancer Hospital, Hefei, Anhui, China
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Ge X, He J, Wang L, Zhao L, Wang Y, Wu G, Liu W, Shu Y, Gong W, Ma XL, Wang Y, Jiang BH, Liu LZ. Epigenetic alterations of CXCL5 in Cr(VI)-induced carcinogenesis. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 838:155713. [PMID: 35660107 PMCID: PMC9290188 DOI: 10.1016/j.scitotenv.2022.155713] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/25/2022] [Accepted: 05/01/2022] [Indexed: 05/14/2023]
Abstract
Chronic exposure to hexavalent chromium compounds [Cr(VI)] is associated with an increased risk of cancers, but the molecular mechanisms remain to be elucidated. In this study, we found that CXCL5 levels in peripheral blood monocytes (PBMCs) and plasma from workers with occupational exposure to Cr(VI) were dramatically upregulated compared to non-exposure healthy subjects, and plasma C-X-C Motif Chemokine Ligand 5 (CXCL5) CXCL5 levels were positively correlated with Cr concentrations in subjects' toenails. Zinc chromate exposed mice showed higher levels of CXCL5 and its receptor CXCR2 in lung tissues, and in PBMCs. Similar CXCL5 upregulation was evident in Cr(VI)-induced transformed (Cr-T) cells with long-term Cr(VI) treatment. Mechanistic studies showed that elevated CXCL5 expression levels were regulated by Cr(VI)-induced histone modifications and DNA hypomethylation, and that the c-Myc/p300 complex was a key upstream regulator of histone H3 acetylation. CXCL5 overexpression promoted Cr(VI)-induced the epithelial to mesenchyme transition (EMT) by upregulating zinc finger E-box binding homeobox 1 (ZEB1) to promote tumor development. Our findings identify a novel mechanism by which CXCL5 is upregulated and promotes EMT and carcinogenesis upon chronic Cr(VI) exposure. Our work also implies that CXCL5 mRNA and protein levels will elevate in PBMCs and serum after occupational Cr(VI) exposure, which may be a potential target and biomarker for cancer prevention and health surveillance among populations exposed to Cr(VI).
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Affiliation(s)
- Xin Ge
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA; Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, 211166, China
| | - Jun He
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Lin Wang
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA; Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Lei Zhao
- Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Yifang Wang
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Gang Wu
- Department of Occupational Health, Changzhou Center of Disease Control, Changzhou, Jiangsu, China
| | - Wenjing Liu
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yongqian Shu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Gong
- Department of Occupational Health, Jiangsu Center of Disease Control, Nanjing, Jiangsu, China
| | - Xin-Liang Ma
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Yajing Wang
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Bing-Hua Jiang
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
| | - Ling-Zhi Liu
- Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
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Deng J, Jiang R, Meng E, Wu H. CXCL5: A coachman to drive cancer progression. Front Oncol 2022; 12:944494. [PMID: 35978824 PMCID: PMC9376318 DOI: 10.3389/fonc.2022.944494] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Chemokines are a class of pro-inflammatory cytokines that can recruit and activate chemotactic cells. C‐X‐C motif chemokine ligand 5 (CXCL5) is a member of the chemokine family binding CXCR2 (C-X-C Motif Chemokine Receptor 2), a G-protein coupled receptor. Accumulated evidence has shown that dysregulated CXCL5 participates in tumor metastasis and angiogenesis in human malignant tumors. In this review, we summarized the advances in research on CXCL5, including its dysregulation in different tumors and the mechanism associated with tumor behavior (formation of the immunosuppressive microenvironment, promotion of tumor angiogenesis, and metastasis). We also summarized and discussed the perspective about the potential application of CXCL5 in tumor therapy targeting the tumor inflammatory microenvironment.
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Genomically Silent Refractory Gastric Cancer in a Young Patient Exhibits Overexpression of CXCL5. Curr Oncol 2022; 29:4725-4733. [PMID: 35877235 PMCID: PMC9320515 DOI: 10.3390/curroncol29070375] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 07/02/2022] [Accepted: 07/05/2022] [Indexed: 12/16/2022] Open
Abstract
Gastric cancer is the third leading cause of cancer-related deaths, with more than one million new cases and approximately 841,000 deaths annually worldwide. We report a case of a young patient (25 years old) with an aggressive form of gastric cancer. The patient had previously been treated for Helicobacter pylori (H. pylori), which is a main risk factor for developing gastric cancer. Genetic testing showed an E-cadherin (CDH1) germline mutation of unknown significance. After eight cycles of chemotherapy, a positron emission tomography (PET) scan showed disease progression with an enlarging hypermetabolic right adnexal mass suspicious for metastatic disease. Tumor pathology demonstrated invasive and poorly differentiated gastric carcinoma. The analysis of the tumor biopsy indicated the very high expression of a chemokine, C-X-C motif chemokine 5 (CXCL5). The combination of H. pylori infection with an existence of a rare CDH1 mutation could have contributed to this aggressive gastric cancer.
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29
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Ghallab AM, Eissa RA, El Tayebi HM. CXCR2 Small-Molecule Antagonist Combats Chemoresistance and Enhances Immunotherapy in Triple-Negative Breast Cancer. Front Pharmacol 2022; 13:862125. [PMID: 35517812 PMCID: PMC9065340 DOI: 10.3389/fphar.2022.862125] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/11/2022] [Indexed: 12/31/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer as the absence of cell surface receptors renders it more difficult to be therapeutically targeted. Chemokine receptor 2 (CXCR2) has been suggested not only to promote therapy resistance and suppress immunotherapy but it also to possess a positive cross-talk with the multifunctional cytokine transforming growth factor beta (TGF-β). Here, we showed that CXCR2 and TGF-β signaling were both upregulated in human TNBC biopsies. CXCR2 inhibition abrogated doxorubicin-mediated TGF-β upregulation in 3D in vitro TNBC coculture with PBMCs and eliminated drug resistance in TNBC mammospheres, suggesting a vital role for CXCR2 in TNBC doxorubicin-resistance via TGF-β signaling regulation. Moreover, CXCR2 inhibition improved the efficacy of the immunotherapeutic drug "atezolizumab" where the combined inhibition of CXCR2 and PDL1 in TNBC in vitro coculture showed an additive effect in cytotoxicity. Altogether, the current study suggests CXCR2 inhibitors as a promising approach to improve TNBC treatment if used in combination with chemotherapy and/or immunotherapy.
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Affiliation(s)
- Alaa M. Ghallab
- The Molecular Pharmacology Research Group, Department of Pharmacology, Toxicology and Clinical Pharmacy, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Reda A. Eissa
- Department of Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Hend M. El Tayebi
- The Molecular Pharmacology Research Group, Department of Pharmacology, Toxicology and Clinical Pharmacy, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
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Hosein AN, Dangol G, Okumura T, Roszik J, Rajapakshe K, Siemann M, Zaid M, Ghosh B, Monberg M, Guerrero PA, Singhi A, Haymaker CL, Clevers H, Abou-Elkacem L, Woermann SM, Maitra A. Loss of Rnf43 Accelerates Kras-Mediated Neoplasia and Remodels the Tumor Immune Microenvironment in Pancreatic Adenocarcinoma. Gastroenterology 2022; 162:1303-1318.e18. [PMID: 34973294 PMCID: PMC8934289 DOI: 10.1053/j.gastro.2021.12.273] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 11/22/2021] [Accepted: 12/22/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS RNF43 is an E3 ubiquitin ligase that is recurrently mutated in pancreatic ductal adenocarcinoma (PDAC) and precursor cystic neoplasms of the pancreas. The impact of RNF43 mutations on PDAC is poorly understood and autochthonous models have not been characterized sufficiently. In this study, we describe a genetically engineered mouse model (GEMM) of PDAC with conditional expression of oncogenic Kras and deletion of the catalytic domain of Rnf43 in exocrine cells. METHODS We generated Ptf1a-Cre;LSL-KrasG12D;Rnf43flox/flox (KRC) and Ptf1a-Cre; LSL-KrasG12D (KC) mice and animal survival was assessed. KRC mice were sacrificed at 2 months, 4 months, and at moribund status followed by analysis of pancreata by single-cell RNA sequencing. Comparative analyses between moribund KRC and a moribund Kras/Tp53-driven PDAC GEMM (KPC) was performed. Cell lines were isolated from KRC and KC tumors and interrogated by cytokine array analyses, ATAC sequencing, and in vitro drug assays. KRC GEMMs were also treated with an anti-CTLA4 neutralizing antibody with treatment response measured by magnetic response imaging. RESULTS We demonstrate that KRC mice display a marked increase in incidence of high-grade cystic lesions of the pancreas and PDAC compared with KC. Importantly, KRC mice have a significantly decreased survival compared with KC mice. Using single-cell RNA sequencing, we demonstrated that KRC tumor progression is accompanied by a decrease in macrophages, as well as an increase in T and B lymphocytes, with evidence of increased immune checkpoint molecule expression and affinity maturation, respectively. This was in stark contrast to the tumor immune microenvironment observed in the KPC PDAC GEMM. Furthermore, expression of the chemokine CXCL5 was found to be specifically decreased in KRC cancer cells by means of epigenetic regulation and emerged as a putative candidate for mediating the unique KRC immune landscape. CONCLUSIONS The KRC GEMM establishes RNF43 as a bona fide tumor suppressor gene in PDAC. This GEMM features a markedly different immune microenvironment compared with previously reported PDAC GEMMs and puts forth a rationale for an immunotherapy approach in this subset of PDAC cases.
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Affiliation(s)
- Abdel Nasser Hosein
- Department of Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Department of Internal Medicine, Division of Hematology & Oncology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Advocate Aurora Health, Vince Lombardi Cancer Clinic - Sheboygan, Wisconsin, USA
| | - Gita Dangol
- Department of Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Takashi Okumura
- Department of Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jason Roszik
- Department of Melanoma Medical Oncology Research, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Kimal Rajapakshe
- Department of Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Megan Siemann
- Department of Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Mohamed Zaid
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Bidyut Ghosh
- Department of Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Maria Monberg
- Department of Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Paola A. Guerrero
- Department of Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Aatur Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Cara L Haymaker
- Department of Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Hans Clevers
- Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht and Princess Maxima Center, Utrecht, the Netherlands
| | - Lotfi Abou-Elkacem
- Department of Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sonja M. Woermann
- Department of Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Anirban Maitra
- Department of Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Muller M, Haghnejad V, Schaefer M, Gauchotte G, Caron B, Peyrin-Biroulet L, Bronowicki JP, Neuzillet C, Lopez A. The Immune Landscape of Human Pancreatic Ductal Carcinoma: Key Players, Clinical Implications, and Challenges. Cancers (Basel) 2022; 14:cancers14040995. [PMID: 35205742 PMCID: PMC8870260 DOI: 10.3390/cancers14040995] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/14/2022] [Accepted: 02/15/2022] [Indexed: 02/04/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadliest cancer worldwide with an overall survival rate, all stages combined, of still <10% at 5 years. The poor prognosis is attributed to challenges in early detection, a low opportunity for radical resection, limited response to chemotherapy, radiotherapy, and resistance to immune therapy. Moreover, pancreatic tumoral cells are surrounded by an abundant desmoplastic stroma, which is responsible for creating a mechanical barrier, preventing appropriate vascularization and leading to poor immune cell infiltration. Accumulated evidence suggests that PDAC is impaired with multiple “immune defects”, including a lack of high-quality effector cells (CD4, CD8 T cells, dendritic cells), barriers to effector cell infiltration due to that desmoplastic reaction, and a dominance of immune cells such as regulatory T cells, myeloid-derived suppressor cells, and M2 macrophages, resulting in an immunosuppressive tumor microenvironment (TME). Although recent studies have brought new insights into PDAC immune TME, its understanding remains not fully elucidated. Further studies are required for a better understanding of human PDAC immune TME, which might help to develop potent new therapeutic strategies by correcting these immune defects with the hope to unlock the resistance to (immune) therapy. In this review, we describe the main effector immune cells and immunosuppressive actors involved in human PDAC TME, as well as their implications as potential biomarkers and therapeutic targets.
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Affiliation(s)
- Marie Muller
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
- Correspondence:
| | - Vincent Haghnejad
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
| | - Marion Schaefer
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
| | - Guillaume Gauchotte
- Department of Pathology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France;
- INSERM U1256, NGERE, Faculty of Medicine, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France
| | - Bénédicte Caron
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
- INSERM U1256, NGERE, Faculty of Medicine, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France
| | - Jean-Pierre Bronowicki
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
- INSERM U1256, NGERE, Faculty of Medicine, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France
| | - Cindy Neuzillet
- Medical Oncology Department, Curie Institute, Versailles Saint-Quentin University (UVQ), Paris Saclay University, 92064 Saint-Cloud, France;
| | - Anthony Lopez
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
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Deng J, Ma X, Ni Y, Li X, Xi W, Tian M, Zhang X, Xiang M, Deng W, Song C, Wu H. Identification of CXCL5 expression as a predictive biomarker associated with response and prognosis of immunotherapy in patients with non-small cell lung cancer. Cancer Med 2022; 11:1787-1795. [PMID: 35150082 PMCID: PMC9041069 DOI: 10.1002/cam4.4567] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 11/24/2021] [Accepted: 12/23/2021] [Indexed: 12/12/2022] Open
Abstract
Background The breakthrough of immunotherapy has revolutionized the treatment of non‐small cell lung cancer (NSCLC). However, only a limited part of patients could derive clinical benefits. To study how immune microenvironment (IME) of patients could influence the therapeutic efficacy of immunotherapy, we evaluated the response patterns of NSCLC patients treated with PD‐1 inhibitors and analyzed the molecules related to prognosis and efficacy of immunotherapy. Methods Tumor samples were collected from 47 NSCLC patients treated with PD‐1 inhibitors. RNA expressions of tumor immune‐related 289 genes were analyzed using NanoString nCounter. Immune infiltration and correlation between clinical information and expression of immune‐related genes were assessed. Results Unsupervised clustering analysis revealed two groups infiltrated with different immune cells and differentially expressed genes (DEGs) including CXCL5, CXCL9, IDO1, and LAG3 were found between groups. Stratification based on DEGs indicated that the group with high expression of CXCL5 was characterized by neutrophils. Univariate and multivariate Cox analysis further demonstrated that CXCL5 mRNA expression was positively associated with worse progression free survival (PFS). Logistic analyses indicated high CXCL5 was associated with worse response to immunotherapy. Conclusions CXCL5 may be a potential biomarker for prognosis and responsiveness to immunotherapy and may be a novel preventive and therapeutic target for NSCLC.
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Affiliation(s)
- Jie Deng
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xuejiao Ma
- State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, Jiangsu, China.,Department of Medicine, Nanjing Simcere Medical Laboratory Science Co., Ltd., Nanjing, Jiangsu, China
| | - Yang Ni
- State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, Jiangsu, China.,Department of Medicine, Nanjing Simcere Medical Laboratory Science Co., Ltd., Nanjing, Jiangsu, China
| | - Xiaomin Li
- State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, Jiangsu, China
| | - Wenjing Xi
- State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, Jiangsu, China
| | - Minqi Tian
- State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, Jiangsu, China
| | - Xing Zhang
- State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, Jiangsu, China.,Department of Medicine, Nanjing Simcere Medical Laboratory Science Co., Ltd., Nanjing, Jiangsu, China
| | - Manyu Xiang
- State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, Jiangsu, China
| | - Wanglong Deng
- State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, Jiangsu, China
| | - Chao Song
- State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, Jiangsu, China.,Department of Medicine, Nanjing Simcere Medical Laboratory Science Co., Ltd., Nanjing, Jiangsu, China
| | - Hao Wu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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Deng J, Fleming JB. Inflammation and Myeloid Cells in Cancer Progression and Metastasis. Front Cell Dev Biol 2022; 9:759691. [PMID: 35127700 PMCID: PMC8814460 DOI: 10.3389/fcell.2021.759691] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 12/24/2021] [Indexed: 12/13/2022] Open
Abstract
To date, the most immunotherapy drugs act upon T cell surface proteins to promote tumoricidal T cell activity. However, this approach has to date been unsuccessful in certain solid tumor types including pancreatic, prostate cancer and glioblastoma. Myeloid-related innate immunity can promote tumor progression through direct and indirect effects on T cell activity; improved understanding of this field may provide another therapeutic avenue for patients with these tumors. Myeloid cells can differentiate into both pro-inflammatory and anti-inflammatory mature form depending upon the microenvironment. Most cancer type exhibit oncogenic activating point mutations (ex. P53 and KRAS) that trigger cytokines production. In addition, tumor environment (ex. Collagen, Hypoxia, and adenosine) also regulated inflammatory signaling cascade. Both the intrinsic and extrinsic factor driving the tumor immune microenvironment and regulating the differentiation and function of myeloid cells, T cells activity and tumor progression. In this review, we will discuss the relationship between cancer cells and myeloid cells-mediated tumor immune microenvironment to promote cancer progression and immunotherapeutic resistance. Furthermore, we will describe how cytokines and chemokines produced by cancer cells influence myeloid cells within immunosuppressive environment. Finally, we will comment on the development of immunotherapeutic strategies with respect to myeloid-related innate immunity.
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Affiliation(s)
- Jenying Deng
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jason B. Fleming
- H. Lee Moffitt Cancer Center, Department of Gastrointestinal Oncology, Tampa, FL, United States
- *Correspondence: Jason B. Fleming,
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Saxena S, Molczyk C, Purohit A, Ehrhorn E, Goel P, Prajapati DR, Atri P, Kaur S, Grandgenett PM, Hollingsworth MA, Batra SK, Singh RK. Differential expression profile of CXC-receptor-2 ligands as potential biomarkers in pancreatic ductal adenocarcinoma. Am J Cancer Res 2022; 12:68-90. [PMID: 35141005 PMCID: PMC8822283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 12/03/2021] [Indexed: 06/14/2023] Open
Abstract
The discovery of early detection markers of pancreatic cancer (PC) disease is highly warranted. We analyzed the expression profile of different CXC-receptor-2 (CXCR2) ligands in PC cases for the potential of biomarker candidates. Analysis of different PDAC microarray datasets with matched normal and pancreatic tumor samples and next-generation sequenced transcriptomics data using an online portal showed significantly high expression of CXCL-1, 3, 5, 6, 8 in the tumors of PC patients. High CXCL5 expression was correlated to poor PC patient survival. Interestingly, mRNA and protein expression analysis of human PC cell lines showed higher CXCL2, 3, and 5 expressions in cell lines derived from metastatic sites than primary tumors. Furthermore, we utilized immunohistochemistry (IHC) to evaluate the expression of CXCR2 ligands in the human PC tumors and observed positive staining for CXCL1, 3, and 8 with a higher average IHC composite score of CXCL3 in the PC tissue specimens than the normal pancreas. We also observed an increase in the expression of mouse CXCL1, 3, and 5 in the pre-cancerous lesions of tumors and metastasis tissues derived from the PDX-cre-LSL-KrasG12D mouse model. Together, our data suggest that different CXCR2 ligands show the potential of being utilized as a diagnostic biomarker in PC patients.
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Affiliation(s)
- Sugandha Saxena
- Department of Pathology and Microbiology, 985950 Nebraska Medical CenterOmaha, NE 68198-5900, USA
| | - Caitlin Molczyk
- Department of Pathology and Microbiology, 985950 Nebraska Medical CenterOmaha, NE 68198-5900, USA
| | - Abhilasha Purohit
- Department of Pathology and Microbiology, 985950 Nebraska Medical CenterOmaha, NE 68198-5900, USA
| | - Evie Ehrhorn
- Department of Pathology and Microbiology, 985950 Nebraska Medical CenterOmaha, NE 68198-5900, USA
| | - Paran Goel
- Department of Pathology and Microbiology, 985950 Nebraska Medical CenterOmaha, NE 68198-5900, USA
| | - Dipakkumar R Prajapati
- Department of Pathology and Microbiology, 985950 Nebraska Medical CenterOmaha, NE 68198-5900, USA
| | - Pranita Atri
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical CenterOmaha, NE 68198-5845, USA
| | - Sukhwinder Kaur
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical CenterOmaha, NE 68198-5845, USA
| | - Paul M Grandgenett
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical CenterOmaha, NE 68198, USA
| | - Michael A Hollingsworth
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical CenterOmaha, NE 68198, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical CenterOmaha, NE 68198-5845, USA
| | - Rakesh K Singh
- Department of Pathology and Microbiology, 985950 Nebraska Medical CenterOmaha, NE 68198-5900, USA
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Varghese B, Del Gaudio N, Cobellis G, Altucci L, Nebbioso A. KDM4 Involvement in Breast Cancer and Possible Therapeutic Approaches. Front Oncol 2021; 11:750315. [PMID: 34778065 PMCID: PMC8581295 DOI: 10.3389/fonc.2021.750315] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 10/13/2021] [Indexed: 12/24/2022] Open
Abstract
Breast cancer (BC) is the second leading cause of cancer death in women, although recent scientific and technological achievements have led to significant improvements in progression-free disease and overall survival of patients. Genetic mutations and epigenetic modifications play a critical role in deregulating gene expression, leading to uncontrolled cell proliferation and cancer progression. Aberrant histone modifications are one of the most frequent epigenetic mechanisms occurring in cancer. In particular, methylation and demethylation of specific lysine residues alter gene accessibility via histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs). The KDM family includes more than 30 members, grouped into six subfamilies and two classes based on their sequency homology and catalytic mechanisms, respectively. Specifically, the KDM4 gene family comprises six members, KDM4A-F, which are associated with oncogene activation, tumor suppressor silencing, alteration of hormone receptor downstream signaling, and chromosomal instability. Blocking the activity of KDM4 enzymes renders them "druggable" targets with therapeutic effects. Several KDM4 inhibitors have already been identified as anticancer drugs in vitro in BC cells. However, no KDM4 inhibitors have as yet entered clinical trials due to a number of issues, including structural similarities between KDM4 members and conservation of the active domain, which makes the discovery of selective inhibitors challenging. Here, we summarize our current knowledge of the molecular functions of KDM4 members in BC, describe currently available KDM4 inhibitors, and discuss their potential use in BC therapy.
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Affiliation(s)
- Benluvankar Varghese
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Napoli, Italy
| | - Nunzio Del Gaudio
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Napoli, Italy
| | - Gilda Cobellis
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Napoli, Italy
| | - Lucia Altucci
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Napoli, Italy.,Biogem Institute of Molecular Biology and Genetics, Ariano Irpino, Italy
| | - Angela Nebbioso
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Napoli, Italy.,Saint Camillus International University of Health and Medical Sciences, Rome, Italy
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Roy S, Kumaravel S, Banerjee P, White TK, O’Brien A, Seelig C, Chauhan R, Ekser B, Bayless KJ, Alpini G, Glaser SS, Chakraborty S. Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma. Cells 2021; 10:3093. [PMID: 34831316 PMCID: PMC8623887 DOI: 10.3390/cells10113093] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/27/2021] [Accepted: 11/02/2021] [Indexed: 12/20/2022] Open
Abstract
Cholangiocarcinoma (CCA), or cancer of bile duct epithelial cells, is a very aggressive malignancy characterized by early lymphangiogenesis in the tumor microenvironment (TME) and lymph node (LN) metastasis which correlate with adverse patient outcome. However, the specific roles of lymphatic endothelial cells (LECs) that promote LN metastasis remains unexplored. Here we aimed to identify the dynamic molecular crosstalk between LECs and CCA cells that activate tumor-promoting pathways and enhances lymphangiogenic mechanisms. Our studies show that inflamed LECs produced high levels of chemokine CXCL5 that signals through its receptor CXCR2 on CCA cells. The CXCR2-CXCL5 signaling axis in turn activates EMT (epithelial-mesenchymal transition) inducing MMP (matrix metalloproteinase) genes such as GLI, PTCHD, and MMP2 in CCA cells that promote CCA migration and invasion. Further, rate of mitochondrial respiration and glycolysis of CCA cells was significantly upregulated by inflamed LECs and CXCL5 activation, indicating metabolic reprogramming. CXCL5 also induced lactate production, glucose uptake, and mitoROS. CXCL5 also induced LEC tube formation and increased metabolic gene expression in LECs. In vivo studies using CCA orthotopic models confirmed several of these mechanisms. Our data points to a key finding that LECs upregulate critical tumor-promoting pathways in CCA via CXCR2-CXCL5 axis, which further augments CCA metastasis.
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Affiliation(s)
- Sukanya Roy
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA; (S.R.); (S.K.); (P.B.); (T.K.W.); (A.O.); (C.S.); (R.C.); (S.S.G.)
| | - Subhashree Kumaravel
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA; (S.R.); (S.K.); (P.B.); (T.K.W.); (A.O.); (C.S.); (R.C.); (S.S.G.)
| | - Priyanka Banerjee
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA; (S.R.); (S.K.); (P.B.); (T.K.W.); (A.O.); (C.S.); (R.C.); (S.S.G.)
| | - Tori K. White
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA; (S.R.); (S.K.); (P.B.); (T.K.W.); (A.O.); (C.S.); (R.C.); (S.S.G.)
| | - April O’Brien
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA; (S.R.); (S.K.); (P.B.); (T.K.W.); (A.O.); (C.S.); (R.C.); (S.S.G.)
| | - Catherine Seelig
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA; (S.R.); (S.K.); (P.B.); (T.K.W.); (A.O.); (C.S.); (R.C.); (S.S.G.)
| | - Rahul Chauhan
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA; (S.R.); (S.K.); (P.B.); (T.K.W.); (A.O.); (C.S.); (R.C.); (S.S.G.)
| | - Burcin Ekser
- Department of Surgery, Division of Transplant Surgery, Indiana University School of Medicine, Indianapolis, IN 46202-3082, USA;
| | - Kayla J. Bayless
- Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA;
| | - Gianfranco Alpini
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN 46202-3082, USA;
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202-3082, USA
| | - Shannon S. Glaser
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA; (S.R.); (S.K.); (P.B.); (T.K.W.); (A.O.); (C.S.); (R.C.); (S.S.G.)
| | - Sanjukta Chakraborty
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA; (S.R.); (S.K.); (P.B.); (T.K.W.); (A.O.); (C.S.); (R.C.); (S.S.G.)
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Huang J, Chen Z, Ding C, Lin S, Wan D, Ren K. Prognostic Biomarkers and Immunotherapeutic Targets Among CXC Chemokines in Pancreatic Adenocarcinoma. Front Oncol 2021; 11:711402. [PMID: 34497764 PMCID: PMC8419473 DOI: 10.3389/fonc.2021.711402] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 07/26/2021] [Indexed: 12/27/2022] Open
Abstract
Background Pancreatic cancer is one of the principal causes of tumor-related death worldwide. CXC chemokines, a subfamily of functional chemotactic peptides, affect the initiation of tumor cells and clinical outcomes in several human malignant tumors. However, the specific biological functions and clinical significance of CXC chemokines in pancreatic cancer have not been clarified. Methods Bioinformatics analysis tools and databases, including ONCOMINE, GEPIA2, the Human Protein Atlas, DAVID, GeneMANIA, cBioPortal, STRING, DGidb, MethSurv, TRRUST, SurvExpress, SurvivalMeth, and TIMER, were utilized to clarify the clinical significance and biological functions of CXC chemokine in pancreatic cancer. Results Except for CXCL11/12, the transcriptional levels of other CXC chemokines in PAAD tissues were significantly elevated, and the expression level of CXCL16 was the highest among these CXC chemokines. Our findings also suggested that all of the CXC chemokines were linked to tumor-immune dysfunction involving the abundance of immune cell infiltration, and the Cox proportional hazard model confirmed that dendritic and CXCL3/5/7/8/11/17 were significantly associated with the clinical outcome of PAAD patients. Furthermore, increasing expressions of CXCL5/9/10/11/17 were related to unfavorable overall survival (OS), and only CXCL17 was a prognostic factor for disease-free survival (DFS) in PAAD patients. The expression pattern and prognostic power of CXC chemokines were further validated in the independent GSE62452 dataset. For the prognostic value of single CpG of DNA methylation of CXC chemokines in patients with PAAD, we identified 3 CpGs of CXCL1, 2 CpGs of CXCL2, 2 CpGs of CXCL3, 3 CpGs of CXCL4, 10 CpGs of CXCL5, 1 CpG of CXCL6, 1 CpG of CXCL7, 3 CpGs of CXCL12, 3 CpGs of CXCL14, and 5 CpGs of CXCL17 that were significantly associated with prognosis in PAAD patients. Moreover, the prognostic value of CXC chemokine signature in PAAD was explored and tested in two independent cohort, and results indicated that the patients in the low-risk group had a better OS compared with the high-risk group. Survival analysis of the DNA methylation of CXC chemokine signature demonstrated that PAAD patients in the high-risk group had longer survival times. Conclusions These findings reveal the novel insights into CXC chemokine expression and their biological functions in the pancreatic cancers, which might serve as accurate prognostic biomarkers and suitable immunotherapeutic targets for patients with pancreatic cancer.
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Affiliation(s)
- Jiacheng Huang
- Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China.,School of Medicine, Zhejiang University, Hangzhou, China.,First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhitao Chen
- Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China.,School of Medicine, Zhejiang University, Hangzhou, China
| | - Chenchen Ding
- Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
| | - Shengzhang Lin
- Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
| | - Dalong Wan
- First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Kuiwu Ren
- First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Fuyang People's Hospital, Fuyang, China
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Siolas D, Vucic E, Kurz E, Hajdu C, Bar-Sagi D. Gain-of-function p53 R172H mutation drives accumulation of neutrophils in pancreatic tumors, promoting resistance to immunotherapy. Cell Rep 2021; 36:109578. [PMID: 34433022 PMCID: PMC8687588 DOI: 10.1016/j.celrep.2021.109578] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 06/16/2021] [Accepted: 07/29/2021] [Indexed: 12/31/2022] Open
Abstract
Tumor genotype can influence the immune microenvironment, which plays a critical role in cancer development and therapy resistance. However, the immune effects of gain-of-function Trp53 mutations have not been defined in pancreatic cancer. We compare the immune profiles generated by KrasG12D-mutated mouse pancreatic ductal epithelial cells (PDECs) engineered genetically to express the Trp53R172H mutation with their p53 wild-type control. KrasG12D/+;Trp53R172H/+ tumors have a distinct immune profile characterized by an influx of CD11b+Ly6G+ neutrophils and concomitant decreases in CD3+ T cells, CD8+ T cells, and CD4+ T helper 1 cells. Knockdown of CXCL2, a neutrophil chemokine, in the tumor epithelial compartment of CRISPR KrasG12D/+;Trp53R172H/+ PDEC tumors reverses the neutrophil phenotype. Neutrophil depletion of mice bearing CRISPR KrasG12D/+;Trp53R172H/+ tumors augments sensitivity to combined CD40 immunotherapy and chemotherapy. These data link Trp53R172H to the presence of intratumoral neutrophils in pancreatic cancer and suggest that tumor genotypes could inform selection of affected individuals for immunotherapy.
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Affiliation(s)
- Despina Siolas
- Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA; Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, USA.
| | - Emily Vucic
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
| | - Emma Kurz
- Molecular Oncology and Tumor Immunology Training Program, NYU Grossman School of Medicine, New York, NY, USA
| | - Cristina Hajdu
- Department of Pathology, NYU Langone Health, New York, NY, USA
| | - Dafna Bar-Sagi
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA.
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Deng J, Kang Y, Cheng CC, Li X, Dai B, Katz MH, Men T, Kim MP, Koay E, Huang H, Brekken RA, Fleming JB. Ddr1-induced neutrophil extracellular traps drive pancreatic cancer metastasis. JCI Insight 2021; 6:e146133. [PMID: 34237033 PMCID: PMC8492346 DOI: 10.1172/jci.insight.146133] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 07/07/2021] [Indexed: 11/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) tumors are characterized by a desmoplastic reaction resulting in dense deposition of collagen that is known to promote cancer progression. A central mediator of pro-tumorigenic collagen signaling is the receptor tyrosine kinase discoid domain receptor 1 (DDR1). DDR1 is a critical driver of a mesenchymal and invasive cancer cell PDAC phenotype. Previous studies have demonstrated that genetic or pharmacologic inhibition of DDR1 reduces PDAC tumorigenesis and metastasis. Here, we investigated whether DDR1 signaling has cancer cell non-autonomous effects that promote PDAC progression and metastasis. We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs) and subsequent cancer cell invasion and metastasis. Moreover, we have identified that collagen-induced CXCL5 production was mediated by a DDR1-PKCθ-SYK-NFkB signaling cascade. Together, these results highlight the critical contribution of collagen I-DDR1 interaction in the formation of an immune microenvironment that promotes PDAC metastasis.
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Affiliation(s)
- Jenying Deng
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America
| | - Ya'an Kang
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America
| | - Chien-Chia Cheng
- Functional Genomics Core, The University of Texas MD Anderson Cancer Center, Houston, United States of America
| | - Xinqun Li
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America
| | - Bingbing Dai
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America
| | - Matthew H Katz
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America
| | - Taoyan Men
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America
| | - Michael P Kim
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America
| | - Eugene Koay
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America
| | - Huocong Huang
- Department of Surgery and Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, United States of America
| | - Rolf A Brekken
- Department of Surgery and Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, United States of America
| | - Jason B Fleming
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, United States of America
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CXCL5/NF- κB Pathway as a Therapeutic Target in Hepatocellular Carcinoma Treatment. JOURNAL OF ONCOLOGY 2021; 2021:9919494. [PMID: 34194499 PMCID: PMC8184336 DOI: 10.1155/2021/9919494] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/08/2021] [Accepted: 05/21/2021] [Indexed: 02/01/2023]
Abstract
Background Hepatocellular carcinoma (HCC) is a common malignant cancer worldwide. CXCL5 has a role in inhibiting cell viability and metastasis in many tumors. In the present study, we investigated the role of CXCL5 in HCC and explored the underlying mechanism. Material and Methods. RT-qPCR and western blot were performed to evaluate the mRNA and protein levels of CXCL5. CCK-8 and transwell assay were applied to measure the proliferative and invasive abilities. Meanwhile, the Kaplan–Meier method was used to assess the survival of HCC patients. Results CXCL5 was upregulated in HCC tissues, which predicted a shorter overall survival in HCC. CXCL5 was a target gene of miR-577, and its expression was mediated by miR-577 in HCC. Knockdown of CXCL5 suppressed HuH-7 cell proliferation, invasion, and EMT and inhibited the NF-κB signaling pathway in cells. Moreover, knockdown of CXCL5 inhibited the xenograft growth of HuH-7 cells. Conclusion Overexpression of CXCL5 predicts poor prognosis in HCC patients. Knockdown of CXCL5 inhibits cell proliferation and invasion through the NF-κB signaling pathway in HCC. The newly identified role of the CXCL5/miR-577/NF-κB axis provides novel insights into the targeted therapy of HCC.
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Wang T, Chen B, Meng T, Liu Z, Wu W. Identification and immunoprofiling of key prognostic genes in the tumor microenvironment of hepatocellular carcinoma. Bioengineered 2021; 12:1555-1575. [PMID: 33955820 PMCID: PMC8806269 DOI: 10.1080/21655979.2021.1918538] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Tumor microenvironment (TME) is involved in the occurrence and development of hepatocellular carcinoma (HCC), and immune cells in the TME have been implicated in its progression and treatment. However, the association of genes involved in the TME with HCC prognosis remains unclear. Thus, in this study, we obtained transcriptomic and clinicopathological data of patients with HCC from The Cancer Genome Atlas to identify key genes in TME associated with HCC prognosis. Stromal and immune cell scores were calculated using the ESTIMATE method, and differentially expressed genes (DEGs) were determined. We identified 830 DEGs, which were further subjected to survival analyses and functional enrichment analysis. Next, we identified prognostic TME-associated DEGs, established a protein-protein interaction (PPI) network, and performed Cox analysis.Consequently, four key prognostic genes (CXCL5, CXCL8, IL18RAP, and TREM2) associated with TME, were identified, in which CXCL5 and IL18RAP may be potential independent prognostic factors. Age, clinical stage, N stage, and risk score were also determined as significant prognostic variables. CIBERSORT was used to predict the constitution and relative content of the immune cells, wherein M0 macrophages were the most closely related to the key genes. In conclusion, CXCL5, CXCL8, IL18RAP, and TREM2 were associated with HCC prognosis and were important for immune cell invasion into the TME. Additionally, IL18RAP expression may contribute toward favorable prognosis in patients with HCC. Consequently, these genes may serve as potential biomarkers and immunotherapeutic targets for HCC.
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Affiliation(s)
- Tianbing Wang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Bang Chen
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Tao Meng
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhiqiang Liu
- Department of General Surgery, Anhui NO.2 Provinicial People's Hospital, Hefei, China
| | - Wenyong Wu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.,Department of General Surgery, Anhui NO.2 Provinicial People's Hospital, Hefei, China
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Purohit A, Saxena S, Varney M, Prajapati DR, Kozel JA, Lazenby A, Singh RK. Host Cxcr2-Dependent Regulation of Pancreatic Cancer Growth, Angiogenesis, and Metastasis. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:759-771. [PMID: 33453178 PMCID: PMC8027924 DOI: 10.1016/j.ajpath.2021.01.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 12/31/2020] [Accepted: 01/06/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) manifests aggressive tumor growth and early metastasis. Crucial steps in tumor growth and metastasis are survival, angiogenesis, invasion, and immunosuppression. Our prior research showed that chemokine CXC- receptor-2 (CXCR2) is expressed on endothelial cells, innate immune cells, and fibroblasts, and regulates angiogenesis and immune responses. Here, we examined whether tumor angiogenesis, growth, and metastasis of CXCR2 ligands expressing PDAC cells are regulated in vivo by a host CXCR2-dependent mechanism. C57BL6 Cxcr2-/- mice were generated following crosses between Cxcr2-/+ female and Cxcr2-/- male. Cxcr2 ligands expressing Kirsten rat sarcoma (KRAS-PDAC) cells were orthotopically implanted in the pancreas of wild-type or Cxcr2-/- C57BL6 mice. No significant difference in PDAC tumor growth was observed. Host Cxcr2 loss led to an inhibition in microvessel density in PDAC tumors. Interestingly, an enhanced spontaneous and experimental liver metastasis was observed in Cxcr2-/- mice compared with wild-type mice. Increased metastasis in Cxcr2-/- mice was associated with an increase in extramedullary hematopoiesis and expansion of neutrophils and immature myeloid precursor cells in the spleen of tumor-bearing mice. These data suggest a dynamic role of host CXCR2 axis in regulating tumor immune suppression, tumor growth, and metastasis.
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Affiliation(s)
- Abhilasha Purohit
- Department of Pathology and Microbiology, Nebraska Medical Center, Omaha, Nebraska
| | - Sugandha Saxena
- Department of Pathology and Microbiology, Nebraska Medical Center, Omaha, Nebraska
| | - Michelle Varney
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | | | - Jessica A Kozel
- Department of Pathology and Microbiology, Nebraska Medical Center, Omaha, Nebraska
| | - Audrey Lazenby
- Department of Pathology and Microbiology, Nebraska Medical Center, Omaha, Nebraska
| | - Rakesh K Singh
- Department of Pathology and Microbiology, Nebraska Medical Center, Omaha, Nebraska.
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Nie Y, Jiang MC, Liu C, Liu Q, Zhu X. CXCL5 Has Potential to Be a Marker for Hepatocellular Carcinoma Prognosis and Was Correlating With Immune Infiltrates. Front Oncol 2021; 11:637023. [PMID: 33869023 PMCID: PMC8045759 DOI: 10.3389/fonc.2021.637023] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 03/01/2021] [Indexed: 01/10/2023] Open
Abstract
Backgrounds Tumor microenvironment (TME) plays a crucial role in the initiation and progression of Hepatocellular Carcinoma (HCC), especially immune infiltrates. However, there is still a challenge in understanding the modulation of the immune and stromal components in TME, especially TME related genes. Methods The proportion of tumor-infiltrating immune cells (TICs) and the immune and stromal scores in 374 HCC patients from The Cancer Genome Atlas (TCGA) database were determined using CIBERSORT and ESTIMATE computational methods. The final screened genes were confirmed by the PPI network and univariate Cox regression of the differentially expressed genes based on different immune or stromal scores. The correlation between the expression levels of the final gene interactions and the clinical characteristics was based on TCGA database and local hospital data. Gene set enrichment analysis (GSEA) and the effect of CXCL5 expression on TICs were conducted. Results There were correlations between the expression of CXCL5 and survival of HCC patients and TMN classification both in TCGA database and local hospital data. The immune-related activities were enriched in the high-expression group; however, the metabolic pathways were enriched in the low-expression group. The result of CIBERSORT analyzing had indicated that CXCL5 expression were correlated with the proportion of NK cells activated, macrophages M0, Mast cells resting, Neutrophils. Conclusions CXCL5 was a potential prognostic marker for HCC and provides clues regarding immune infiltrates, which offers extra insight for therapeutics of HCC, however, more independent cohorts and functional experiments of CXCL5 are warranted.
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Affiliation(s)
- Yuan Nie
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Mei-Chun Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Cong Liu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Qi Liu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xuan Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
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Zhang W, Wang H, Sun M, Deng X, Wu X, Ma Y, Li M, Shuoa SM, You Q, Miao L. CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target. Cancer Commun (Lond) 2021; 40:69-80. [PMID: 32237072 PMCID: PMC7163794 DOI: 10.1002/cac2.12010] [Citation(s) in RCA: 147] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 01/31/2020] [Indexed: 12/14/2022] Open
Abstract
The components of the tumor microenvironment (TME) in solid tumors, especially chemokines, are currently attracting much attention from scientists. C-X-C motif chemokine ligand 5 (CXCL5) is one of the important chemokines in TME. Overexpression of CXCL5 is closely related to the survival time, recurrence and metastasis of cancer patients. In TME, CXCL5 binds to its receptors, such as C-X-C motif chemokine receptor 2 (CXCR2), to participate in the recruitment of immune cells and promote angiogenesis, tumor growth, and metastasis. The CXCL5/CXCR2 axis can act as a bridge between tumor cells and host cells in TME. Blocking the transmission of CXCL5/CXCR2 signals can increase the sensitivity and effectiveness of immunotherapy and slow down tumor progression. CXCL5 and CXCR2 are also regarded as biomarkers for predicting prognosis and molecular targets for customizing the treatment. In this review, we summarized the current literature regarding the biological functions and clinical significance of CXCL5/CXCR2 axis in TME. The possibility to use CXCL5 and CXCR2 as potential prognostic biomarkers and therapeutic targets in cancer is also discussed.
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Affiliation(s)
- Wen Zhang
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, P. R. China
| | - Huishan Wang
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, P. R. China
| | - Mingyang Sun
- Department of Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, P. R. China
| | - Xueting Deng
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, P. R. China
| | - Xueru Wu
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, P. R. China
| | - Yilan Ma
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, P. R. China
| | - Mengjing Li
- Department of Biotherapy, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, P. R. China.,Key Laboratory for Aging and Disease, Nanjing Medical University, Nanjing, 210011, Jiangsu, P. R. China
| | - Said Maisam Shuoa
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, P. R. China
| | - Qiang You
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, P. R. China.,Department of Biotherapy, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, P. R. China.,Key Laboratory for Aging and Disease, Nanjing Medical University, Nanjing, 210011, Jiangsu, P. R. China
| | - Lin Miao
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, P. R. China
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Merz V, Gaule M, Zecchetto C, Cavaliere A, Casalino S, Pesoni C, Contarelli S, Sabbadini F, Bertolini M, Mangiameli D, Milella M, Fedele V, Melisi D. Targeting KRAS: The Elephant in the Room of Epithelial Cancers. Front Oncol 2021; 11:638360. [PMID: 33777798 PMCID: PMC7991835 DOI: 10.3389/fonc.2021.638360] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 01/27/2021] [Indexed: 12/13/2022] Open
Abstract
Mutations of the proto-oncogene KRAS are the most frequent gain-of-function alterations found in cancer. KRAS is mutated in about 30% of all human tumors, but it could reach more than 90% in certain cancer types such as pancreatic adenocarcinoma. Although historically considered to be undruggable, a particular KRAS mutation, the G12C variant, has recently emerged as an actionable alteration especially in non-small cell lung cancer (NSCLC). KRASG12C and pan-KRAS inhibitors are being tested in clinical trials and have recently shown promising activity. Due to the difficulties in direct targeting of KRAS, other approaches are being explored. The inhibition of target upstream activators or downstream effectors of KRAS pathway has shown to be moderately effective given the evidence of emerging mechanisms of resistance. Various synthetic lethal partners of KRAS have recently being identified and the inhibition of some of those might prove to be successful in the future. The study of escape mechanisms to KRAS inhibition could support the utility of combination strategies in overcoming intrinsic and adaptive resistance and enhancing clinical benefit of KRASG12C inhibitors. Considering the role of the microenvironment in influencing tumor initiation and promotion, the immune tumor niche of KRAS mutant tumors has been deeply explored and characterized for its unique immunosuppressive skewing. However, a number of aspects remains to be fully understood, and modulating this tumor niche might revert the immunoresistance of KRAS mutant tumors. Synergistic associations of KRASG12C and immune checkpoint inhibitors are being tested.
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Affiliation(s)
- Valeria Merz
- Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy
- Medical Oncology Unit, Santa Chiara Hospital, Trento, Italy
| | - Marina Gaule
- Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy
- Section of Medical Oncology, Università degli Studi di Verona, Verona, Italy
| | - Camilla Zecchetto
- Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy
- Section of Medical Oncology, Università degli Studi di Verona, Verona, Italy
| | - Alessandro Cavaliere
- Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy
- Section of Medical Oncology, Università degli Studi di Verona, Verona, Italy
| | - Simona Casalino
- Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy
- Section of Medical Oncology, Università degli Studi di Verona, Verona, Italy
| | - Camilla Pesoni
- Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy
- Section of Medical Oncology, Università degli Studi di Verona, Verona, Italy
| | - Serena Contarelli
- Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy
| | - Fabio Sabbadini
- Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy
| | - Monica Bertolini
- Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy
| | - Domenico Mangiameli
- Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy
| | - Michele Milella
- Section of Medical Oncology, Università degli Studi di Verona, Verona, Italy
| | - Vita Fedele
- Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy
| | - Davide Melisi
- Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy
- Section of Medical Oncology, Università degli Studi di Verona, Verona, Italy
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Serum CXCL5 level is associated with tumor progression in penile cancer. Biosci Rep 2021; 41:227614. [PMID: 33458757 PMCID: PMC7843497 DOI: 10.1042/bsr20202133] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 01/09/2021] [Accepted: 01/14/2021] [Indexed: 12/01/2022] Open
Abstract
Chemokine (C-X-C motif) ligand 5 is an important regulator of tumor progression in many cancers, and could serve as potential serum cancer biomarker. Our initial analysis identified CXCL5 as a cancer-related gene highly expressed in PC. Patients with PC exhibited markedly higher preoperative serum CXCL5 levels compared with that in healthy individuals (P<0.001). The area under the curve (AUC) was 0.880 with the sensitivity of 84.0%, and specificity of 80.4% to distinguish PC. Serum CXCL5 levels were also significantly decreased following tumor resection in patients with PC (P=0.001). Preoperative serum CXCL5 level was significantly associated with clinicopathological characteristics including T stage (P=0.001), nodal status (P<0.001), and pelvic lymph node metastasis (P=0.018). Cox regression analysis showed that serum CXCL5 level could serve as an independent prognostic factor for disease-free survival with a HR of 6.363 (95% CI: 2.185–18.531, P=0.001). CXCL5 and its receptor CXCR2 exhibited correlated expression pattern in PC tissues. Differential CXCL5 expression was observed in normal penile tissues, PC cell lines, and their culture supernatants. Furthermore, knockdown of CXCL5 or CXCR2 expression markedly suppressed malignant phenotypes (cell proliferation, clonogenesis, apoptosis escape, migration, and invasion), attenuated STAT3 and AKT signaling, and reduced MMP2/9 secretion in PC cell lines. In conclusion, our findings revealed that serum CXCL5 level might serve as a potential diagnostic and prognostic cancer biomarker for penile cancer. Autocrine CXCL5/CXCR2 signaling might activate multiple downstream oncogenic signaling pathways (STAT3, AKT, MMP2/9) to promote malignant progression of PC, which may warrant further investigation in the future.
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Yu M, Ma X, Jiang D, Wang L, Zhan Q, Zhao J. CXC chemokine ligand 5 (CXCL5) disrupted the permeability of human brain microvascular endothelial cells via regulating p38 signal. Microbiol Immunol 2021; 65:40-47. [PMID: 33026667 DOI: 10.1111/1348-0421.12854] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 06/27/2020] [Accepted: 09/30/2020] [Indexed: 01/07/2023]
Abstract
The ischemia-reperfusion-induced damage in human brain microvascular endothelial cells (BMECs) is associated with disruption of the blood-brain barrier. CXC chemokine ligand 5 (CXCL5) is reported to be up-regulated in ischemic stroke. However, the detailed function of CXCL5 in this pathological process remains largely unclear. To further analyze the function of CXCL5 in ischemic stroke, an oxygen-glucose deprivation model on human BMECs was constructed to mimic the ischemic stroke condition in vitro. Cell proliferation was analyzed using a cell counting kit-8 (CCK-8) assay. Quantitative real-time polymerase chain reaction and western blot were utilized to determine gene expression. The barrier function of BMECs was assessed using a fluorescently labeled dextran assay and a trans-epithelial/endothelial electrical resistance (TEER) technique. The results indicated that CXCL5 antibody (anti-CXCL5) promoted the proliferation of model cells, whereas it reduced the permeability. Moreover, the TEER value of model cells was enhanced in the presence of anti-CXCL5. Therefore, these findings demonstrated that CXCL5 silencing attenuated the ischemic/hypoxic-induced injury in human BMECs. Importantly, human recombinant protein CXCL5 (Re-CXCL5) deeply disrupted the function of BMECs in the normoxic condition. Furthermore, the p38 inhibitor SB203580 significantly abolished the function of CXCL5 in model cells. More importantly, similar results were also obtained in BMECs under normoxic conditions in the presence of Re-CXCL5. These results indicated that CXCL5 might regulate the function of BMECs by mediating the p38 pathway. This investigation not only enhanced the understanding of the biological effect of CXCL5 in human BMECs under ischemic/hypoxic conditions but also indicated its potential value as a therapeutic target for ischemic-induced brain disease.
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Affiliation(s)
- Min Yu
- Department of Neurology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaokun Ma
- Department of Nuclear Medicine, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dudu Jiang
- Department of Neurology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lijing Wang
- Department of Neurology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qing Zhan
- Department of Neurology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiangmin Zhao
- Department of Radiology, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Wu MY, Shen M, Xu MD, Yu ZY, Tao M. FOLFIRINOX regulated tumor immune microenvironment to extend the survival of patients with resectable pancreatic ductal adenocarcinoma. Gland Surg 2020; 9:2125-2135. [PMID: 33447563 DOI: 10.21037/gs-20-828] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly malignant tumors worldwide due to its ineffective diagnosis and poor prognosis. The longest median overall survival (OS) to PDAC patients has been provided by FOLFIRINOX. It is essential to identify the mechanisms of FOLFIRINOX to gain new insights for the treatment of PDAC. Methods We compared gene expression levels of PDAC patients who received neoadjuvant FOLFIRINOX prior to surgery with those of patients who received no neoadjuvant chemotherapy. Bioinformatics analysis was applied to screen differentially expressed genes (DEGs). Three microarray data sets were downloaded to analyze gene expression data between PDAC and adjacent non-tumor tissues. Overlapping DEGs were subjected to Kaplan-Meier survival analysis. The genes relating to poor outcomes and would be decreased after FOLFIRINOX were input into the Oncomine, University of Alabama Cancer (UALCAN), and LinkedOmics databases to analyze the gene expression and regulation networks. Results A total of 83 differentially expressed genes (DEGs) were screened and subjected to bioinformatics analysis, which indicated FOLFIRINOX influenced the immune microenvironment of PDAC. Seventy-three genes significantly associated with the OS of PDAC patients. A Venn diagram revealed CXCL5 and PLAU were related to poor outcomes and would decrease after FOLFIRINOX chemotherapy of PDAC patients. It turned out that CXCL5 participated in the immune response-regulating signaling pathway in PDAC patients. Conclusions FOLFIRINOX regulated tumor immunity by reducing expression of the immunosuppressive gene CXCL5, laying a foundation for further study of combination therapy of FOLFIRINOX and immunotherapy.
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Affiliation(s)
- Meng-Yao Wu
- Department of Oncology, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Meng Shen
- Department of Oncology, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Meng-Dan Xu
- Department of Oncology, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zheng-Yuan Yu
- Department of Oncology, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Min Tao
- Department of Oncology, First Affiliated Hospital of Soochow University, Suzhou, China
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Mochizuki K, Oishi N, Kawai M, Odate T, Tahara I, Inoue T, Kasai K, Kondo T. Expressions of IL-8 and CXCL5 in uterine endometrioid carcinomas which have frequent neutrophil infiltration and comparison to colorectal adenocarcinoma. Histol Histopathol 2020; 35:1503-1510. [PMID: 33185249 DOI: 10.14670/hh-18-281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
In endometrioid carcinomas (ECs) of the uterine corpus, neutrophil accumulation within the carcinoma cell clusters is a representative microscopic finding. Because this accumulation is active, some sort of transmitter ought to exist between the EC cells and neutrophils. Interleukin-8 (IL-8) and C-X-C motif chemokine ligand 5 (CXCL5) is a cytokine that attracts neutrophils in vivo. In this study, we investigated IL-8, CXCL5 and C-X-C motif chemokine receptor 2 (CXCR2) (their chemokine receptor) expressions in ECs by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). There are few reports on the relationship between these chemokines and ECs. For comparison, we enrolled samples of colorectal adenocarcinoma (CRAC), it is another representative tumor with neutrophil infiltration. We analyzed 30 ECs and 30 CRACs. We confirmed IL-8 expression (H-score ≥50 points) in 40% of EC and 7% of CRAC samples; CXCL5 expression in 7% of EC and 10% of CRAC samples; CXCR2 expression in 83% of EC and 53% of CRAC samples by immunohistochemistry. We examined each mRNA (IL-8 and CXCL5) expression of 3 representative EC and 3 CRAC samples. Finding IL-8 expression might indicate that this cytokine is important for the process of neutrophil accumulation, particularly within ECs. The participation of CXCL5 regarding neutrophil accumulation within their carcinoma cell clusters might be restrictive compared to IL-8.
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Affiliation(s)
- Kunio Mochizuki
- Department of Pathology, University of Yamanashi, Chuo, Japan.
| | - Naoki Oishi
- Department of Pathology, University of Yamanashi, Chuo, Japan
| | - Masataka Kawai
- Department of Pathology, University of Yamanashi, Chuo, Japan
| | - Toru Odate
- Department of Pathology, University of Yamanashi, Chuo, Japan
| | - Ippei Tahara
- Department of Pathology, University of Yamanashi, Chuo, Japan
| | - Tomohiro Inoue
- Department of Pathology, University of Yamanashi, Chuo, Japan
| | - Kazunari Kasai
- Department of Pathology, University of Yamanashi, Chuo, Japan
| | - Tetsuo Kondo
- Department of Pathology, University of Yamanashi, Chuo, Japan
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Chen H, Wang X, Wu F, Mo X, Hu C, Wang M, Xu H, Yao C, Xia H, Lan L. Centromere protein F is identified as a novel therapeutic target by genomics profile and contributing to the progression of pancreatic cancer. Genomics 2020; 113:1087-1095. [PMID: 33166601 DOI: 10.1016/j.ygeno.2020.10.039] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 07/22/2020] [Accepted: 10/30/2020] [Indexed: 11/19/2022]
Abstract
Pancreatic cancer (PC) is the most severe and serious deadliest cancer type worldwide. Centromeric proteins (CENPs) family are involved in centromere formation and kinetochore organization during mitosis and play an important role in cancers. Here, we analyzed all CENPs in a panel of PC tissues and non-tumor tissues by genomics profile. We identified that CENPF is significantly upregulated in PC and correlated with poor prognosis of patients. Furthermore, silencing CENPF significantly inhibited PC cell proliferation, migration and epithelial-mesenchymal transition (EMT), and caused cell cycle arrest at the G2/M phase, meanwhile, in vivo growth of pancreatic cells. Moreover, the TNF pathway and longevity regulating pathways are two potential pathways, which were regulated by CENPF. These findings investigated the clinical and functional contribution of CENPF as a novel biomarker for PC.
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Affiliation(s)
- Hongjin Chen
- Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, China
| | - Xiaoming Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241001, China
| | - Fubing Wu
- Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, China
| | - Xiao Mo
- Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, China
| | - Chao Hu
- Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, China
| | - Mei Wang
- Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, China
| | - Haojun Xu
- Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, China
| | - Chengyun Yao
- Jiangsu Cancer Hospital & The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Institute of Cancer Research, Nanjing 2100092, China.
| | - Hongping Xia
- Department of Pathology, School of Basic Medical Sciences & Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241001, China; Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Jiangsu Cancer Hospital & The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Institute of Cancer Research, Nanjing 2100092, China.
| | - Linhua Lan
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
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