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Hu X, Wang P, Wang T, Cao J, Du K, Scarlat MM, Liu L, Li Y, Wang X, Wang H, Ma H, Wang L, Jin L, Hou Z. Establishment of fracture blister model and analysis of plasma protein markers in rats. Front Immunol 2025; 16:1547491. [PMID: 40297588 PMCID: PMC12034566 DOI: 10.3389/fimmu.2025.1547491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 03/10/2025] [Indexed: 04/30/2025] Open
Abstract
Purpose Fracture blister (FB) is a frequent complication in orthopedic surgery. The primary objective of this study was to refine the animal model of FB and to identify plasma protein markers associated with its development and progression. Methods In this study, Sprague-Dawley (SD) rats were used as experimental subjects. Various pressures and compression durations were applied to the lower limbs of rats with fractures to compare the differential expression patterns (DEPs) between the pressure-time combination that resulted in the highest incidence of blisters and other groups. Subsequently, we investigated the variations in DEPs expression across different time intervals of the established model. Results Our findings indicate that following a lower limb fracture in SD rats, the highest incidence of blister formation was observed under conditions of 450 mmHg pressure and 9 hours of compression (46%, 7/15). In this group, the levels of CD44 and B2M were significantly elevated, while those of Activin R2A were reduced. Furthermore, we investigated the temporal profile of the group with the highest incidence of blister formation and found that CXCL16 and ROBO1 reached peak secretion 48 hours post-injury, followed by a subsequent decline. Additionally, the secretion of IL-2RG and IL-7 continued to increase 48 hours after the injury. Conclusions the increase of CD44 and B2M and the decrease of Activin R2A might be the potential influencing factors for the higher incidence of fracture blisters. CXCL16 and ROBO1 reached their peak 48 hours after the end of molding, and IL-2 RG and IL-7 R continued to increase 48 hours after the end of molding, which will provide a new direction for the study of the occurrence and development mechanism of fracture blisters.
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Affiliation(s)
- Xin Hu
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China
- Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, Hebei, China
| | - Peiyuan Wang
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China
- Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, Hebei, China
| | - Tao Wang
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China
- Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, Hebei, China
| | - Jingcheng Cao
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China
- Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, Hebei, China
| | - Kezheng Du
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China
- Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, Hebei, China
| | | | - Lin Liu
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China
- Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, Hebei, China
| | - Yutong Li
- Baoding University, Baoding, Hebei, China
| | - Xin Wang
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China
| | - Haofei Wang
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China
- Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, Hebei, China
| | - Huijie Ma
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Ling Wang
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China
- Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, Hebei, China
| | - Lin Jin
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China
- Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, Hebei, China
| | - Zhiyong Hou
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China
- Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, Hebei, China
- Engineering Research Center of Orthopedic Minimally Invasive Intelligent Equipment, Ministry of Education, Shijiazhuang, China
- National Health Commission (NHC) Key Laboratory of Intelligent Orthopaedic Equipment, Shijiazhuang, Hebei, China
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Mempel TR, Malehmir M. Chemokines that govern T cell activity in tumors. Curr Opin Immunol 2025; 92:102510. [PMID: 39662216 PMCID: PMC11729545 DOI: 10.1016/j.coi.2024.102510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 11/12/2024] [Accepted: 11/19/2024] [Indexed: 12/13/2024]
Abstract
Local regulation of T cell-mediated immunity to solid tumors occurs at multiple levels, including their recruitment from the bloodstream to the tumor microenvironment (TME), coordinated crosstalk with different subsets of antigen-presenting cells (APCs) controlling their local survival, proliferation, and effector differentiation, as well as their egress from tumors via lymphatics. At each level, chemokines play essential roles, for instance, by guiding directional T cell migration across blood and lymphatic endothelial barriers or by promoting their spatial proximity and direct physical interactions with APCs to enable functional crosstalk. In this article, we will review recent mechanistic insights into the chemokine axes that guide T cell functions in TMEs in light of the emerging functional state heterogeneity of CD8+ effector T cells and our growing understanding of how regulatory T cells restrain antitumor activity.
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Affiliation(s)
- Thorsten R Mempel
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
| | - Mohsen Malehmir
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
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Chaudhary JK, Danga AK, Kumari A, Bhardwaj A, Rath PC. Role of chemokines in aging and age-related diseases. Mech Ageing Dev 2025; 223:112009. [PMID: 39631472 DOI: 10.1016/j.mad.2024.112009] [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: 06/01/2024] [Revised: 11/21/2024] [Accepted: 11/25/2024] [Indexed: 12/07/2024]
Abstract
Chemokines (chemotactic cytokines) play essential roles in developmental process, immune cell trafficking, inflammation, immunity, angiogenesis, cellular homeostasis, aging, neurodegeneration, and tumorigenesis. Chemokines also modulate response to immunotherapy, and consequently influence the therapeutic outcome. The mechanisms underlying these processes are accomplished by interaction of chemokines with their cognate cell surface G protein-coupled receptors (GPCRs) and subsequent cellular signaling pathways. Chemokines play crucial role in influencing aging process and age-related diseases across various tissues and organs, primarily through inflammatory responses (inflammaging), recruitment of macrophages, and orchestrated trafficking of other immune cells. Chemokines are categorized in four distinct groups based on the position and number of the N-terminal cysteine residues; namely, the CC, CXC, CX3C, and (X)C. They mediate inflammatory responses, and thereby considerably impact aging process across multiple organ-systems. Therefore, understanding the underlying mechanisms mediated by chemokines may be of crucial importance in delaying and/or modulating the aging process and preventing age-related diseases. In this review, we highlight recent progress accomplished towards understanding the role of chemokines and their cellular signaling pathways involved in aging and age-relaed diseases of various organs. Moreover, we explore potential therapeutic strategies involving anti-chemokines and chemokine receptor antagonists aimed at reducing aging and mitigating age-related diseases. One of the modern methods in this direction involves use of chemokine receptor antagonists and anti-chemokines, which suppress the pro-inflammatory response, thereby helping in resolution of inflammation. Considering the wide-spectrum of functional involvements of chemokines in aging and associated diseases, several clinical trials are being conducted to develop therapeutic approaches using anti-chemokine and chemokine receptor antagonists to improve life span and promote healthy aging.
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Affiliation(s)
- Jitendra Kumar Chaudhary
- Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India; Department of Zoology, Shivaji College, University of Delhi, New Delhi 110027, India.
| | - Ajay Kumar Danga
- Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
| | - Anita Kumari
- Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
| | - Akshay Bhardwaj
- Regional Centre for Biotechnology, 3rd Milestone, Faridabad-Gurugram Expressway, Faridabad Road, Faridabad, Haryana 121001, India.
| | - Pramod C Rath
- Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
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4
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Chen J, Choi JJY, Lin PY, Huang EJ. Pathogenesis of Germinal Matrix Hemorrhage: Insights from Single-Cell Transcriptomics. ANNUAL REVIEW OF PATHOLOGY 2025; 20:221-243. [PMID: 39401848 PMCID: PMC11759652 DOI: 10.1146/annurev-pathmechdis-111523-023446] [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] [Indexed: 01/25/2025]
Abstract
The germinal matrix harbors neurogenic niches in the subpallium of the prenatal human brain that produce abundant GABAergic neurons. In preterm infants, the germinal matrix is particularly vulnerable to developing hemorrhage, which disrupts neurogenesis and causes severe neurodevelopmental sequelae. However, the disease mechanisms that promote germinal matrix hemorrhage remain unclear. Here, we review recent advances using single-cell transcriptomics to uncover novel mechanisms that govern neurogenesis and angiogenesis in the germinal matrix of the prenatal human brain. These approaches also reveal the critical role of immune-vascular interaction that promotes vascular morphogenesis in the germinal matrix and how proinflammatory factors from activated neutrophils and monocytes can disrupt this process, leading to hemorrhage. Collectively, these results reveal fundamental disease mechanisms and therapeutic interventions for germinal matrix hemorrhage.
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Affiliation(s)
- Jiapei Chen
- Weill Institute for Neurosciences, University of California, San Francisco, California, USA
- Department of Pathology, University of California, San Francisco, California, USA
- Biomedical Sciences Graduate Program, University of California, San Francisco, California, USA;
| | - Jennifer Ja-Yoon Choi
- Weill Institute for Neurosciences, University of California, San Francisco, California, USA
- Department of Pathology, University of California, San Francisco, California, USA
| | - Pin-Yeh Lin
- Weill Institute for Neurosciences, University of California, San Francisco, California, USA
- Department of Pathology, University of California, San Francisco, California, USA
| | - Eric J Huang
- Pathology Service, Veterans Administration Health Care System, San Francisco, California, USA
- Weill Institute for Neurosciences, University of California, San Francisco, California, USA
- Department of Pathology, University of California, San Francisco, California, USA
- Biomedical Sciences Graduate Program, University of California, San Francisco, California, USA;
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5
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Chen J, Crouch EE, Zawadzki ME, Jacobs KA, Mayo LN, Choi JJY, Lin PY, Shaikh S, Tsui J, Gonzalez-Granero S, Waller S, Kelekar A, Kang G, Valenzuela EJ, Birrueta JO, Diafos LN, Wedderburn-Pugh K, Di Marco B, Xia W, Han CZ, Coufal NG, Glass CK, Fancy SPJ, Alfonso J, Kriegstein AR, Oldham MC, Garcia-Verdugo JM, Kutys ML, Lehtinen MK, Combes AJ, Huang EJ. Proinflammatory immune cells disrupt angiogenesis and promote germinal matrix hemorrhage in prenatal human brain. Nat Neurosci 2024; 27:2115-2129. [PMID: 39349662 PMCID: PMC11537974 DOI: 10.1038/s41593-024-01769-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 08/19/2024] [Indexed: 10/28/2024]
Abstract
Germinal matrix hemorrhage (GMH) is a devastating neurodevelopmental condition affecting preterm infants, but why blood vessels in this brain region are vulnerable to rupture remains unknown. Here we show that microglia in prenatal mouse and human brain interact with nascent vasculature in an age-dependent manner and that ablation of these cells in mice reduces angiogenesis in the ganglionic eminences, which correspond to the human germinal matrix. Consistent with these findings, single-cell transcriptomics and flow cytometry show that distinct subsets of CD45+ cells from control preterm infants employ diverse signaling mechanisms to promote vascular network formation. In contrast, CD45+ cells from infants with GMH harbor activated neutrophils and monocytes that produce proinflammatory factors, including azurocidin 1, elastase and CXCL16, to disrupt vascular integrity and cause hemorrhage in ganglionic eminences. These results underscore the brain's innate immune cells in region-specific angiogenesis and how aberrant activation of these immune cells promotes GMH in preterm infants.
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Affiliation(s)
- Jiapei Chen
- Department of Pathology and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA
- Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA
| | - Elizabeth E Crouch
- Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
| | - Miriam E Zawadzki
- Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
- Harvard/MIT MD-PhD Program, Harvard Medical School, Boston, MA, USA
- Graduate Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA
| | - Kyle A Jacobs
- Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, CA, USA
| | - Lakyn N Mayo
- Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, CA, USA
- UCSF-UC Berkeley Joint Graduate Program in Bioengineering, University of California San Francisco, San Francisco, CA, USA
| | - Jennifer Ja-Yoon Choi
- Department of Pathology and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA
| | - Pin-Yeh Lin
- Department of Pathology and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA
| | - Saba Shaikh
- UCSF CoLab, University of California San Francisco, San Francisco, CA, USA
| | - Jessica Tsui
- UCSF CoLab, University of California San Francisco, San Francisco, CA, USA
| | - Susana Gonzalez-Granero
- Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, Valencia, Spain
| | - Shamari Waller
- Department of Pathology and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA
| | - Avani Kelekar
- Department of Pathology and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA
| | - Gugene Kang
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA
- Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, CA, USA
| | - Edward J Valenzuela
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
| | - Janeth Ochoa Birrueta
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
| | - Loukas N Diafos
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
| | - Kaylee Wedderburn-Pugh
- Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA
- Medical Scientist Training Program, University of California San Francisco, San Francisco, CA, USA
| | - Barbara Di Marco
- Department of Clinical Neurobiology, University Hospital Heidelberg and German Cancer Research Center, Heidelberg, Germany
| | - Wenlong Xia
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Claudia Z Han
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
| | - Nicole G Coufal
- Department of Pediatrics, University of California San Diego, San Diego, CA, USA
| | - Christopher K Glass
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
| | - Stephen P J Fancy
- Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Julieta Alfonso
- Department of Clinical Neurobiology, University Hospital Heidelberg and German Cancer Research Center, Heidelberg, Germany
| | - Arnold R Kriegstein
- Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
- Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, CA, USA
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Michael C Oldham
- Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA
- Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, CA, USA
| | - Jose Manuel Garcia-Verdugo
- Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, Valencia, Spain
| | - Matthew L Kutys
- Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA
- Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, CA, USA
- UCSF-UC Berkeley Joint Graduate Program in Bioengineering, University of California San Francisco, San Francisco, CA, USA
| | - Maria K Lehtinen
- Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
- Graduate Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA
| | - Alexis J Combes
- Department of Pathology and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA
- UCSF CoLab, University of California San Francisco, San Francisco, CA, USA
| | - Eric J Huang
- Department of Pathology and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
- Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA.
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA.
- Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, CA, USA.
- Pathology Service 113B, San Francisco VA Health Care Systems, San Francisco, CA, USA.
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Thatikonda V, Lyu H, Jurado S, Kostyrko K, Bristow CA, Albrecht C, Alpar D, Arnhof H, Bergner O, Bosch K, Feng N, Gao S, Gerlach D, Gmachl M, Hinkel M, Lieb S, Jeschko A, Machado AA, Madensky T, Marszalek ED, Mahendra M, Melo-Zainzinger G, Molkentine JM, Jaeger PA, Peng DH, Schenk RL, Sorokin A, Strauss S, Trapani F, Kopetz S, Vellano CP, Petronczki M, Kraut N, Heffernan TP, Marszalek JR, Pearson M, Waizenegger IC, Hofmann MH. Co-targeting SOS1 enhances the antitumor effects of KRAS G12C inhibitors by addressing intrinsic and acquired resistance. NATURE CANCER 2024; 5:1352-1370. [PMID: 39103541 PMCID: PMC11424490 DOI: 10.1038/s43018-024-00800-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 07/08/2024] [Indexed: 08/07/2024]
Abstract
Combination approaches are needed to strengthen and extend the clinical response to KRASG12C inhibitors (KRASG12Ci). Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRASG12Ci seemed to be driven by upregulation of MRAS activity, which both SOS1i and SHP2i were found to potently inhibit. Knockdown of SHOC2, a MRAS complex partner, partially restored response to KRASG12Ci treatment. These results suggest KRASG12C plus SOS1i to be a promising strategy for treating both KRASG12Ci naive and relapsed KRASG12C-mutant tumors.
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Affiliation(s)
- Venu Thatikonda
- Boehringer Ingelheim RCV, Vienna, Austria.
- Exscientia, Vienna, Austria.
| | - Hengyu Lyu
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | | | - Christopher A Bristow
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | | | | | | | | | - Ningping Feng
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sisi Gao
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | | | | | | | | | - Annette A Machado
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Ethan D Marszalek
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mikhila Mahendra
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Jessica M Molkentine
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - David H Peng
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Alexey Sorokin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | | | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Christopher P Vellano
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | | | - Timothy P Heffernan
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Joseph R Marszalek
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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7
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Ullah A, Jiao W, Shen B. The role of proinflammatory cytokines and CXC chemokines (CXCL1-CXCL16) in the progression of prostate cancer: insights on their therapeutic management. Cell Mol Biol Lett 2024; 29:73. [PMID: 38745115 PMCID: PMC11094955 DOI: 10.1186/s11658-024-00591-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 05/06/2024] [Indexed: 05/16/2024] Open
Abstract
Reproductive cancers are malignancies that develop in the reproductive organs. One of the leading cancers affecting the male reproductive system on a global scale is prostate cancer (PCa). The negative consequences of PCa metastases endure and are severe, significantly affecting mortality and life quality for those who are affected. The association between inflammation and PCa has captured interest for a while. Inflammatory cells, cytokines, CXC chemokines, signaling pathways, and other elements make up the tumor microenvironment (TME), which is characterized by inflammation. Inflammatory cytokines and CXC chemokines are especially crucial for PCa development and prognosis. Cytokines (interleukins) and CXC chemokines such as IL-1, IL-6, IL-7, IL-17, TGF-β, TNF-α, CXCL1-CXCL6, and CXCL8-CXCL16 are thought to be responsible for the pleiotropic effects of PCa, which include inflammation, progression, angiogenesis, leukocyte infiltration in advanced PCa, and therapeutic resistance. The inflammatory cytokine and CXC chemokines systems are also promising candidates for PCa suppression and immunotherapy. Therefore, the purpose of this work is to provide insight on how the spectra of inflammatory cytokines and CXC chemokines evolve as PCa develops and spreads. We also discussed recent developments in our awareness of the diverse molecular signaling pathways of these circulating cytokines and CXC chemokines, as well as their associated receptors, which may one day serve as PCa-targeted therapies. Moreover, the current status and potential of theranostic PCa therapies based on cytokines, CXC chemokines, and CXC receptors (CXCRs) are examined.
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Affiliation(s)
- Amin Ullah
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine and Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Wang Jiao
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine and Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Bairong Shen
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine and Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
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8
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Cheng M, Jia Z, Zhang G, Wang Y, Li S, Yang S, Li C, Geng C. Gastric metastasis from breast cancer: five cases and a single-institutional review. J Int Med Res 2024; 52:3000605241233988. [PMID: 38483129 PMCID: PMC10943725 DOI: 10.1177/03000605241233988] [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: 09/28/2023] [Accepted: 01/29/2024] [Indexed: 03/18/2024] Open
Abstract
Gastric metastasis from breast cancer has a high rate of misdiagnosis and missed diagnosis. Data of patients who had gastric metastasis from breast cancer were retrieved from our hospital between 2014 and 2020. The gastric metastasis from breast cancer incidence was 0.04% (5/14,169 cases of breast cancer). Four patients had invasive lobular carcinoma, and the other patient had invasive ductal carcinoma. The time from the initial diagnosis of breast cancer to the appearance of gastric metastasis ranged from 0 to 12 years. One patient's endoscopic presentation was similar to mucosal-associated lymphoid tissue lymphoma and presented with gastric mucosal congestion and edema, widened wrinkles, mixed color fading, and redness. The initial pathological diagnosis of this patient was mucosal-associated lymphoid tissue lymphoma, and breast cancer was finally confirmed by immunohistochemistry. Hormonal receptors were highly expressed in four patients with primary and metastasis lesions and were negative in one patient. Human epidermal growth factor receptor 2 was negative in all patients. Mammaglobin and GATA3 were positive in all patients. In conclusion, the gastric metastasis of breast cancer incidence rate is low, and misdiagnosis can lead to insufficient or excessive treatment. Multiple biopsies and immunohistochemistry should be performed to diagnose gastric metastasis of breast cancer.
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Affiliation(s)
- Meng Cheng
- Breast Center, The 4th Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, P.R. China
- Key Laboratory in Hebei Province for Molecular Medicine of Breast Cancer, Shijiazhuang, Hebei Province, P.R. China
| | - Zhanli Jia
- Pathology Department, The 4th Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, P.R. China
| | - Guoyu Zhang
- Breast Center, The 4th Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, P.R. China
| | - Yingnan Wang
- Gastroenterology Department, The 4th Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, P.R. China
| | - Sainan Li
- Breast Center, The 4th Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, P.R. China
- Key Laboratory in Hebei Province for Molecular Medicine of Breast Cancer, Shijiazhuang, Hebei Province, P.R. China
| | - Shan Yang
- Breast Center, The 4th Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, P.R. China
- Key Laboratory in Hebei Province for Molecular Medicine of Breast Cancer, Shijiazhuang, Hebei Province, P.R. China
| | - Chunxiao Li
- Breast Center, The 4th Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, P.R. China
| | - Cuizhi Geng
- Breast Center, The 4th Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, P.R. China
- Key Laboratory in Hebei Province for Molecular Medicine of Breast Cancer, Shijiazhuang, Hebei Province, P.R. China
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9
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Abstract
For our immune system to contain or eliminate malignant solid tumours, both myeloid and lymphoid haematopoietic cells must not only extravasate from the bloodstream into the tumour tissue but also further migrate to various specialized niches of the tumour microenvironment to functionally interact with each other, with non-haematopoietic stromal cells and, ultimately, with cancer cells. These interactions regulate local immune cell survival, proliferative expansion, differentiation and their execution of pro-tumour or antitumour effector functions, which collectively determine the outcome of spontaneous or therapeutically induced antitumour immune responses. None of these interactions occur randomly but are orchestrated and critically depend on migratory guidance cues provided by chemokines, a large family of chemotactic cytokines, and their receptors. Understanding the functional organization of the tumour immune microenvironment inevitably requires knowledge of the multifaceted roles of chemokines in the recruitment and positioning of its cellular constituents. Gaining such knowledge will not only generate new insights into the mechanisms underlying antitumour immunity or immune tolerance but also inform the development of biomarkers (or 'biopatterns') based on spatial tumour tissue analyses, as well as novel strategies to therapeutically engineer immune responses in patients with cancer. Here we will discuss recent observations on the role of chemokines in the tumour microenvironment in the context of our knowledge of their physiological functions in development, homeostasis and antimicrobial responses.
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Affiliation(s)
- Thorsten R Mempel
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
| | - Julia K Lill
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Lukas M Altenburger
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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10
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Baruah P, Marshall J, Jones PN, Major T, Pucino V, O'Neil JD, Nefla M, McGettrick H, Monksfield P, Irving R, Buckley CD. Fibroblasts Derived From Vestibular Schwannoma Express Protumorogenic Markers. Otol Neurotol 2023; 44:e755-e765. [PMID: 37733967 DOI: 10.1097/mao.0000000000004011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/23/2023]
Abstract
BACKGROUND AND AIM Vestibular schwannomas (VSs), despite being histologically benign, cause significant morbidity because of their challenging intracranial location and the propensity for growth. The role of the stroma and particularly fibroblasts, in the progression of VS, is not completely understood. This study examines the profile of fibroblasts in VS. METHODS Seventeen patients undergoing surgical excision of VS were recruited into the study. Reverse transcription with quantitative polymerase chain reaction (RT-qPCR) was performed on VS tissue samples and fibroblast-associated molecules examined. Immunofluorescence and immunohistochemistry in VS tissue were used to study the expression of fibroblast markers CD90 and podoplanin in situ. Fibroblast cultures were established from VS, and RT-qPCR analysis was performed on a panel of fibroblast markers on VS and control tissue fibroblasts. RESULTS Several fibroblast-associated molecules including members of galectin family and matrix metalloproteinases were found to be expressed in VS tissue on RT-qPCR analysis. In situ, expression of CD90 and podoplanin was observed in VS tissue both on immunohistochemistry and immunofluorescence. RT-qPCR analysis of fibroblasts from VS and control vestibular neuroepithelium (NE) showed a higher expression of several molecules of the galectin and matrix metalloproteinases family on VS fibroblasts compared with NE fibroblasts. CONCLUSION This work examines fibroblasts from VS and shows qualitative differences from NE fibroblasts on RT-qPCR. Further understanding of the fibroblast function in the progression of VS will potentially unveil new targets to manage VS growth.
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Affiliation(s)
| | - Jennifer Marshall
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Philip N Jones
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Triin Major
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Valentina Pucino
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - John D O'Neil
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Meriam Nefla
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Helen McGettrick
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Peter Monksfield
- Department of ENT, University Hospitals of Birmingham NHS Trust, Birmingham
| | - Richard Irving
- Department of ENT, University Hospitals of Birmingham NHS Trust, Birmingham
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11
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Li J, Ramzan F, Zhong G. Investigating novel biomarkers in uterine corpus endometrial carcinoma: in silico analysis and clinical specimens validation via RT-qPCR and immunohistochemistry. Am J Cancer Res 2023; 13:4376-4400. [PMID: 37818076 PMCID: PMC10560950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 08/17/2023] [Indexed: 10/12/2023] Open
Abstract
The rising incidence and mortality rate of Uterine Corpus Endometrial Carcinoma (UCEC) pose significant health concerns. CC and CXC chemokines have been linked to tumorigenesis and cancer progression. Recognizing the growing significance of CC and CXC chemokines' diagnostic and prognostic significance in diverse cancer types, our objective was to comprehensively analyze the diagnostic and prognostic values of hub genes from the CC and CXC chemokines in UCEC, utilizing both in silico and clinical samples and cell lines-based approaches. In silico analyses include STRING, Cytoscape, Cytohubba, The Cancer Genome Atlas (TCGA) datasets analysis via the UALCAN, GEPIA, OncoDB, and MuTarget, SurvivalGenie, MEXPRESS, cBioPoratal, TIMER, ENCORI, and DrugBank. Meanwhile, clinical samples and cell lines based analyses include Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), targeted bisulfite sequencing (bisulfite-seq) analysis, and immunohistochemistry (IHC). Through present study, we identified CCL25 (CC motif chemokine ligand 25), CXCL10 (C-X-C motif chemokine ligand 10), CXCL12 (C-X-C motif chemokine ligand 12), and CXCL16 (C-X-C motif chemokine ligand 16) as crucial hub genes among the CC and CXC chemokines. Analyzing the expression data from TCGA, we observed a significant up-regulation of CCL25, CXCL10, and CXCL16 in UCEC samples compared to controls. In contrast, we noted a significant down-regulation of CXCL12 expression in UCEC samples. On clinical UCEC samples and cell lines analysis, the significant higher expression of CCL25, CXCL10, and CXCL16 and significant lower expression of CXCL12 were also denoted in UCEC samples than the controls via RT-qPCR and IHC analyses. Moreover, in silico analysis also confirmed the abnormal promoter methylation levels of the hub genes in TCGA UCEC samples, which was later validated by the clinical samples using targeted based bisulfite-seq analysis. In addition, various additional aspects of the CCL25, CXCL10, CXCL12, and CXCL16 have also been uncovered in UCEC during the present study. Our findings offer novel insights that contribute to the clinical utility of CCL25, CXCL10, CXCL12, and CXCL16 chemokines as potential diagnostic and prognostic biomarkers in UCEC.
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Affiliation(s)
- Jie Li
- Health Management Center, The Second Affiliated Hospital of Hainan Medical UniversityHaikou 570311, Hainan, China
| | - Faiqah Ramzan
- Gomal Center of Bio-Chemistry and Biotechnology (GCBB), Gomal UniversityDera Ismail Khan 29050, Pakistan
| | - Guiping Zhong
- Health Management Center, The Second Affiliated Hospital of Hainan Medical UniversityHaikou 570311, Hainan, China
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12
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Wu Y, Clark KC, Niranjan B, Chüeh AC, Horvath LG, Taylor RA, Daly RJ. Integrative characterisation of secreted factors involved in intercellular communication between prostate epithelial or cancer cells and fibroblasts. Mol Oncol 2023; 17:469-486. [PMID: 36608258 PMCID: PMC9980303 DOI: 10.1002/1878-0261.13376] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 12/05/2022] [Accepted: 01/05/2023] [Indexed: 01/07/2023] Open
Abstract
Reciprocal interactions between prostate cancer cells and carcinoma-associated fibroblasts (CAFs) mediate cancer development and progression; however, our understanding of the signalling pathways mediating these cellular interactions remains incomplete. To address this, we defined secretome changes upon co-culture of prostate epithelial or cancer cells with fibroblasts that mimic bi-directional communication in tumours. Using antibody arrays, we profiled conditioned media from mono- and co-cultures of prostate fibroblasts, epithelial and cancer cells, identifying secreted proteins that are upregulated in co-culture compared to mono-culture. Six of these (CXCL10, CXCL16, CXCL6, FST, PDGFAA, IL-17B) were functionally screened by siRNA knockdown in prostate cancer cell/fibroblast co-cultures, revealing a key role for follistatin (FST), a secreted glycoprotein that binds and bioneutralises specific members of the TGF-β superfamily, including activin A. Expression of FST by both cell types was required for the fibroblasts to enhance prostate cancer cell proliferation and migration, whereas FST knockdown in co-culture grafts decreased tumour growth in mouse xenografts. This study highlights the complexity of prostate cancer cell-fibroblast communication, demonstrates that co-culture secretomes cannot be predicted from individual cultures, and identifies FST as a tumour-microenvironment-derived secreted factor that represents a candidate therapeutic target.
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Affiliation(s)
- Yunjian Wu
- Cancer Program, Biomedicine Discovery InstituteMonash UniversityClaytonVictoriaAustralia
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVictoriaAustralia
| | - Kimberley C. Clark
- Cancer Program, Biomedicine Discovery InstituteMonash UniversityClaytonVictoriaAustralia
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVictoriaAustralia
| | - Birunthi Niranjan
- Cancer Program, Biomedicine Discovery InstituteMonash UniversityClaytonVictoriaAustralia
- Department of Anatomy and Developmental BiologyMonash UniversityClaytonVictoriaAustralia
| | - Anderly C. Chüeh
- Cancer Program, Biomedicine Discovery InstituteMonash UniversityClaytonVictoriaAustralia
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVictoriaAustralia
| | - Lisa G. Horvath
- Garvan Institute of Medical ResearchDarlinghurstNew South WalesAustralia
- University of SydneyNew South WalesAustralia
- Chris O'Brien LifehouseSydneyNew South WalesAustralia
| | - Renea A. Taylor
- Cancer Program, Biomedicine Discovery InstituteMonash UniversityClaytonVictoriaAustralia
- Department of PhysiologyMonash UniversityClaytonVictoriaAustralia
- Cancer Research Division, Peter MacCallum Cancer CentreThe University of MelbourneVictoriaAustralia
| | - Roger J. Daly
- Cancer Program, Biomedicine Discovery InstituteMonash UniversityClaytonVictoriaAustralia
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVictoriaAustralia
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13
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Thatikonda V, Lu H, Jurado S, Kostyrko K, Bristow CA, Bosch K, Feng N, Gao S, Gerlach D, Gmachl M, Lieb S, Jeschko A, Machado AA, Marszalek ED, Mahendra M, Jaeger PA, Sorokin A, Strauss S, Trapani F, Kopetz S, Vellano CP, Petronczki M, Kraut N, Heffernan TP, Marszalek JR, Pearson M, Waizenegger I, Hofmann MH. Combined KRAS G12C and SOS1 inhibition enhances and extends the anti-tumor response in KRAS G12C-driven cancers by addressing intrinsic and acquired resistance. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.23.525210. [PMID: 36747713 PMCID: PMC9900819 DOI: 10.1101/2023.01.23.525210] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Efforts to improve the anti-tumor response to KRASG12C targeted therapy have benefited from leveraging combination approaches. Here, we compare the anti-tumor response induced by the SOS1-KRAS interaction inhibitor, BI-3406, combined with a KRASG12C inhibitor (KRASG12Ci) to those induced by KRASG12Ci alone or combined with SHP2 or EGFR inhibitors. In lung cancer and colorectal cancer (CRC) models, BI-3406 plus KRASG12Ci induces an anti-tumor response stronger than that observed with KRASG12Ci alone and comparable to those by the other combinations. This enhanced anti-tumor response is associated with a stronger and extended suppression of RAS-MAPK signaling. Importantly, BI-3406 plus KRASG12Ci treatment delays the emergence of acquired adagrasib resistance in both CRC and lung cancer models and is associated with re-establishment of anti-proliferative activity in KRASG12Ci-resistant CRC models. Our findings position KRASG12C plus SOS1 inhibition therapy as a promising strategy for treating both KRASG12C-mutated tumors as well as for addressing acquired resistance to KRASG12Ci.
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Affiliation(s)
| | - Hengyu Lu
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sabine Jurado
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Kaja Kostyrko
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Christopher A. Bristow
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Karin Bosch
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Ningping Feng
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sisi Gao
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | | | - Simone Lieb
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | | | - Annette A. Machado
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ethan D. Marszalek
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mikhila Mahendra
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Alexey Sorokin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | | | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Christopher P. Vellano
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Norbert Kraut
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Timothy P. Heffernan
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Joseph R. Marszalek
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mark Pearson
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
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14
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Catalano M, Roviello G, Santi R, Villari D, Spatafora P, Galli IC, Sessa F, Conte FL, Mini E, Cai T, Nesi G. Inflammation in Urological Malignancies: The Silent Killer. Int J Mol Sci 2023; 24:866. [PMID: 36614308 PMCID: PMC9821648 DOI: 10.3390/ijms24010866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/02/2022] [Accepted: 12/28/2022] [Indexed: 01/05/2023] Open
Abstract
Several studies have investigated the role of inflammation in promoting tumorigenesis and cancer progression. Neoplastic as well as surrounding stromal and inflammatory cells engage in well-orchestrated reciprocal interactions to establish an inflammatory tumor microenvironment. The tumor-associated inflammatory tissue is highly plastic, capable of continuously modifying its phenotypic and functional characteristics. Accumulating evidence suggests that chronic inflammation plays a critical role in the development of urological cancers. Here, we review the origins of inflammation in urothelial, prostatic, renal, testicular, and penile cancers, focusing on the mechanisms that drive tumor initiation, growth, progression, and metastasis. We also discuss how tumor-associated inflammatory tissue may be a diagnostic marker of clinically significant tumor progression risk and the target for future anti-cancer therapies.
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Affiliation(s)
- Martina Catalano
- School of Human Health Sciences, University of Florence, 50134 Florence, Italy
| | - Giandomenico Roviello
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, 50139 Florence, Italy
| | - Raffaella Santi
- Section of Pathological Anatomy, Department of Health Sciences, University of Florence, 50139 Florence, Italy
| | - Donata Villari
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Pietro Spatafora
- Unit of Urological Robotic Surgery and Renal Transplantation, Careggi Teaching Hospital, 50134 Florence, Italy
| | - Ilaria Camilla Galli
- Histopathology and Molecular Diagnostics, Careggi Teaching Hospital, 50139 Florence, Italy
| | - Francesco Sessa
- Unit of Urological Robotic Surgery and Renal Transplantation, Careggi Teaching Hospital, 50134 Florence, Italy
| | | | - Enrico Mini
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, 50139 Florence, Italy
| | - Tommaso Cai
- Department of Urology, Santa Chiara Regional Hospital, 38122 Trento, Italy
| | - Gabriella Nesi
- Section of Pathological Anatomy, Department of Health Sciences, University of Florence, 50139 Florence, Italy
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15
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Drouillard D, Craig BT, Dwinell MB. Physiology of chemokines in the cancer microenvironment. Am J Physiol Cell Physiol 2023; 324:C167-C182. [PMID: 36317799 PMCID: PMC9829481 DOI: 10.1152/ajpcell.00151.2022] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 10/20/2022] [Accepted: 10/21/2022] [Indexed: 01/07/2023]
Abstract
Chemokines are chemotactic cytokines whose canonical functions govern movement of receptor-expressing cells along chemical gradients. Chemokines are a physiological system that is finely tuned by ligand and receptor expression, ligand or receptor oligomerization, redundancy, expression of atypical receptors, and non-GPCR binding partners that cumulatively influence discrete pharmacological signaling responses and cellular functions. In cancer, chemokines play paradoxical roles in both the directed emigration of metastatic, receptor-expressing cancer cells out of the tumor as well as immigration of tumor-infiltrating immune cells that culminate in a tumor-unique immune microenvironment. In the age of precision oncology, strategies to effectively harness the power of immunotherapy requires consideration of chemokine gradients within the unique spatial topography and temporal influences with heterogeneous tumors. In this article, we review current literature on the diversity of chemokine ligands and their cellular receptors that detect and process chemotactic gradients and illustrate how differences between ligand recognition and receptor activation influence the signaling machinery that drives cellular movement into and out of the tumor microenvironment. Facets of chemokine physiology across discrete cancer immune phenotypes are contrasted to existing chemokine-centered therapies in cancer.
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Affiliation(s)
- Donovan Drouillard
- Medical Scientist Training Program, Medical College of Wisconsin, Milwaukee, Wisconsin
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Brian T Craig
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Michael B Dwinell
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Center for Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
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16
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JIANG S, ZHANG W, LU Y. Development and validation of novel inflammatory response-related gene signature for sepsis prognosis. J Zhejiang Univ Sci B 2022; 23:1028-1041. [PMID: 36518055 PMCID: PMC9758714 DOI: 10.1631/jzus.b2200285] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Due to the low specificity and sensitivity of biomarkers in sepsis diagnostics, the prognosis of sepsis patient outcomes still relies on the assessment of clinical symptoms. Inflammatory response is crucial to sepsis onset and progression; however, the significance of inflammatory response-related genes (IRRGs) in sepsis prognosis is uncertain. This study developed an IRRG-based signature for sepsis prognosis and immunological function. The Gene Expression Omnibus (GEO) database was retrieved for two sepsis microarray datasets, GSE64457 and GSE69528, followed by gene set enrichment analysis (GSEA) comparing sepsis and healthy samples. A predictive signature for IRRGs was created using least absolute shrinkage and selection operator (LASSO). To confirm the efficacy and reliability of the new prognostic signature, Cox regression, Kaplan-Meier (K-M) survival, and receiver operating characteristic (ROC) curve analyses were performed. Subsequently, we employed the GSE95233 dataset to independently validate the prognostic signature. A single-sample GSEA (ssGSEA) was conducted to quantify the immune cell enrichment score and immune-related pathway activity. We found that more gene sets were enriched in the inflammatory response in sepsis patient samples than in healthy patient samples, as determined by GSEA. The signature of nine IRRGs permitted the patients to be classified into two risk categories. Patients in the low-risk group showed significantly better 28-d survival than those in the high-risk group. ROC curve analysis corroborated the predictive capacity of the signature, with the area under the curve (AUC) for 28-d survival reaching 0.866. Meanwhile, the ssGSEA showed that the two risk groups had different immune states. The validation set and external dataset showed that the signature was clinically predictive. In conclusion, a signature consisting of nine IRRGs can be utilized to predict prognosis and influence the immunological status of sepsis patients. Thus, intervention based on these IRRGs may become a therapeutic option in the future.
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Affiliation(s)
- Shuai JIANG
- Department of Emergency Medicine, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou310003, China,Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases, Hangzhou310003, China
| | - Wenyuan ZHANG
- Department of Anesthesiology and Intensive Care, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou310003, China
| | - Yuanqiang LU
- Department of Emergency Medicine, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou310003, China,Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases, Hangzhou310003, China,Yuanqiang LU,
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17
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Mabrouk N, Tran T, Sam I, Pourmir I, Gruel N, Granier C, Pineau J, Gey A, Kobold S, Fabre E, Tartour E. CXCR6 expressing T cells: Functions and role in the control of tumors. Front Immunol 2022; 13:1022136. [PMID: 36311728 PMCID: PMC9597613 DOI: 10.3389/fimmu.2022.1022136] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 09/27/2022] [Indexed: 11/13/2022] Open
Abstract
CXCR6 is a receptor for the chemokine CXCL16, which exists as a membrane or soluble form. CXCR6 is a marker for resident memory T (TRM) cells that plays a role in immunosurveillance through their interaction with epithelial cells. The interaction of CXCR6 with CXCL16 expressed at the membrane of certain subpopulations of intratumor dendritic cells (DC) called DC3, ideally positions these CXCR6+ T cells to receive a proliferation signal from IL-15 also presented by DC3. Mice deficient in cxcr6 or blocking the interaction of CXCR6 with its ligand, experience a poorer control of tumor proliferation by CD8+ T cells, but also by NKT cells especially in the liver. Intranasal vaccination induces CXCL16 production in the lungs and is associated with infiltration by TRM expressing CXCR6, which are then required for the efficacy of anti-tumor vaccination. Therapeutically, the addition of CXCR6 to specific CAR-T cells enhances their intratumoral accumulation and prolongs survival in animal models of pancreatic, ovarian and lung cancer. Finally, CXCR6 is part of immunological signatures that predict response to immunotherapy based on anti-PD-(L)1 in various cancers. In contrast, a protumoral role of CXCR6+T cells has also been reported mainly in Non-alcoholic steatohepatitis (NASH) due to a non-antigen specific mechanism. The targeting and amplification of antigen-specific TRM expressing CXCR6 and its potential use as a biomarker of response to immunotherapy opens new perspectives in cancer treatment.
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Affiliation(s)
| | - Thi Tran
- Université ParisCité, INSERM, PARCC, Paris, France
| | - Ikuan Sam
- Université ParisCité, INSERM, PARCC, Paris, France
| | - Ivan Pourmir
- Université ParisCité, INSERM, PARCC, Paris, France
| | - Nadège Gruel
- Institut Curie, PSL Research University, Department of Translational Research, Paris, France
- INSERM U830, Equipe labellisée LNCC, Siredo Oncology Centre, Institut Curie, Paris, France
| | - Clémence Granier
- Université ParisCité, INSERM, PARCC, Paris, France
- Immunology, APHP, Hôpital Europeen Georges Pompidou and Hôpital Necker, Paris, France
| | - Joséphine Pineau
- Université ParisCité, INSERM, PARCC, Paris, France
- Immunology, APHP, Hôpital Europeen Georges Pompidou and Hôpital Necker, Paris, France
| | - Alain Gey
- Université ParisCité, INSERM, PARCC, Paris, France
- Immunology, APHP, Hôpital Europeen Georges Pompidou and Hôpital Necker, Paris, France
| | - Sebastian Kobold
- Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Elizabeth Fabre
- Université ParisCité, INSERM, PARCC, Paris, France
- Lung Oncology Unit, APHP, Hôpital Européen Georges Pompidou, Paris, France
| | - Eric Tartour
- Université ParisCité, INSERM, PARCC, Paris, France
- Immunology, APHP, Hôpital Europeen Georges Pompidou and Hôpital Necker, Paris, France
- Equipe Labellisée Ligue contre le Cancer, Paris, France
- *Correspondence: Eric Tartour,
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18
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Song H, Weinstein HNW, Allegakoen P, Wadsworth MH, Xie J, Yang H, Castro EA, Lu KL, Stohr BA, Feng FY, Carroll PR, Wang B, Cooperberg MR, Shalek AK, Huang FW. Single-cell analysis of human primary prostate cancer reveals the heterogeneity of tumor-associated epithelial cell states. Nat Commun 2022; 13:141. [PMID: 35013146 PMCID: PMC8748675 DOI: 10.1038/s41467-021-27322-4] [Citation(s) in RCA: 125] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 10/29/2021] [Indexed: 12/31/2022] Open
Abstract
Prostate cancer is the second most common malignancy in men worldwide and consists of a mixture of tumor and non-tumor cell types. To characterize the prostate cancer tumor microenvironment, we perform single-cell RNA-sequencing on prostate biopsies, prostatectomy specimens, and patient-derived organoids from localized prostate cancer patients. We uncover heterogeneous cellular states in prostate epithelial cells marked by high androgen signaling states that are enriched in prostate cancer and identify a population of tumor-associated club cells that may be associated with prostate carcinogenesis. ERG-negative tumor cells, compared to ERG-positive cells, demonstrate shared heterogeneity with surrounding luminal epithelial cells and appear to give rise to common tumor microenvironment responses. Finally, we show that prostate epithelial organoids harbor tumor-associated epithelial cell states and are enriched with distinct cell types and states from their parent tissues. Our results provide diagnostically relevant insights and advance our understanding of the cellular states associated with prostate carcinogenesis.
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Affiliation(s)
- Hanbing Song
- grid.266102.10000 0001 2297 6811Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143 USA
| | - Hannah N. W. Weinstein
- grid.266102.10000 0001 2297 6811Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143 USA
| | - Paul Allegakoen
- grid.266102.10000 0001 2297 6811Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143 USA
| | - Marc H. Wadsworth
- grid.116068.80000 0001 2341 2786The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139 USA ,grid.116068.80000 0001 2341 2786Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology, Cambridge, MA 02139 USA ,grid.116068.80000 0001 2341 2786Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 USA ,grid.116068.80000 0001 2341 2786Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 USA ,grid.66859.340000 0004 0546 1623Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142 USA
| | - Jamie Xie
- grid.266102.10000 0001 2297 6811Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143 USA
| | - Heiko Yang
- grid.266102.10000 0001 2297 6811Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Department of Urology, University of California, San Francisco, San Francisco, CA 94143 USA
| | - Ethan A. Castro
- grid.266102.10000 0001 2297 6811Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143 USA
| | - Kevin L. Lu
- grid.266102.10000 0001 2297 6811Department of Pathology, University of California, San Francisco, San Francisco, CA 94143 USA
| | - Bradley A. Stohr
- grid.266102.10000 0001 2297 6811Department of Pathology, University of California, San Francisco, San Francisco, CA 94143 USA
| | - Felix Y. Feng
- grid.266102.10000 0001 2297 6811Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Department of Urology, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Departments of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94143 USA
| | - Peter R. Carroll
- grid.266102.10000 0001 2297 6811Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Department of Urology, University of California, San Francisco, San Francisco, CA 94143 USA
| | - Bruce Wang
- grid.266102.10000 0001 2297 6811Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA 94143 USA
| | - Matthew R. Cooperberg
- grid.266102.10000 0001 2297 6811Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Department of Urology, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.410372.30000 0004 0419 2775Division of Hematology and Oncology, Department of Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121 USA
| | - Alex K. Shalek
- grid.116068.80000 0001 2341 2786The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139 USA ,grid.116068.80000 0001 2341 2786Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology, Cambridge, MA 02139 USA ,grid.116068.80000 0001 2341 2786Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 USA ,grid.116068.80000 0001 2341 2786Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 USA ,grid.66859.340000 0004 0546 1623Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142 USA
| | - Franklin W. Huang
- grid.266102.10000 0001 2297 6811Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.266102.10000 0001 2297 6811Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143 USA ,grid.410372.30000 0004 0419 2775Division of Hematology and Oncology, Department of Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121 USA
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Ghollasi M, Ghasembaglou S, Rahban D, Korani M, Motallebnezhad M, Asadi M, Zarredar H, Salimi A. Prospects for Manipulation of Mesenchymal Stem Cells in Tumor Therapy: Anti-Angiogenesis Property on the Spotlight. Int J Stem Cells 2021; 14:351-365. [PMID: 34456189 PMCID: PMC8611310 DOI: 10.15283/ijsc20146] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 06/01/2021] [Accepted: 06/16/2021] [Indexed: 11/10/2022] Open
Abstract
The interactions between the tumor microenvironment and the tumor cells confers a condition that accelerate or decelerate the development of tumor. Of these cells, mesenchymal stem cells (MSCs) have the potential to modulate the tumor cells. MSCs have been established with double functions, whereby contribute to a tumorigenic or anti-tumor setting. Clinical studies have indicated the potential of MSCs to be used as tool in treating the human cancer cells. One of the advantageous features of MSCs that make them as a well-suited tool for cancer therapy is the natural tumor-trophic migration potential. A key specification of the tumor development has been stablished to be angiogenesis. As a result, manipulation of angiogenesis has become an attractive approach for cancer therapy. This review article will seek to clarify the anti-angiogenesis strategy in modulating the MSCs to treat the tumor cells.
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Affiliation(s)
- Marzieh Ghollasi
- Department of Cell and Molecular Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran
| | - Shahram Ghasembaglou
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Dariush Rahban
- Department of Nanomedicine, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Korani
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Morteza Motallebnezhad
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Milad Asadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Basic Oncology, Ege University, Institute of Health Sciences, Izmir, Turkey
| | - Habib Zarredar
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Ali Salimi
- Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Saxena S, Singh RK. Chemokines orchestrate tumor cells and the microenvironment to achieve metastatic heterogeneity. Cancer Metastasis Rev 2021; 40:447-476. [PMID: 33959849 PMCID: PMC9863248 DOI: 10.1007/s10555-021-09970-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 04/22/2021] [Indexed: 01/26/2023]
Abstract
Chemokines, a subfamily of the cell cytokines, are low molecular weight proteins known to induce chemotaxis in leukocytes in response to inflammatory and pathogenic signals. A plethora of literature demonstrates that chemokines and their receptors regulate tumor progression and metastasis. With these diverse functionalities, chemokines act as a fundamental link between the tumor cells and their microenvironment. Recent studies demonstrate that the biology of chemokines and their receptor in metastasis is complex as numerous chemokines are involved in regulating site-specific tumor growth and metastasis. Successful treatment of disseminated cancer is a significant challenge. The most crucial problem for treating metastatic cancer is developing therapy regimes capable of overcoming heterogeneity problems within primary tumors and among metastases and within metastases (intralesional). This heterogeneity of malignant tumor cells can be related to metastatic potential, response to chemotherapy or specific immunotherapy, and many other factors. In this review, we have emphasized the role of chemokines in the process of metastasis and metastatic heterogeneity. Individual chemokines may not express the full potential to address metastatic heterogeneity, but chemokine networks need exploration. Understanding the interplay between chemokine-chemokine receptor networks between the tumor cells and their microenvironment is a novel approach to overcome the problem of metastatic heterogeneity. Recent advances in the understanding of chemokine networks pave the way for developing a potential targeted therapeutic strategy to treat metastatic cancer.
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Affiliation(s)
- Sugandha Saxena
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 Nebraska Medical Center, Omaha, NE, 68198-5900, USA
| | - Rakesh K Singh
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 Nebraska Medical Center, Omaha, NE, 68198-5900, USA.
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21
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Abstract
Today, cancer is one of the leading causes of death worldwide. Lately, cytokine and chemokine imbalances have gained attention amongst different involved pathways in cancer development and attracted much consideration in cancer research. CXCL16, as a member of the CXC subgroup of chemokines, has been attributed to be responsible for immune cell infiltration into the tumour microenvironment. The aberrant expression of CXCL16 has been observed in various cancers. This chemokine has been shown to play a conflicting role in tumour development through inducing pro-inflammatory conditions. The infiltration of various immune and non-immune cells such as lymphocytes, cancer-associated fibroblasts and myeloid-derived suppressor cells by CXCL16 into the tumour microenvironment has complicated the tumour fate. Given this diverse role of CXCL16 in cancer, a better understanding of its function might build-up our knowledge about tumour biology. Hence, this study aimed to review the impact of CXCL16 in cancer and explored its therapeutic application. Consideration of these findings might provide opportunities to achieve novel approaches in cancer treatment and its prognosis.
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The Role of CXCL16 in the Pathogenesis of Cancer and Other Diseases. Int J Mol Sci 2021; 22:ijms22073490. [PMID: 33800554 PMCID: PMC8036711 DOI: 10.3390/ijms22073490] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/23/2021] [Accepted: 03/26/2021] [Indexed: 12/15/2022] Open
Abstract
CXCL16 is a chemotactic cytokine belonging to the α-chemokine subfamily. It plays a significant role in the progression of cancer, as well as the course of atherosclerosis, renal fibrosis, and non-alcoholic fatty liver disease (NAFLD). Since there has been no review paper discussing the importance of this chemokine in various diseases, we have collected all available knowledge about CXCL16 in this review. In the first part of the paper, we discuss background information about CXCL16 and its receptor, CXCR6. Next, we focus on the importance of CXCL16 in a variety of diseases, with an emphasis on cancer. We discuss the role of CXCL16 in tumor cell proliferation, migration, invasion, and metastasis. Next, we describe the role of CXCL16 in the tumor microenvironment, including involvement in angiogenesis, and its significance in tumor-associated cells (cancer associated fibroblasts (CAF), microglia, tumor-associated macrophages (TAM), tumor-associated neutrophils (TAN), mesenchymal stem cells (MSC), myeloid suppressor cells (MDSC), and regulatory T cells (Treg)). Finally, we focus on the antitumor properties of CXCL16, which are mainly caused by natural killer T (NKT) cells. At the end of the article, we summarize the importance of CXCL16 in cancer therapy.
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Guo JN, Li MQ, Deng SH, Chen C, Ni Y, Cui BB, Liu YL. Prognostic Immune-Related Analysis Based on Differentially Expressed Genes in Left- and Right-Sided Colon Adenocarcinoma. Front Oncol 2021; 11:640196. [PMID: 33763372 PMCID: PMC7982460 DOI: 10.3389/fonc.2021.640196] [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] [Received: 12/10/2020] [Accepted: 01/27/2021] [Indexed: 02/05/2023] Open
Abstract
Background Colon adenocarcinoma (COAD) can be divided into left-sided and right-sided COAD (LCCs and RCCs, respectively). They have unique characteristics in various biological aspects, particularly immune invasion and prognosis. The purpose of our study was to develop a prognostic risk scoring model (PRSM) based on differentially expressed immune-related genes (IRGs) between LCCs and RCCs, therefore the prognostic key IRGs could be identified. Methods The gene sets and clinical information of COAD patients were derived from TCGA and GEO databases. The comparison of differentially expressed genes (DEGs) of LCCs and RCCs were conducted with appliance of “Limma” analysis. The establishment about co-expression modules of DEGs related with immune score was conducted by weighted gene co-expression network analysis (WGCNA). Furthermore, we screened the module genes and completed construction of gene pairs. The analysis of the prognosis and the establishment of PRSM were performed with univariate- and lasso-Cox regression. We employed the PRSM in the model group and verification group for the purpose of risk group assignment and PRSM accuracy verification. Finally, the identification of the prognostic key IRGs was guaranteed by the adoption of functional enrichment, “DisNor” and protein-protein interaction (PPI). Results A total of 215 genes were screened out by differential expression analysis and WGCNA. A PRSM with 16 immune-related gene pairs (IRGPs) was established upon the genes pairing. Furthermore, we confirmed that the risk score was an independent factor for survival by univariate- and multivariate-Cox regression. The prognosis of high-risk group in model group (P < 0.001) and validation group (P = 0.014) was significantly worse than that in low-risk group. Treg cells (P < 0.001) and macrophage M0 (P = 0.015) were highly expressed in the high-risk group. The functional analysis indicated that there was significant up-regulation with regard of lymphocyte and cytokine related terms in low-risk group. Finally, we identified five prognostic key IRGs associated with better prognosis through PPI and prognostic analysis, including IL2RB, TRIM22, CIITA, CXCL13, and CXCR6. Conclusion Through the analysis and screening of the DEGs between LCCs and RCCs, we constructed a PRSM which could predicate prognosis of LCCs and RCCs, and five prognostic key IRGs were identified as well. Therefore, the basis for identifying the benefits of immunotherapy and immunomodulatory was built.
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Affiliation(s)
- Jun-Nan Guo
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ming-Qi Li
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Shen-Hui Deng
- Department of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chen Chen
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yin Ni
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Bin-Bin Cui
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yan-Long Liu
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
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Ma Z, Ma C, Zhang Q, Bai Y, Mu K, Liu X, Yang Q. Role of CXCL16 in BLM-induced epithelial-mesenchymal transition in human A549 cells. Respir Res 2021; 22:42. [PMID: 33549109 PMCID: PMC7866482 DOI: 10.1186/s12931-021-01646-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 01/31/2021] [Indexed: 12/01/2022] Open
Abstract
Alveolar epithelial cells play an essential role in the initiation and progression of pulmonary fibrosis, and the occurrence of epithelial–mesenchymal transition (EMT) may be the early events of pulmonary fibrosis. Recent studies have shown chemokines are involved in the complex process of EMT, and CXC chemokine ligand 16 (CXCL16) is also associated with many fibrosis-related diseases. However, whether CXCL16 is dysregulated in alveolar epithelial cells and the role of CXCL16 in modulating EMT in pulmonary fibrosis has not been reported. In this study, we found that CXCL16 and its receptor C-X-C motif chemokine receptor 6 (CXCR6) were upregulated in bleomycin induced EMT in human alveolar type II-like epithelial A549 cells. Synergistic effect of CXCL16 and bleomycin in promoting EMT occurrence, extracellular matrix (ECM) excretion, as well as the pro-inflammatory and pro-fibrotic cytokines productions in A549 cells were observed, and those biological functions were impaired by CXCL16 siRNA. We further confirmed that CXCL16 regulated EMT in A549 cells via the TGF-β1/Smad3 pathways. These results indicated that CXCL16 could promote pulmonary fibrosis by promoting the process of EMT via the TGF-β1/Smad3 signaling pathway.
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Affiliation(s)
- Zhenzhen Ma
- Department of Rheumatology and Immunology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.,Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, 100191, China
| | - Chunyan Ma
- Department of Rheumatology and Immunology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.,Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Qingfeng Zhang
- Department of Rheumatology and Immunology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Yang Bai
- Department of Rheumatology and Immunology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Kun Mu
- Department of Pathology, Qilu Hospital, Shandong University, Jinan, 250012, China
| | - Xiangyuan Liu
- Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, 100191, China.
| | - Qingrui Yang
- Department of Rheumatology and Immunology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China. .,Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
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Enoxaparin prevents CXCL16/ADAM10-mediated cisplatin renal toxicity: Role of the coagulation system and the transcriptional factor NF-κB. Life Sci 2021; 270:119120. [PMID: 33545204 DOI: 10.1016/j.lfs.2021.119120] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 01/04/2021] [Accepted: 01/12/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS C-X-C ligand 16 (CXCL16) is an exceptional chemokine that is expressed as transmembrane and soluble forms. Our aim is to shed lights on the role of CXCL16/ADAM10 (a disintegrin and metalloproteinase) in cisplatin (CP)-induced renal toxicity as well as possible protective effect of enoxaparin. MAIN METHODS Male albino mice were injected with CP (30 mg/kg, i.p.) in the presence or absence of enoxaparin (ENOX) (5 mg/kg, i.p.). Renal toxicity markers, serum level of cystatin-c, complete blood count (CBC), prothrombin time (Pt) and tissue expression of CXCL16, ADAM10, cluster of differentiation 3 (CD3), fibrinogen, tissue factor (TF), nuclear factor-κB (NF-κB) and tumour necrosis factor α (TNF-α) were measured. Besides, serum CXCL16 and histopathology were also analyzed. KEY FINDINGS CP increased renal toxicity markers, renal expression of CXCL16/ADAM10, fibrinogen, TF and CD3 tissue expression in a time-dependent manner, and elevated serum cystatin-c, CXCL16 and tissue TNF-α, NF-κB. Alternatively, ENOX restored the deteriorated parameters and reduced tissue level of NF-κB. SIGNIFICANCE This report, for the first time, showed that soluble CXCL16 resulting from ADAM10 cleavage may recruit T-cells to the renal glomeruli and tubules in CP toxicity. Furthermore, TF and fibrin, have similar expression and location pattern like CXCL16 and ADAM10 suggesting their possible interrelation. ENOX successfully restored the deteriorated parameters suggesting it may be an effective nephroprotective adjuvant therapy.
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Li Y, Wu T, Gong S, Zhou H, Yu L, Liang M, Shi R, Wu Z, Zhang J, Li S. Analysis of the Prognosis and Therapeutic Value of the CXC Chemokine Family in Head and Neck Squamous Cell Carcinoma. Front Oncol 2021; 10:570736. [PMID: 33489879 PMCID: PMC7820708 DOI: 10.3389/fonc.2020.570736] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 10/29/2020] [Indexed: 12/24/2022] Open
Abstract
The CXC chemokines belong to a family which includes 17 different CXC members. Accumulating evidence suggests that CXC chemokines regulate tumor cell proliferation, invasion, and metastasis in various types of cancers by influencing the tumor microenvironment. The different expression profiles and specific function of each CXC chemokine in head and neck squamous cell carcinoma (HNSCC) are not yet clarified. In our work, we analyzed the altered expression, interaction network, and clinical data of CXC chemokines in patients with HNSCC by using the following: the Oncomine dataset, cBioPortal, Metascape, String analysis, GEPIA, and the Kaplan–Meier plotter. The transcriptional level analysis suggested that the mRNA levels of CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, CXCL9, CXCL10, CXCL11, and CXCL13 increased in HNSCC tissue samples when compared to the control tissue samples. The expression levels of CXCL9, CXCL10, CXCL11, CXCL12, and CXCL14 were associated with various tumor stages in HNSCC. Clinical data analysis showed that high transcription levels of CXCL2, CXCL3, and CXCL12, were linked with low relapse-free survival (RFS) in HNSCC patients. On the other hand, high CXCL14 levels predicted high RFS outcomes in HNSCC patients. Meanwhile, increased gene transcription levels of CXCL9, CXCL10, CXCL13, CXCL14, and CXCL17 were associated with a higher overall survival (OS) advantage in HNSCC patients, while high levels of CXCL1, and CXCL8 were associated with poor OS in all HNSCC patients. This study implied that CXCL1, CXCL2, CXCL3, CXCL8, and CXCL12 could be used as prognosis markers to identify low survival rate subgroups of patients with HNSCC as well as be potential suitable therapeutic targets for HNSCC patients. Additionally, CXCL9, CXCL10, CXCL13, CXCL14, and CXCL17 could be used as functional prognosis biomarkers to identify better survival rate subgroups of patients with HNSCC.
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Affiliation(s)
- Yongchao Li
- Key Laboratory of Protection & Utilization of Biological Resources in Tarim Basin, College of Life Sciences, Tarim University, Alar, China
| | - Tinghui Wu
- Key Laboratory of Protection & Utilization of Biological Resources in Tarim Basin, College of Life Sciences, Tarim University, Alar, China
| | - Shujuan Gong
- Key Laboratory of Protection & Utilization of Biological Resources in Tarim Basin, College of Life Sciences, Tarim University, Alar, China
| | - Hangzheng Zhou
- Key Laboratory of Protection & Utilization of Biological Resources in Tarim Basin, College of Life Sciences, Tarim University, Alar, China
| | - Lufei Yu
- Key Laboratory of Protection & Utilization of Biological Resources in Tarim Basin, College of Life Sciences, Tarim University, Alar, China
| | - Meiyan Liang
- Key Laboratory of Protection & Utilization of Biological Resources in Tarim Basin, College of Life Sciences, Tarim University, Alar, China
| | - Ruijun Shi
- Key Laboratory of Protection & Utilization of Biological Resources in Tarim Basin, College of Life Sciences, Tarim University, Alar, China
| | - Zhenhui Wu
- Key Laboratory of Protection & Utilization of Biological Resources in Tarim Basin, College of Life Sciences, Tarim University, Alar, China
| | - Jinpei Zhang
- Key Laboratory of Protection & Utilization of Biological Resources in Tarim Basin, College of Life Sciences, Tarim University, Alar, China
| | - Shuwei Li
- Key Laboratory of Protection & Utilization of Biological Resources in Tarim Basin, College of Life Sciences, Tarim University, Alar, China
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Han X, Liu Z. Long non‑coding RNA JPX promotes gastric cancer progression by regulating CXCR6 and autophagy via inhibiting miR‑197. Mol Med Rep 2020; 23:60. [PMID: 33215222 PMCID: PMC7723066 DOI: 10.3892/mmr.2020.11698] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 09/11/2020] [Indexed: 12/27/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) serve a crucial role in gastric cancer (GC) progression. However, the molecular mechanism underlying lncRNA JPX transcript, XIST activator (JPX) in the tumorigenesis of GC is not completely understood. Reverse transcription-quantitative PCR (RT-qPCR) and western blotting were performed to detect gene expression. A luciferase reporter gene assay was conducted to determine the relationship between microRNA (miR)-197 and JPX or C-X-C motif chemokine receptor 6 (CXCR6). Cell viability, migration and invasion were determined by performing MTT, wound healing and Transwell assays, respectively. The Cancer Genome Atlas database and the RT-qPCR results indicated that JPX expression was upregulated and miR-197 expression was downregulated in patients with GC and in GC cells. Moreover, high JPX expression and low miR-197 expression in patients with GC indicated poor prognosis. miR-197 expression was directly inhibited by JPX. Compared with the short hairpin RNA (sh) negative control (NC) group, NCI-N87 and MKN-45 cells in the shJPX group displayed decreased cell viability and invasion, as well as a wider scratch width. NCI-N87 and MKN-45 cells in the shJPX + miR-197 inhibitor group had increased viability and invasion, but a narrower scratch width compared with the shJPX group. It was also identified that miR-197 directly inhibited CXCR6 expression. miR-197 inhibited Beclin1 protein expression and promoted p62 protein expression. Compared with the NC group, NCI-N87 and MKN-45 cells in the miR-197 mimic group had decreased cell viability and invasion, and a wider scratch width. Enhanced cell viability and invasion, and a narrower scratch width was also observed in the miR-197 mimic + CXCR6 and miR-197 mimic + Beclin1 groups, compared with the miR-197 mimic group. Collectively, the results indicated that lncRNA JPX promoted GC progression by regulating CXCR6 and autophagy via inhibiting miR-197. Furthermore, JPX knockdown regulated GC cell phenotype by promoting miR-197.
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Affiliation(s)
- Xuejing Han
- Department of Digestion, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210036, P.R. China
| | - Zheng Liu
- Department of Digestion, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210036, P.R. China
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Caruso FP, Garofano L, D'Angelo F, Yu K, Tang F, Yuan J, Zhang J, Cerulo L, Pagnotta SM, Bedognetti D, Sims PA, Suvà M, Su XD, Lasorella A, Iavarone A, Ceccarelli M. A map of tumor-host interactions in glioma at single-cell resolution. Gigascience 2020; 9:giaa109. [PMID: 33155039 PMCID: PMC7645027 DOI: 10.1093/gigascience/giaa109] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 08/08/2020] [Accepted: 09/17/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Single-cell RNA sequencing is the reference technique for characterizing the heterogeneity of the tumor microenvironment. The composition of the various cell types making up the microenvironment can significantly affect the way in which the immune system activates cancer rejection mechanisms. Understanding the cross-talk signals between immune cells and cancer cells is of fundamental importance for the identification of immuno-oncology therapeutic targets. RESULTS We present a novel method, single-cell Tumor-Host Interaction tool (scTHI), to identify significantly activated ligand-receptor interactions across clusters of cells from single-cell RNA sequencing data. We apply our approach to uncover the ligand-receptor interactions in glioma using 6 publicly available human glioma datasets encompassing 57,060 gene expression profiles from 71 patients. By leveraging this large-scale collection we show that unexpected cross-talk partners are highly conserved across different datasets in the majority of the tumor samples. This suggests that shared cross-talk mechanisms exist in glioma. CONCLUSIONS Our results provide a complete map of the active tumor-host interaction pairs in glioma that can be therapeutically exploited to reduce the immunosuppressive action of the microenvironment in brain tumor.
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Affiliation(s)
- Francesca Pia Caruso
- Department of Electrical Engineering and Information Technology (DIETI), University of Naples “Federico II”, Via Claudio 21, 80128 Naples, Italy
- Bioinformatics Lab, BIOGEM, Via Camporeale, 83031 Ariano Irpino, Italy
| | - Luciano Garofano
- Department of Electrical Engineering and Information Technology (DIETI), University of Naples “Federico II”, Via Claudio 21, 80128 Naples, Italy
- Institute for Cancer Genetics, Columbia University, 1130 St Nicholas Ave, New York, NY 10032, USA
| | - Fulvio D'Angelo
- Bioinformatics Lab, BIOGEM, Via Camporeale, 83031 Ariano Irpino, Italy
- Institute for Cancer Genetics, Columbia University, 1130 St Nicholas Ave, New York, NY 10032, USA
| | - Kai Yu
- Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, 5 Yiheyuan Rd, Haidian District, 100871 Beijing, China
| | - Fuchou Tang
- Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, 5 Yiheyuan Rd, Haidian District, 100871 Beijing, China
| | - Jinzhou Yuan
- Department of Science and Technologies, Università degli Studi del Sannio, Via de Sanctis, 82100 Benevento, Italy
- Cancer Program, Sidra Medicine, Al Luqta Street, Zone 52, Education City, 26999, Doha Qatar
| | - Jing Zhang
- Institute for Cancer Genetics, Columbia University, 1130 St Nicholas Ave, New York, NY 10032, USA
| | - Luigi Cerulo
- Bioinformatics Lab, BIOGEM, Via Camporeale, 83031 Ariano Irpino, Italy
- Department of Science and Technologies, Università degli Studi del Sannio, Via de Sanctis, 82100 Benevento, Italy
| | - Stefano M Pagnotta
- Department of Science and Technologies, Università degli Studi del Sannio, Via de Sanctis, 82100 Benevento, Italy
| | - Davide Bedognetti
- Cancer Program, Sidra Medicine, Al Luqta Street, Zone 52, Education City, 26999, Doha Qatar
- Department of Internal Medicine and Medical Specialties (Di.M.I.), University of Genoa, Viale Benedetto XV 10, 16132 Genoa, Italy
| | - Peter A Sims
- Department of Systems Biology, Columbia University Irving Medical Center, 1130 St Nicholas Ave, New York , NY 10032, USA
- Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, 1130 St Nicholas Ave, New York, NY 10032, USA
| | - Mario Suvà
- Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, 55 Fruit St, Boston, MA 02114, USA
- Broad Institute of Harvard and MIT, 415 Main St, Cambridge, MA 02142, USA
| | - Xiao-Dong Su
- Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, 5 Yiheyuan Rd, Haidian District, 100871 Beijing, China
| | - Anna Lasorella
- Institute for Cancer Genetics, Columbia University, 1130 St Nicholas Ave, New York, NY 10032, USA
- Department of Pathology and Cell Biology, Columbia University Medical Center, 1130 St Nicholas Ave, New York , NY 10032 USA
| | - Antonio Iavarone
- Institute for Cancer Genetics, Columbia University, 1130 St Nicholas Ave, New York, NY 10032, USA
- Department of Pathology and Cell Biology, Columbia University Medical Center, 1130 St Nicholas Ave, New York , NY 10032 USA
- Department of Neurology, Columbia University Medical Center, 1130 St Nicholas Ave, New York, NY 10032, USA
| | - Michele Ceccarelli
- Department of Electrical Engineering and Information Technology (DIETI), University of Naples “Federico II”, Via Claudio 21, 80128 Naples, Italy
- Bioinformatics Lab, BIOGEM, Via Camporeale, 83031 Ariano Irpino, Italy
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Guo H, Ahn S, Zhang L. Benzene-associated immunosuppression and chronic inflammation in humans: a systematic review. Occup Environ Med 2020; 78:oemed-2020-106517. [PMID: 32938756 PMCID: PMC7960562 DOI: 10.1136/oemed-2020-106517] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 08/01/2020] [Accepted: 08/13/2020] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Recent evidence has accumulated that the immune system is intimately intertwined with cancer development. Two key characteristics of carcinogens in which the immune system plays a central role are chronic inflammation and immunosuppression. In this systematic review, we investigated the association of chronic inflammatory and immunosuppressive outcomes with benzene, a widely used industrial chemical. Benzene has been confirmed to cause acute myeloid leukaemia and suspected to cause non-Hodgkin lymphoma, two cancers of the blood-forming system that affect immune cells. METHODS We systematically searched PubMed and Embase for all relevant studies using a combination of Medical Subject Headings (MeSH) and selected key words. The detailed review protocol, including search strategy, was registered with PROSPERO, the international prospective register of systematic reviews (#CRD42019138611). RESULTS Based on all human studies selected in the final review, we report new evidence of a benzene-induced immunosuppressive effect on the adaptive immune system and activation of the innate immune system to cause inflammation. In particular, benzene significantly lowers the number of white blood cells, particularly lymphocytes such as CD4+ T-cells, B-cells and natural killer cells, and increases proinflammatory biomarkers at low levels of exposure. CONCLUSION To the best of our knowledge, this is the first comprehensive review of benzene's immunotoxicity in humans. Based on results obtained from this review, we propose two potential immunotoxic mechanisms of how benzene induces leukaemia/lymphoma: (1) cancer invasion caused by proinflammatory cytokine production, and (2) cancer promotion via impaired immunosurveillance. Further studies will be required to confirm the connection between benzene exposure and its effects on the immune system.
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Affiliation(s)
- Helen Guo
- Division of Environmental Health Sciences, School of Public Health, University of California Berkeley, Berkeley, California, USA
| | - Stacy Ahn
- Division of Environmental Health Sciences, School of Public Health, University of California Berkeley, Berkeley, California, USA
| | - Luoping Zhang
- Division of Environmental Health Sciences, School of Public Health, University of California Berkeley, Berkeley, California, USA
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Yu H, Yang A, Liu L, Mak JYW, Fairlie DP, Cowley S. CXCL16 Stimulates Antigen-Induced MAIT Cell Accumulation but Trafficking During Lung Infection Is CXCR6-Independent. Front Immunol 2020; 11:1773. [PMID: 32849637 PMCID: PMC7426740 DOI: 10.3389/fimmu.2020.01773] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 07/02/2020] [Indexed: 12/20/2022] Open
Abstract
Mucosa-associated invariant T (MAIT) cells are a unique T cell subset that contributes to protective immunity against microbial pathogens, but little is known about the role of chemokines in recruiting MAIT cells to the site of infection. Pulmonary infection with Francisella tularensis live vaccine strain (LVS) stimulates the accrual of large numbers of MAIT cells in the lungs of mice. Using this infection model, we find that MAIT cells are predominantly CXCR6+ but do not require CXCR6 for accumulation in the lungs. However, CXCR6 does contribute to long-term retention of MAIT cells in the airway lumen after clearance of the infection. We also find that MAIT cells are not recruited from secondary lymphoid organs and largely proliferate in situ in the lungs after infection. Nevertheless, the only known ligand for CXCR6, CXCL16, is sufficient to drive MAIT cell accumulation in the lungs in the absence of infection when administered in combination with the MAIT cell antigen 5-OP-RU. Overall, this new data advances the understanding of mechanisms that facilitate MAIT cell accumulation and retention in the lungs.
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Affiliation(s)
- Huifeng Yu
- Laboratory of Mucosal Pathogens and Cellular Immunology, Division of Bacterial Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States
| | - Amy Yang
- Laboratory of Mucosal Pathogens and Cellular Immunology, Division of Bacterial Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States
| | - Ligong Liu
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, QLD, Australia
| | - Jeffrey Y W Mak
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, QLD, Australia
| | - David P Fairlie
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, QLD, Australia
| | - Siobhan Cowley
- Laboratory of Mucosal Pathogens and Cellular Immunology, Division of Bacterial Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States
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31
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Cytokines and Chemokines as Mediators of Prostate Cancer Metastasis. Int J Mol Sci 2020; 21:ijms21124449. [PMID: 32585812 PMCID: PMC7352203 DOI: 10.3390/ijms21124449] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 06/19/2020] [Accepted: 06/21/2020] [Indexed: 12/16/2022] Open
Abstract
The consequences of prostate cancer metastasis remain severe, with huge impact on the mortality and overall quality of life of affected patients. Despite the convoluted interplay and cross talk between various cell types and secreted factors in the metastatic process, cytokine and chemokines, along with their receptors and signaling axis, constitute important factors that help drive the sequence of events that lead to metastasis of prostate cancer. These proteins are involved in extracellular matrix remodeling, epithelial-mesenchymal-transition, angiogenesis, tumor invasion, premetastatic niche creation, extravasation, re-establishment of tumor cells in secondary organs as well as the remodeling of the metastatic tumor microenvironment. This review presents an overview of the main cytokines/chemokines, including IL-6, CXCL12, TGFβ, CXCL8, VEGF, RANKL, CCL2, CX3CL1, IL-1, IL-7, CXCL1, and CXCL16, that exert modulatory roles in prostate cancer metastasis. We also provide extensive description of their aberrant expression patterns in both advanced disease states and metastatic sites, as well as their functional involvement in the various stages of the prostate cancer metastatic process.
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Ball MS, Bhandari R, Torres GM, Martyanov V, ElTanbouly MA, Archambault K, Whitfield ML, Liby KT, Pioli PA. CDDO-Me Alters the Tumor Microenvironment in Estrogen Receptor Negative Breast Cancer. Sci Rep 2020; 10:6560. [PMID: 32300202 PMCID: PMC7162855 DOI: 10.1038/s41598-020-63482-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 03/20/2020] [Indexed: 01/27/2023] Open
Abstract
The tumor microenvironment (TME) is an essential contributor to the development and progression of malignancy. Within the TME, tumor associated macrophages (TAMs) mediate angiogenesis, metastasis, and immunosuppression, which inhibits infiltration of tumor-specific cytotoxic CD8+ T cells. In previous work, we demonstrated that the synthetic triterpenoid CDDO-methyl ester (CDDO-Me) converts breast TAMs from a tumor-promoting to a tumor-inhibiting activation state in vitro. We show now that CDDO-Me remodels the breast TME, redirecting TAM activation and T cell tumor infiltration in vivo. We demonstrate that CDDO-Me significantly attenuates IL-10 and VEGF expression but stimulates TNF production, and reduces surface expression of CD206 and CD115, markers of immunosuppressive TAMs. CDDO-Me treatment redirects the TAM transcriptional profile, inducing signaling pathways associated with immune stimulation, and inhibits TAM tumor infiltration, consistent with decreased expression of CCL2. In CDDO-Me-treated mice, both the absolute number and proportion of splenic CD4+ T cells were reduced, while the proportion of CD8+ T cells was significantly increased in both tumors and spleen. Moreover, mice fed CDDO-Me demonstrated significant reductions in numbers of CD4+ Foxp3+ regulatory T cells within tumors. These results demonstrate for the first time that CDDO-Me relieves immunosuppression in the breast TME and unleashes host adaptive anti-tumor immunity.
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Affiliation(s)
- Michael S Ball
- Department of Microbiology and Immunology, Geisel School of Medicine, Lebanon, New Hampshire, United States of America
| | - Rajan Bhandari
- Department of Microbiology and Immunology, Geisel School of Medicine, Lebanon, New Hampshire, United States of America
| | - Gretel M Torres
- Department of Microbiology and Immunology, Geisel School of Medicine, Lebanon, New Hampshire, United States of America
| | - Viktor Martyanov
- Department of Biomedical Data Science, Geisel School of Medicine, Lebanon, New Hampshire, United States of America
| | - Mohamed A ElTanbouly
- Department of Microbiology and Immunology, Geisel School of Medicine, Lebanon, New Hampshire, United States of America
| | - Kim Archambault
- Department of Biomedical Data Science, Geisel School of Medicine, Lebanon, New Hampshire, United States of America
| | - Michael L Whitfield
- Department of Biomedical Data Science, Geisel School of Medicine, Lebanon, New Hampshire, United States of America
| | - Karen T Liby
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, United States of America
| | - Patricia A Pioli
- Department of Microbiology and Immunology, Geisel School of Medicine, Lebanon, New Hampshire, United States of America.
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Figueiredo CR, Kalirai H, Sacco JJ, Azevedo RA, Duckworth A, Slupsky JR, Coulson JM, Coupland SE. Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development. J Pathol 2020; 250:420-439. [PMID: 31960425 PMCID: PMC7216965 DOI: 10.1002/path.5384] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 12/28/2019] [Accepted: 01/14/2020] [Indexed: 12/22/2022]
Abstract
Immunotherapy using immune checkpoint inhibitors (ICIs) induces durable responses in many metastatic cancers. Metastatic uveal melanoma (mUM), typically occurring in the liver, is one of the most refractory tumours to ICIs and has dismal outcomes. Monosomy 3 (M3), polysomy 8q, and BAP1 loss in primary uveal melanoma (pUM) are associated with poor prognoses. The presence of tumour-infiltrating lymphocytes (TILs) within pUM and surrounding mUM - and some evidence of clinical responses to adoptive TIL transfer - strongly suggests that UMs are indeed immunogenic despite their low mutational burden. The mechanisms that suppress TILs in pUM and mUM are unknown. We show that BAP1 loss is correlated with upregulation of several genes associated with suppressive immune responses, some of which build an immune suppressive axis, including HLA-DR, CD38, and CD74. Further, single-cell analysis of pUM by mass cytometry confirmed the expression of these and other markers revealing important functions of infiltrating immune cells in UM, most being regulatory CD8+ T lymphocytes and tumour-associated macrophages (TAMs). Transcriptomic analysis of hepatic mUM revealed similar immune profiles to pUM with BAP1 loss, including the expression of IDO1. At the protein level, we observed TAMs and TILs entrapped within peritumoural fibrotic areas surrounding mUM, with increased expression of IDO1, PD-L1, and β-catenin (CTNNB1), suggesting tumour-driven immune exclusion and hence the immunotherapy resistance. These findings aid the understanding of how the immune response is organised in BAP1 - mUM, which will further enable functional validation of detected biomarkers and the development of focused immunotherapeutic approaches. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Carlos R Figueiredo
- Department of Molecular and Clinical Cancer Medicine, ITMUniversity of LiverpoolLiverpoolUK
- Department of the Faculty of Medicine, MediCity Research Laboratory and Institute of BiomedicineUniversity of TurkuTurkuFinland
| | - Helen Kalirai
- Department of Molecular and Clinical Cancer Medicine, ITMUniversity of LiverpoolLiverpoolUK
| | - Joseph J Sacco
- Department of Molecular and Clinical Cancer Medicine, ITMUniversity of LiverpoolLiverpoolUK
- Department of Medical OncologyThe Clatterbridge Cancer CentreWirralUK
| | - Ricardo A Azevedo
- Department of Cancer BiologyThe University of Texas–MD Anderson Cancer CenterHoustonTXUSA
| | - Andrew Duckworth
- Department of Molecular and Clinical Cancer Medicine, ITMUniversity of LiverpoolLiverpoolUK
| | - Joseph R Slupsky
- Department of Molecular and Clinical Cancer Medicine, ITMUniversity of LiverpoolLiverpoolUK
| | - Judy M Coulson
- Department of Cellular and Molecular PhysiologyUniversity of LiverpoolLiverpoolUK
| | - Sarah E Coupland
- Department of Molecular and Clinical Cancer Medicine, ITMUniversity of LiverpoolLiverpoolUK
- Liverpool Clinical LaboratoriesRoyal Liverpool University HospitalLiverpoolUK
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Catalano S, Panza S, Augimeri G, Giordano C, Malivindi R, Gelsomino L, Marsico S, Giordano F, Győrffy B, Bonofiglio D, Andò S, Barone I. Phosphodiesterase 5 (PDE5) Is Highly Expressed in Cancer-Associated Fibroblasts and Enhances Breast Tumor Progression. Cancers (Basel) 2019; 11:cancers11111740. [PMID: 31698786 PMCID: PMC6895904 DOI: 10.3390/cancers11111740] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 10/25/2019] [Accepted: 11/04/2019] [Indexed: 02/06/2023] Open
Abstract
The overexpression of phosphodiesterase (PDE) 5 is frequently found in various human cancers, such as those of the breast. However, PDE5’s role in the tumor microenvironment is still unknown. As PDE5 represents a high-value therapeutic target, we investigated whether the expression and function of PDE5 in breast cancer-associated fibroblasts (CAFs) may be clinically relevant to malignant progression. PDE5 expression was increased in human breast cancer stroma compared with normal stroma and was correlated to a shorter overall survival. Treatment of CAFs, isolated from breast tumor biopsies, with selective PDE5 inhibitors inhibited their proliferation, motility, and invasiveness, and negatively controlled tumor–stroma interactions in both ‘in vitro’ and ‘in vivo’ models. PDE5 stable overexpression transformed immortalized mouse embryonic fibroblasts (MEFs) towards an activated fibroblast phenotype, impacting their intrinsic characteristics and paracrine effects on breast cancer cell growth and migration through an enhanced production of the C-X-C motif chemokine 16 (CXCL16). On the other hand, CAF exposure to PDE5 inhibitors was associated with reduced CXCL16 expression and secretion. Importantly, CXCL16 levels in breast cancer stroma showed a strong correlation with PDE5 levels and poor patient outcomes. In conclusion, PDE5 is overexpressed in breast cancer stroma, enhances the tumor-stimulatory activities of fibroblasts, and impacts clinical outcomes; thus, we propose this enzyme as an attractive candidate for prognosis and a potential target for treatments in breast cancer patients.
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Affiliation(s)
- Stefania Catalano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (S.C.); (S.P.); (G.A.); (C.G.); (R.M.); (L.G.); (S.M.); (F.G.); (D.B.)
| | - Salvatore Panza
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (S.C.); (S.P.); (G.A.); (C.G.); (R.M.); (L.G.); (S.M.); (F.G.); (D.B.)
| | - Giuseppina Augimeri
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (S.C.); (S.P.); (G.A.); (C.G.); (R.M.); (L.G.); (S.M.); (F.G.); (D.B.)
| | - Cinzia Giordano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (S.C.); (S.P.); (G.A.); (C.G.); (R.M.); (L.G.); (S.M.); (F.G.); (D.B.)
- Centro Sanitario, University of Calabria, 87036 Rende (CS), Italy
| | - Rocco Malivindi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (S.C.); (S.P.); (G.A.); (C.G.); (R.M.); (L.G.); (S.M.); (F.G.); (D.B.)
| | - Luca Gelsomino
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (S.C.); (S.P.); (G.A.); (C.G.); (R.M.); (L.G.); (S.M.); (F.G.); (D.B.)
| | - Stefania Marsico
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (S.C.); (S.P.); (G.A.); (C.G.); (R.M.); (L.G.); (S.M.); (F.G.); (D.B.)
| | - Francesca Giordano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (S.C.); (S.P.); (G.A.); (C.G.); (R.M.); (L.G.); (S.M.); (F.G.); (D.B.)
| | - Balázs Győrffy
- MTA TTK Lendület Cancer Biomarker Research Group, Semmelweis University 2nd Dept. of Pediatrics, 1094 Budapest, Hungary;
| | - Daniela Bonofiglio
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (S.C.); (S.P.); (G.A.); (C.G.); (R.M.); (L.G.); (S.M.); (F.G.); (D.B.)
| | - Sebastiano Andò
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (S.C.); (S.P.); (G.A.); (C.G.); (R.M.); (L.G.); (S.M.); (F.G.); (D.B.)
- Centro Sanitario, University of Calabria, 87036 Rende (CS), Italy
- Correspondence: (S.A.); (I.B.); Tel.: +39-0984-496201 (S.A.); +39-0984-496216 (I.B.); Fax: +39-0984-496203 (S.A. & I.B.)
| | - Ines Barone
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (S.C.); (S.P.); (G.A.); (C.G.); (R.M.); (L.G.); (S.M.); (F.G.); (D.B.)
- Correspondence: (S.A.); (I.B.); Tel.: +39-0984-496201 (S.A.); +39-0984-496216 (I.B.); Fax: +39-0984-496203 (S.A. & I.B.)
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Rani A, Dasgupta P, Murphy JJ. Prostate Cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:2119-2137. [DOI: 10.1016/j.ajpath.2019.07.007] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Revised: 07/02/2019] [Accepted: 07/25/2019] [Indexed: 02/06/2023]
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Javan MR, Khosrojerdi A, Moazzeni SM. New Insights Into Implementation of Mesenchymal Stem Cells in Cancer Therapy: Prospects for Anti-angiogenesis Treatment. Front Oncol 2019; 9:840. [PMID: 31555593 PMCID: PMC6722482 DOI: 10.3389/fonc.2019.00840] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 08/15/2019] [Indexed: 12/12/2022] Open
Abstract
Tumor microenvironment interacts with tumor cells, establishing an atmosphere to contribute or suppress the tumor development. Among the cells which play a role in the tumor microenvironment, mesenchymal stem cells (MSCs) have been demonstrated to possess the ability to orchestrate the fate of tumor cells, drawing the attention to the field. MSCs have been considered as cells with double-bladed effects, implicating either tumorigenic or anti-tumor activity. On the other side, the promising potential of MSCs in treating human cancer cells has been observed from the clinical studies. Among the beneficial characteristics of MSCs is the natural tumor-trophic migration ability, providing facility for drug delivery and, therefore, targeted treatment to detach tumor and metastatic cells. Moreover, these cells have been the target of engineering approaches, due to their easily implemented traits, in order to obtain the desired expression of anti-angiogenic, anti-proliferative, and pro-apoptotic properties, according to the tumor type. Tumor angiogenesis is the key characteristic of tumor progression and metastasis. Manipulation of angiogenesis has become an attractive approach for cancer therapy since the introduction of the first angiogenesis inhibitor, namely bevacizumab, for metastatic colorectal cancer therapy. This review tries to conclude the approaches, with focus on anti-angiogenesis approach, in implementing the MSCs to combat against tumor cell progression.
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Affiliation(s)
- Mohammad Reza Javan
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Arezou Khosrojerdi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Mohammad Moazzeni
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Najberg M, Haji Mansor M, Boury F, Alvarez-Lorenzo C, Garcion E. Reversing the Tumor Target: Establishment of a Tumor Trap. Front Pharmacol 2019; 10:887. [PMID: 31456685 PMCID: PMC6699082 DOI: 10.3389/fphar.2019.00887] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 07/15/2019] [Indexed: 12/19/2022] Open
Abstract
Despite the tremendous progress made in the field of cancer therapy in recent years, certain solid tumors still cannot be successfully treated. Alongside classical treatments in the form of chemotherapy and/or radiotherapy, targeted treatments such as immunotherapy that cause fewer side effects emerge as new options in the clinics. However, these alternative treatments may not be useful for treating all types of cancers, especially for killing infiltrative and circulating tumor cells (CTCs). Recent advances pursue the trapping of these cancer cells within a confined area to facilitate their removal for therapeutic and diagnostic purposes. A good understanding of the mechanisms behind tumor cell migration may drive the design of traps that mimic natural tumor niches and guide the movement of the cancer cells. To bring this trapping idea into reality, strong efforts are being made to create structured materials that imitate myelinated fibers, blood vessels, or pre-metastatic niches and incorporate chemical cues such as chemoattractants or adhesive proteins. In this review, the different strategies used (or could be used) to trap tumor cells are described, and relevant examples of their performance are analyzed.
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Affiliation(s)
- Mathie Najberg
- CRCINA, INSERM, Université de Nantes, Université d’Angers, Angers, France
- Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, R + D Pharma Group (GI-1645), Facultad de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - Muhammad Haji Mansor
- CRCINA, INSERM, Université de Nantes, Université d’Angers, Angers, France
- Center for Education and Research on Macromolecules (CERM), Université de Liège, Liège, Belgium
| | - Frank Boury
- CRCINA, INSERM, Université de Nantes, Université d’Angers, Angers, France
| | - Carmen Alvarez-Lorenzo
- Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, R + D Pharma Group (GI-1645), Facultad de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - Emmanuel Garcion
- CRCINA, INSERM, Université de Nantes, Université d’Angers, Angers, France
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Chinnappan M, Gunewardena S, Chalise P, Dhillon NK. Analysis of lncRNA-miRNA-mRNA Interactions in Hyper-proliferative Human Pulmonary Arterial Smooth Muscle Cells. Sci Rep 2019; 9:10533. [PMID: 31324852 PMCID: PMC6642142 DOI: 10.1038/s41598-019-46981-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 07/03/2019] [Indexed: 01/09/2023] Open
Abstract
We previously reported enhanced proliferation of smooth muscle cells on the combined exposure of HIV proteins and cocaine leading to the development of HIV-pulmonary arterial hypertension. Here, we attempt to comprehensively understand the interactions between long noncoding RNAs (lncRNAs), mRNAs and micro-RNAs (miRNAs) to determine their role in smooth muscle hyperplasia. Differential expression of lncRNAs, mRNAs and miRNAs were obtained by microarray and small-RNA sequencing from HPASMCs treated with and without cocaine and/or HIV-Tat. LncRNA to mRNA associations were conjectured by analyzing their genomic proximity and by interrogating their association to vascular diseases and cancer co-expression patterns reported in the relevant databases. Neuro-active ligand receptor signaling, Ras signaling and PI3-Akt pathway were among the top pathways enriched in either differentially expressed mRNAs or mRNAs associated to lncRNAs. HPASMC with combined exposure to cocaine and Tat (C + T) vs control identified the following top lncRNA-mRNA pairs, ENST00000495536-HOXB13, T216482-CBL, ENST00000602736-GDF7, and, TCONS_00020413-RND1. Many of the down-regulated miRNAs in the HPASMCs treated with C + T were found to be anti-proliferative and targets of up-regulated lncRNAs targeting up-regulated mRNAs, including down-regulation of miR-185, -491 and up-regulation of corresponding ENST00000585387. Specific knock down of the selected lncRNAs highlighted the importance of non-coding RNAs in smooth muscle hyperplasia.
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MESH Headings
- Cocaine/pharmacology
- Gene Expression Regulation
- Gene Knockdown Techniques
- Gene Ontology
- HIV Infections/complications
- Humans
- Hyperplasia
- Hypertension, Pulmonary/etiology
- MicroRNAs/biosynthesis
- MicroRNAs/genetics
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- Pulmonary Artery/metabolism
- Pulmonary Artery/pathology
- RNA, Long Noncoding/biosynthesis
- RNA, Long Noncoding/genetics
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- Tissue Array Analysis
- tat Gene Products, Human Immunodeficiency Virus/pharmacology
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Affiliation(s)
- Mahendran Chinnappan
- Division of Pulmonary and Critical Care Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Sumedha Gunewardena
- Department of Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA
- Kansas Intellectual and Developmental Disabilities Research Center, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Prabhakar Chalise
- Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Navneet K Dhillon
- Division of Pulmonary and Critical Care Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.
- Department of Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA.
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Mesenchymal Stem Cells as Regulators of Carcinogenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1144:147-166. [DOI: 10.1007/5584_2018_311] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Guarrera S, Viberti C, Cugliari G, Allione A, Casalone E, Betti M, Ferrante D, Aspesi A, Casadio C, Grosso F, Libener R, Piccolini E, Mirabelli D, Dianzani I, Magnani C, Matullo G. Peripheral Blood DNA Methylation as Potential Biomarker of Malignant Pleural Mesothelioma in Asbestos-Exposed Subjects. J Thorac Oncol 2018; 14:527-539. [PMID: 30408567 DOI: 10.1016/j.jtho.2018.10.163] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 10/02/2018] [Accepted: 10/27/2018] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Malignant pleural mesothelioma (MPM) is an aggressive tumor strongly associated with asbestos exposure. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for noninvasive early diagnostic tests to monitor asbestos-exposed people. METHODS We used a genome-wide methylation array to identify, in asbestos-exposed subjects, novel blood DNA methylation markers of MPM in 163 MPM cases and 137 cancer-free controls (82 MPM cases and 68 controls, training set; replication in 81 MPM cases and 69 controls, test set) sampled from the same areas. RESULTS Evidence of differential methylation between MPM cases and controls was found (more than 800 cytosine-guanine dinucleotide sites, false discovery rate p value (pfdr) < 0.05), mainly in immune system-related genes. Considering the top differentially methylated signals, seven single- cytosine-guanine dinucleotides and five genomic regions of coordinated methylation replicated with similar effect size in the test set (pfdr < 0.05). The top hypomethylated single-CpG (cases versus controls effect size less than -0.15, pfdr < 0.05 in both the training and test sets) was detected in FOXK1 (Forkhead-box K1) gene, an interactor of BAP1 which was found mutated in MPM tissue and as germline mutation in familial MPM. In the test set, comparison of receiver operating characteristic curves and the area under the curve (AUC) of two models, including or excluding methylation, showed a significant increase in case/control discrimination when considering DNA methylation together with asbestos exposure (AUC = 0.81 versus AUC = 0.89, DeLong's test p = 0.0013). CONCLUSIONS We identified signatures of differential methylation in DNA from whole blood between asbestos exposed MPM cases and controls. Our results provide the rationale to further investigate, in prospective studies, the potential use of blood DNA methylation profiles for the identification of early changes related to the MPM carcinogenic process.
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Affiliation(s)
- Simonetta Guarrera
- Italian Institute for Genomic Medicine, IIGM, Turin, Italy; Department of Medical Sciences, University of Turin, Turin, Italy
| | - Clara Viberti
- Italian Institute for Genomic Medicine, IIGM, Turin, Italy; Department of Medical Sciences, University of Turin, Turin, Italy
| | - Giovanni Cugliari
- Italian Institute for Genomic Medicine, IIGM, Turin, Italy; Department of Medical Sciences, University of Turin, Turin, Italy
| | - Alessandra Allione
- Italian Institute for Genomic Medicine, IIGM, Turin, Italy; Department of Medical Sciences, University of Turin, Turin, Italy
| | - Elisabetta Casalone
- Italian Institute for Genomic Medicine, IIGM, Turin, Italy; Department of Medical Sciences, University of Turin, Turin, Italy
| | - Marta Betti
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | - Daniela Ferrante
- Medical Statistics and Cancer Epidemiology Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy; Cancer Epidemiology Unit, CPO-Piemonte, Novara, Italy
| | - Anna Aspesi
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | | | - Federica Grosso
- Division of Medical Oncology, SS. Antonio e Biagio General Hospital, Alessandria, Italy
| | - Roberta Libener
- Pathology Unit, SS. Antonio e Biagio General Hospital, Alessandria, Italy
| | - Ezio Piccolini
- Pneumology Unit, Santo Spirito Hospital, Casale Monferrato (AL), Italy
| | - Dario Mirabelli
- Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, Turin, Italy; Cancer Epidemiology Unit, CPO Piemonte, Turin, Italy; Interdepartmental Center for Studies on Asbestos and Other Toxic Particulates "G. Scansetti," University of Turin, Turin, Italy
| | - Irma Dianzani
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy; Interdepartmental Center for Studies on Asbestos and Other Toxic Particulates "G. Scansetti," University of Turin, Turin, Italy
| | - Corrado Magnani
- Medical Statistics and Cancer Epidemiology Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy; Cancer Epidemiology Unit, CPO-Piemonte, Novara, Italy; Interdepartmental Center for Studies on Asbestos and Other Toxic Particulates "G. Scansetti," University of Turin, Turin, Italy
| | - Giuseppe Matullo
- Italian Institute for Genomic Medicine, IIGM, Turin, Italy; Department of Medical Sciences, University of Turin, Turin, Italy; Interdepartmental Center for Studies on Asbestos and Other Toxic Particulates "G. Scansetti," University of Turin, Turin, Italy; Medical Genetics Unit, AOU Città della Salute e della Scienza, Turin, Italy.
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Jiang L, Yang M, Li X, Wang Y, Zhou G, Zhao J. CXC Motif Ligand 16 Promotes Nonalcoholic Fatty Liver Disease Progression via Hepatocyte-Stellate Cell Crosstalk. J Clin Endocrinol Metab 2018; 103:3974-3985. [PMID: 30053055 DOI: 10.1210/jc.2018-00762] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Accepted: 07/13/2018] [Indexed: 12/25/2022]
Abstract
CONTEXT Nonalcoholic fatty liver disease (NAFLD) is a focus of attention because of its prevalence. CXC motif ligand 16 (CXCL16) has been studied in inflammatory and metabolic diseases. OBJECTIVE To investigate the role of CXCL16 in steatosis and fibrosis in patients with NAFLD. DESIGN Liver specimens and sera of patients with NAFLD were collected from 2012 to 2017. SETTING Beijing 302 Hospital. PARTICIPANTS 117 patients with NAFLD and 15 healthy controls. INTERVENTIONS None. MAIN OUTCOME MEASURES The main outcome measures were CXCL16 levels in sera and biopsy specimens of patients with NAFLD. RESULTS CXCL16 serum level was markedly elevated in patients with NAFLD, especially in those at the S3 steatosis level according to the steatosis, activity, and fibrosis (SAF) scoring system. The different serum levels of CXCL16 between groups were due to data in patients with A or F scores ≥2, according to the SAF scoring system. CXCL16 accumulated around steatotic hepatocytes in biopsy specimens. In vitro, CXCL16 treatment led to severe steatosis of hepatocytes in the hepatocyte-stellate cell coculture system and suppressed the respiration rate of hepatocytes. Lipogenic gene expression and hepatic stellate cell activation indexes were increased in a CXCL16 overexpression system. In addition, ligands in the Hedgehog pathway cascade were downregulated in hepatocytes. CONCLUSIONS CXCL16 was highly expressed in patients with NAFLD, suggesting that it may contribute to steatotic and fibrotic progression. CXCL16 may be a potential noninvasive marker of NAFLD and a future potential therapeutic target to treat NAFLD.
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Affiliation(s)
- Lina Jiang
- Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China
| | - Mei Yang
- Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China
| | - Xi Li
- Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China
| | - Yijin Wang
- Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China
| | - Guangde Zhou
- Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China
| | - Jingmin Zhao
- Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China
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Guerrero S, López-Cortés A, Indacochea A, García-Cárdenas JM, Zambrano AK, Cabrera-Andrade A, Guevara-Ramírez P, González DA, Leone PE, Paz-Y-Miño C. Analysis of Racial/Ethnic Representation in Select Basic and Applied Cancer Research Studies. Sci Rep 2018; 8:13978. [PMID: 30228363 PMCID: PMC6143551 DOI: 10.1038/s41598-018-32264-x] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 07/26/2018] [Indexed: 12/15/2022] Open
Abstract
Over the past decades, consistent studies have shown that race/ethnicity have a great impact on cancer incidence, survival, drug response, molecular pathways and epigenetics. Despite the influence of race/ethnicity in cancer outcomes and its impact in health care quality, a comprehensive understanding of racial/ethnic inclusion in oncological research has never been addressed. We therefore explored the racial/ethnic composition of samples/individuals included in fundamental (patient-derived oncological models, biobanks and genomics) and applied cancer research studies (clinical trials). Regarding patient-derived oncological models (n = 794), 48.3% have no records on their donor's race/ethnicity, the rest were isolated from White (37.5%), Asian (10%), African American (3.8%) and Hispanic (0.4%) donors. Biobanks (n = 8,293) hold specimens from unknown (24.56%), White (59.03%), African American (11.05%), Asian (4.12%) and other individuals (1.24%). Genomic projects (n = 6,765,447) include samples from unknown (0.6%), White (91.1%), Asian (5.6%), African American (1.7%), Hispanic (0.5%) and other populations (0.5%). Concerning clinical trials (n = 89,212), no racial/ethnic registries were found in 66.95% of participants, and records were mainly obtained from Whites (25.94%), Asians (4.97%), African Americans (1.08%), Hispanics (0.16%) and other minorities (0.9%). Thus, two tendencies were observed across oncological studies: lack of racial/ethnic information and overrepresentation of Caucasian/White samples/individuals. These results clearly indicate a need to diversify oncological studies to other populations along with novel strategies to enhanced race/ethnicity data recording and reporting.
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Affiliation(s)
- Santiago Guerrero
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Av. Mariscal Sucre and Mariana de Jesús, Block I, 2nd floor, 170129, Quito, Ecuador.
| | - Andrés López-Cortés
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Av. Mariscal Sucre and Mariana de Jesús, Block I, 2nd floor, 170129, Quito, Ecuador
| | - Alberto Indacochea
- Gene Regulation, Stem Cells and Cancer Programme, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Oncology and Molecular Pathology Research Group-VHIR- Vall d' Hebron Institut de Recerca-Vall d' Hebron Hospital, P/de la Vall d'Hebron, Barcelona, Spain
| | - Jennyfer M García-Cárdenas
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Av. Mariscal Sucre and Mariana de Jesús, Block I, 2nd floor, 170129, Quito, Ecuador
| | - Ana Karina Zambrano
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Av. Mariscal Sucre and Mariana de Jesús, Block I, 2nd floor, 170129, Quito, Ecuador
| | - Alejandro Cabrera-Andrade
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Av. Mariscal Sucre and Mariana de Jesús, Block I, 2nd floor, 170129, Quito, Ecuador
- Carrera de Enfermería, Facultad de Ciencias de la Salud, Universidad de las Américas, Avenue de los Granados, Quito, 170125, Ecuador
- Grupo de Bio-Quimioinformática, Universidad de las Américas, Avenue de los Granados, Quito, 170125, Ecuador
| | - Patricia Guevara-Ramírez
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Av. Mariscal Sucre and Mariana de Jesús, Block I, 2nd floor, 170129, Quito, Ecuador
| | - Diana Abigail González
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Av. Mariscal Sucre and Mariana de Jesús, Block I, 2nd floor, 170129, Quito, Ecuador
| | - Paola E Leone
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Av. Mariscal Sucre and Mariana de Jesús, Block I, 2nd floor, 170129, Quito, Ecuador
| | - César Paz-Y-Miño
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Av. Mariscal Sucre and Mariana de Jesús, Block I, 2nd floor, 170129, Quito, Ecuador.
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Wang X, Shang W, Chang Y, Li X. Methylation Signature Genes Identification of the Lung Squamous Cell Carcinoma Occurrence and Recognition Research. J Comput Biol 2018; 25:1161-1169. [PMID: 30059254 DOI: 10.1089/cmb.2018.0069] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
DNA methylation (DNAm) is one of the most important epigenetic event effecting gene expression, and aberrant DNAm has been implicated in the initiation and progression of human cancers. To identify methylation (ME) signature genes for the pathogenesis of lung squamous cell carcinoma (LUSC), the pattern recognition method was used to analyze the genome-wide gene ME data, which were collected from the LUSC normal and cancer stage I samples in The Cancer Genome Atlas project database. A total of 102 ME signature genes were identified by means of a combination of statistical methods such as correlation, analysis of variance, and Elastic Net. The accuracy and specificity are all above 99%, sensitivity is 100%, and Matthews correlation coefficient is higher than 0.99 through the machine learning method modeling, which are higher than the previous study. The Kyoto Encyclopedia of Genes and Genomes pathway analysis and Gene Ontology enrichment analysis indicated the highly related relationship among these genes. They also indicated the immediate relationship between our signature genes and the occurrence of LUSC, which is very important to the understanding of its mechanism and to the development of new targeted therapy.
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Affiliation(s)
- Xuedong Wang
- College of Life Science and Bioengineering, Beijing University of Technology , Beijing, China
| | - Wenhui Shang
- College of Life Science and Bioengineering, Beijing University of Technology , Beijing, China
| | - Yu Chang
- College of Life Science and Bioengineering, Beijing University of Technology , Beijing, China
| | - Xiaoqin Li
- College of Life Science and Bioengineering, Beijing University of Technology , Beijing, China
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Hong L, Wang S, Li W, Wu D, Chen W. Tumor-associated macrophages promote the metastasis of ovarian carcinoma cells by enhancing CXCL16/CXCR6 expression. Pathol Res Pract 2018; 214:1345-1351. [PMID: 30049511 DOI: 10.1016/j.prp.2018.07.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 06/25/2018] [Accepted: 07/08/2018] [Indexed: 12/31/2022]
Abstract
This study investigated the underlying mechanism by which C-X-C motif chemokine ligand 16 (CXCL16)/C-X-C motif chemokine receptor 6 (CXCR6) signaling is activated by tumor-associated macrophages and assists in regulating the metastasis of ovarian carcinoma. Specimens of ovarian carcinoma tissue and adjacent tissue were collected from 20 ovarian carcinoma patients. Human THP-1 cells were induced to differentiate into macrophages, which were then co-cultured with SKOV3 cells and low concentrations of tumor necrosis factor-α (TNF-α) to simulate the inflammatory microenvironment of ovarian carcinoma. Additionally, small interfering RNA (siRNA) targeting CXCR6 was transfected into SKOV3 cells; after which, the levels of nuclear factor kappa B p65 (NF-κB p65) protein and phosphorylated PI3K and Akt were measured. The migration and invasion abilities of the SKOV3 cells were also tested. The levels of TNF-α, interluekin-6 (IL-6), NF-κB p65, CXCL16, and CXCR6 expression in the ovarian carcinoma tissues were higher than those in the precancerous tissues. CXCR6 expression was positively correlated with TNF-α, IL-6, and CXCL16 expression. Co-culture of SKOV3 cells with macrophages significantly promoted CXCL16, CXCR6, NF-κB, and p65 expression by the SKOV3 cells, increased their levels of phosphorylated PI3K and Akt, and increased the migration and invasion abilities of SKOV3 cells. Silencing of CXCR6 or blocking the PI3K/Akt signal pathway markedly attenuated the expression of NF-κB p65 and phosphorylation of PI3K and Akt, as well as the migration and invasion abilities of SKOV3 cells. These findings demonstrate that macrophages can promote the migration and invasion of ovarian carcinoma cells by affecting the CXCL16/CXCR6 pathway.
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Affiliation(s)
- Lan Hong
- Department of Gynecology, Hainan General Hospital, Haikou, 570311, Hainan Province, China; Southern Medical University, Guangzhou, 510515, Guangdong Province, China
| | - Shengtan Wang
- Department of Gynecology, Hainan General Hospital, Haikou, 570311, Hainan Province, China
| | - Wei Li
- Department of Gynecology, Hainan General Hospital, Haikou, 570311, Hainan Province, China
| | - Dongcai Wu
- Department of Obstetrics, Hainan General Hospital, Haikou, 570311, Hainan Province, China
| | - Wangsheng Chen
- Department of Radiology, Hainan General Hospital, Haikou, 570311, Hainan Province, China.
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Ma AJ, Zhu XY, Yang SN, Pan XD, Wang T, Wang Y, Xiao X, Liu SH. Associations of CXCL16, miR‑146a and miR‑146b in atherosclerotic apolipoprotein E‑knockout mice. Mol Med Rep 2018; 18:2995-3002. [PMID: 30015963 DOI: 10.3892/mmr.2018.9270] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 06/14/2018] [Indexed: 11/06/2022] Open
Abstract
Atherosclerosis is the primary cause of cardiovascular and cerebrovascular diseases. Recent studies have revealed that C‑X‑C motif chemokine ligand 16 (CXCL16), microRNA (miR)‑146a and miR‑146b may have important roles in atherosclerotic diseases. However, the associations of CXCL16, miR‑146a and miR‑146b in atherosclerotic diseases in vivo remain unclear. Previous studies have demonstrated that miR‑146a and miR‑146b may negatively regulate the toll like receptor (TLR4)/nuclear factor (NF)‑κB signaling pathway to repress the inflammatory response. The present study investigated the associations of CXCL16, miR‑146a and miR‑146b in atherosclerotic apolipoprotein E (ApoE)‑/‑ mice in vivo. The expression levels of CXCL16, TLR4/NF‑κB signaling pathway, miR‑146a and miR‑146b in the control and atherosclerotic ApoE‑/‑ mice were investigated via reverse transcription‑quantitative polymerase chain reaction and western blot analysis. The present study demonstrated that the expression of CXCL16 was significantly upregulated in atherosclerotic ApoE‑/‑ mice compared with control ApoE‑/‑ mice. The expression levels of TRL4, interleukin‑1 receptor‑associated kinase 1, tumor necrosis factor receptor associated factor 6, NF‑κB, tumor necrosis factor‑α and interleukin‑1β were also significantly upregulated in atherosclerotic ApoE‑/‑ mice compared with control mice. However, the present study revealed that the expression levels of miR‑146a and miR‑146b were significantly downregulated in atherosclerotic ApoE‑/‑ mice compared with control ApoE‑/‑ mice. Overall, the results of the present study suggested that CXCL16 may regulate the TRL4/NF‑κB/CXCL16 signaling pathway, and that miR‑146a and miR‑146b may negatively regulate CXCL16 via this pathway in atherosclerosis in vivo.
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Affiliation(s)
- Ai-Jun Ma
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266033, P.R. China
| | - Xiao-Yan Zhu
- Department of Critical Care Medicine, The Affiliated Hiser Hospital of Qingdao University, Qingdao, Shandong 266033, P.R. China
| | - Shao-Nan Yang
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266033, P.R. China
| | - Xu-Dong Pan
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266033, P.R. China
| | - Ting Wang
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266033, P.R. China
| | - Yuan Wang
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266033, P.R. China
| | - Xing Xiao
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266033, P.R. China
| | - Shi-Hai Liu
- Medical Animal Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266033, P.R. China
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Liang K, Liu Y, Eer D, Liu J, Yang F, Hu K. High CXC Chemokine Ligand 16 (CXCL16) Expression Promotes Proliferation and Metastasis of Lung Cancer via Regulating the NF-κB Pathway. Med Sci Monit 2018; 24:405-411. [PMID: 29353287 PMCID: PMC5788242 DOI: 10.12659/msm.906230] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND CXC chemokine ligand 16 (CXCL16) is a soluble chemokine with a transmembrane domain, playing an important role in inflammatory regulation. NF-κB has a critical role in tumor progression. Recent studies focused on the effect of CXCL16 on tumor progression. However, few reports showed the influence of CXCL16 on lung cancer, especially in regulating NF-κB activity. Here we investigated CXCL16 expression and its clinical significance in lung cancer, as well as the effect on lung cancer cell biological characteristics by regulating NF-κB. MATERIAL AND METHODS CXCL16 expression in lung cancer was detected and its associations with clinical characteristics were analyzed. Proliferation and invasion of A549 and PC-9 cells was measured before and after silencing CXCL16 or inhibiting the NF-κB pathway, separately. RESULTS The positive rate of CXCL16 in lung cancer tissue was significantly higher than that in adjacent tissue, and that in patients with lymphatic metastasis was significantly higher than that in patients without (all, P<0.05). The positive rate of CXCL16 was significantly (P<0.05) positively corrected with poor prognosis of lung cancer. Silencing CXCL16 not only suppressed proliferation and invasion of A549 and PC-9 cells, but also significantly (P<0.05) inhibited c-Rel, p105, and Rel-B in the NF-κB pathway. Inhibiting NF-κB also suppressed proliferation and invasion of A549 and PC-9 cells, which was similar to the results after silencing CXCL16. CONCLUSIONS Enhanced CXCL16 expression in lung cancer tissue promoted the proliferation and invasion of lung cancer cells. CXCL16 might promote proliferation and invasion of lung cancer by regulating the NF-κB pathway.
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Affiliation(s)
- Kun Liang
- Department of Respiratory Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (mainland)
| | - Yanru Liu
- Department of Respiratory Medicine, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia, China (mainland)
| | - Dun Eer
- Department of Respiratory Medicine, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia, China (mainland)
| | - Jingbin Liu
- Department of Respiratory, Hospital of FIRMACO (The Fourth Affiliated Hospital of Inner Mongolia Medical University), Baotou, Inner Mongolia, China (mainland)
| | - Fan Yang
- Department of Respiratory, Hospital of FIRMACO (The Fourth Affiliated Hospital of Inner Mongolia Medical University), Baotou, Inner Mongolia, China (mainland)
| | - Ke Hu
- Department of Respiratory Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (mainland)
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Chang Y, Zhou L, Xu L, Fu Q, Yang Y, Lin Z, Xu J. High expression of CXC chemokine receptor 6 associates with poor prognosis in patients with clear cell renal cell carcinoma. Urol Oncol 2017; 35:675.e17-675.e24. [PMID: 28918166 DOI: 10.1016/j.urolonc.2017.08.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 08/19/2017] [Accepted: 08/21/2017] [Indexed: 12/22/2022]
Abstract
PURPOSE Accumulating evidence indicates that CXC chemokine receptor 6 (CXCR6) has a crucial role in cancer development and progression, however, its role in clear cell renal cell carcinoma (ccRCC) remains obscure. The aim of this study is to investigate the prognostic value of CXCR6 expression in patients with ccRCC following surgery. MATERIALS AND METHODS This study retrospectively included 239 patients with ccRCC who underwent nephrectomy and had paraffin tissue available at a single center. CXCR6 expression in tumor tissue was evaluated by immunohistochemistry and its associations with overall survival (OS) and recurrence-free survival (RFS) were investigated. RESULTS A total of 47.3% tumors were considered as high expression of CXCR6, which was significantly associated with the male sex (P = 0.003) and high Fuhrman grade (P<0.001). A high expression of CXCR6 indicated a reduced OS (P<0.001) and RFS (P = 0.007). Multivariate analysis demonstrated that CXCR6 expression was an independent prognostic factor of OS (hazard ratio = 2.604; 95% CI: 1.338-5.068; P = 0.005) and RFS (hazard ratio = 1.957; 95% CI: 1.065-3.595; P = 0.031). Subgroup analysis found that CXCR6 expression could differentiate survival risks among patients with high-risk disease. Moreover, a nomogram integrating CXCR6 expression and traditional clinical and pathologic features was established and predicted postsurgical recurrence-risk well at 3- and 5-year. CONCLUSIONS The expression of CXCR6 in tumor tissue may serve as a potential prognostic biomarker to refine clinical prognosis prediction combined with traditional clinical and pathological analysis for patients with ccRCC after surgery.
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Affiliation(s)
- Yuan Chang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lin Zhou
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Le Xu
- Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Qiang Fu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yuanfeng Yang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zongming Lin
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Jiejie Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
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Hao Y, Li Y, Li H, Lyu M, Zhang D, Fu R, Guan Y, Wang S, Sun B, Dou X, Zhang L, Yang R. Increased plasma sCXCL16 levels may have a relationship with Th1/Th2 imbalance in primary immune thrombocytopenia. Cytokine 2017; 99:124-131. [PMID: 28886489 DOI: 10.1016/j.cyto.2017.08.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 08/26/2017] [Accepted: 08/30/2017] [Indexed: 02/08/2023]
Abstract
Primary immune thrombocytopenia (ITP) is a disease of autoimmunity in which there are Th1/Th2 imbalance and disordered cytokine profiles. CXC chemokine ligand 16 (CXCL16) was proved to implicate in some autoimmune diseases. Our research aimed to determine plasma soluble CXCL16 (sCXCL16) levels and its effects in ITP. We used ELISA to measure plasma sCXCL16, IFN-γ and IL-4 and flow cytometry to determine expression of CXCR6 on lymphocyte subsets. We used real-time PCR to detect the CXCL16 and CXCR6 mRNA expression. Additionally, plasma sCXCL16, CXCL16 and CXCR6 mRNA levels of 8 patients were monitored before and after treatment. We found that patients with active ITP had higher circulating sCXCL16 in plasma than healthy controls and patients in remission. Meanwhile, negative relationships between sCXCL16 and platelet count, IL-4 and positive relationships between sCXCL16 and IFN-γ, IFN-γ/IL-4 ratio were observed. Besides, expression of CXCR6 on lymphocyte subsets and mRNA levels of CXCL16 and CXCR6 were all increased in active ITP. Additionally, plasma sCXCL16 and IFN-γ levels and CXCR6 mRNA expression were down-regulated after effective treatment compared with those before treatment. Thus, increased plasma sCXCL16 might be implicated in the pathogenesis of ITP and have a relationship with Th1/Th2 imbalance.
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Affiliation(s)
- Yating Hao
- State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, PR China
| | - Yang Li
- State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, PR China
| | - Huiyuan Li
- State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, PR China
| | - Mingen Lyu
- State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, PR China
| | - Donglei Zhang
- State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, PR China
| | - Rongfeng Fu
- State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, PR China
| | - Yue Guan
- State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, PR China
| | - Shixuan Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, PR China
| | - Boyang Sun
- State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, PR China
| | - Xueqing Dou
- State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, PR China
| | - Lei Zhang
- State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, PR China
| | - Renchi Yang
- State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, PR China.
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Ke C, Ren Y, Lv L, Hu W, Zhou W. Association between CXCL16/CXCR6 expression and the clinicopathological features of patients with non-small cell lung cancer. Oncol Lett 2017; 13:4661-4668. [PMID: 28599467 PMCID: PMC5452963 DOI: 10.3892/ol.2017.6088] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 02/13/2017] [Indexed: 01/02/2023] Open
Abstract
Lung cancer is a major cause of morbidity and mortality worldwide, therefore identifying biomarkers for the early detection, grading or postoperative follow-up of lung cancer is of clinical significance. In the present study, expression of lung tissue (t)-CXCL16 and t-CXCR6 was examined in 58 patients with non-small cell lung cancer (NSCLC) using immunohistochemical staining, and serum (s)-CXCL16 levels were detected in 58 patients with NSCLC and in 32 normal volunteers using an ELISA. A follow-up was performed every 4 months between January 2014 and January 2015. Compared with the normal volunteers, the s-CXCL16 concentration in patients with NSCLC significantly increased (329.47±135.38 vs. 572.82±116.05 pg/ml, respectively; P<0.001). When grouped according to TNM stage, the expression of t-CXCL16 (60 vs. 85.71%; P=0.029), t-CXCR6 (53.33 vs. 78.57%; P=0.043) and s-CXCL16 (26.67 vs. 57.14%, P=0.019) in the stage I-II subgroup was significantly lower compared with that of the stage III-IV subgroup. The positive expression rate of t-CXCL16 (91.18%) and t-CXCR6 (79.41%) in the lymph node metastasis subgroup was significantly higher compared with that of the corresponding non-lymph node metastasis subgroup (50 and 45.83%, respectively; P<0.01). Additionally, the positive expression rate of t-CXCL16 in the smoking subgroup was 100%, which was significantly higher compared with that of the non-smoking subgroup (23.81%) (P<0.001). The follow-up and mortality rates were 100% (58/58) and 13.79% (8/58), respectively. Within the time period of the present study, the survival time was 4-18 months, and the mean survival time was 16.6 months. In conclusion, the expression of t-CXCL16 and t-CXCR6 is positively correlated with the TNM stage and lymph node metastasis in patients with NSCLC. Additionally, there was a significant increase in s-CXCL16 levels in patients with NSCLC, suggesting that CXCL16 could be used as a supplementary biomarker for the early detection of NSCLC.
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Affiliation(s)
- Chuangwu Ke
- Department of Thoracic Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Yanchen Ren
- Department of Thoracic Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Lu Lv
- Department of Thoracic Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Weidong Hu
- Department of Thoracic Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.,Hubei Cancer Clinical Study Center and Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Wenhui Zhou
- Medical Center for Human Reproduction, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China
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Milioli HH, Tishchenko I, Riveros C, Berretta R, Moscato P. Basal-like breast cancer: molecular profiles, clinical features and survival outcomes. BMC Med Genomics 2017; 10:19. [PMID: 28351365 PMCID: PMC5370447 DOI: 10.1186/s12920-017-0250-9] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 03/03/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Basal-like constitutes an important molecular subtype of breast cancer characterised by an aggressive behaviour and a limited therapy response. The outcome of patients within this subtype is, however, divergent. Some individuals show an increased risk of dying in the first five years, and others a long-term survival of over ten years after the diagnosis. In this study, we aim at identifying markers associated with basal-like patients' survival and characterising subgroups with distinct disease outcome. METHODS We explored the genomic and transcriptomic profiles of 351 basal-like samples from the METABRIC and ROCK data sets. Two selection methods, labelled Differential and Survival filters, were employed to determine genes/probes that are differentially expressed in tumour and control samples, and are associated with overall survival. These probes were further used to define molecular subgroups, which vary at the microRNA level and in DNA copy number. RESULTS We identified the expression signature of 80 probes that distinguishes between two basal-like subgroups with distinct clinical features and survival outcomes. Genes included in this list have been mainly linked to cancer immune response, epithelial-mesenchymal transition and cell cycle. In particular, high levels of CXCR6, HCST, C3AR1 and FPR3 were found in Basal I; whereas HJURP, RRP12 and DNMT3B appeared over-expressed in Basal II. These genes exhibited the highest betweenness centrality and node degree values and play a key role in the basal-like breast cancer differentiation. Further molecular analysis revealed 17 miRNAs correlated to the subgroups, including hsa-miR-342-5p, -150, -155, -200c and -17. Additionally, increased percentages of gains/amplifications were detected on chromosomes 1q, 3q, 8q, 10p and 17q, and losses/deletions on 4q, 5q, 8p and X, associated with reduced survival. CONCLUSIONS The proposed signature supports the existence of at least two subgroups of basal-like breast cancers with distinct disease outcome. The identification of patients at a low risk may impact the clinical decisions-making by reducing the prescription of high-dose chemotherapy and, consequently, avoiding adverse effects. The recognition of other aggressive features within this subtype may be also critical for improving individual care and for delineating more effective therapies for patients at high risk.
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Affiliation(s)
- Heloisa H. Milioli
- Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, Lot 1, Kookaburra Circuit, New Lambton Heights, 2305 Australia
- School of Environmental and Life Sciences, The University of Newcastle, University Drive, Callaghan, 2308 Australia
| | - Inna Tishchenko
- Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, Lot 1, Kookaburra Circuit, New Lambton Heights, 2305 Australia
- School of Electrical Engineering and Computer Science, The University of Newcastle, University Drive, Callaghan, 2308 Australia
| | - Carlos Riveros
- CReDITSS Unit, Hunter Medical Research Institute, Lot 1, Kookaburra Circuit, New Lambton Heights, 2305 Australia
| | - Regina Berretta
- Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, Lot 1, Kookaburra Circuit, New Lambton Heights, 2305 Australia
- School of Electrical Engineering and Computer Science, The University of Newcastle, University Drive, Callaghan, 2308 Australia
| | - Pablo Moscato
- Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, Lot 1, Kookaburra Circuit, New Lambton Heights, 2305 Australia
- School of Electrical Engineering and Computer Science, The University of Newcastle, University Drive, Callaghan, 2308 Australia
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