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1
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Iwanaga R, Yamamoto TM, Gomez K, Nguyen LL, Woodruff ER, Post MD, Mikeska RG, Danis E, Danhorn T, Boorgula MP, Mitra SS, Marjon NA, Bitler BG, Brubaker LW. Tumor-Intrinsic Activity of Chromobox 2 Remodels the Tumor Microenvironment in High-grade Serous Carcinoma. CANCER RESEARCH COMMUNICATIONS 2024; 4:1919-1932. [PMID: 38984891 PMCID: PMC11298703 DOI: 10.1158/2767-9764.crc-24-0027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 05/29/2024] [Accepted: 07/02/2024] [Indexed: 07/11/2024]
Abstract
Chromobox 2 (CBX2), an epigenetic reader and component of polycomb repressor complex 1, is highly expressed in >75% of high-grade serous carcinoma. Increased CBX2 expression is associated with poorer survival, whereas CBX2 knockdown leads to improved chemotherapy sensitivity. In a high-grade serous carcinoma immune-competent murine model, knockdown of CBX2 decreased tumor progression. We sought to explore the impact of modulation of CBX2 on the tumor immune microenvironment (TIME), understanding that the TIME plays a critical role in disease progression and development of therapy resistance. Exploration of existing datasets demonstrated that elevated CBX2 expression significantly correlated with specific immune cell types in the TIME. RNA sequencing and pathway analysis of differentially expressed genes demonstrated immune signature enrichment. Confocal microscopy and co-culture experiments found that modulation of CBX2 leads to increased recruitment and infiltration of macrophages. Flow cytometry of macrophages cultured with CBX2-overexpressing cells showed increased M2-like macrophages and decreased phagocytosis activity. Cbx2 knockdown in the Trp53-null, Brca2-null ID8 syngeneic murine model (ID8 Trp53-/-Brca2-/-) led to decreased tumor progression compared with the control. NanoString immuno-oncology panel analysis suggested that knockdown in Cbx2 shifts immune cell composition, with an increase in macrophages. Multispectral immunohistochemistry (mIHC) further confirmed an increase in macrophage infiltration. Increased CBX2 expression leads to recruitment and polarization of protumor macrophages, and targeting CBX2 may serve to modulate the TIME to enhance the efficacy of immune therapies. SIGNIFICANCE CBX2 expression correlates with the TIME. CBX2 modulation shifts the macrophage population, potentially leading to an immunosuppressive microenvironment, highlighting CBX2 as a target to improve efficacy of immunotherapy.
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Affiliation(s)
- Ritsuko Iwanaga
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
| | - Tomomi M. Yamamoto
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
| | - Karina Gomez
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
| | - Lily L. Nguyen
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
| | - Elizabeth R. Woodruff
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
| | - Miriam D. Post
- Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
| | - Railey G. Mikeska
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
| | - Etienne Danis
- University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
- Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
| | - Thomas Danhorn
- University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
- Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
| | - Meher P. Boorgula
- University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
- Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
| | - Siddhartha S. Mitra
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado.
| | - Nicole A. Marjon
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
| | - Benjamin G. Bitler
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
| | - Lindsay W. Brubaker
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
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2
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Dombroski JA, Fabiano AR, Knoblauch SV, Rowland SJ, Gibson-Corley KN, King MR. Tumor nano-lysate activates dendritic cells to evoke a preventative immune response. J Immunol Methods 2024; 524:113601. [PMID: 38092224 PMCID: PMC11163877 DOI: 10.1016/j.jim.2023.113601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 12/05/2023] [Accepted: 12/09/2023] [Indexed: 12/18/2023]
Abstract
A tumor nano-lysate "TNL" vaccine comprised of sonicated 4T1 cells was developed, characterized and implemented for the prevention of triple-negative breast cancer. This study aimed to gain a better understanding of the immune response behind the success of the vaccine in vivo, through use of ex vivo and in vivo assays. Here, we analyze the activation of various immune cells isolated from healthy mouse spleens and find that antigen-presenting cells (APCs) such as dendritic cells (DCs) are being activated following 24 h incubation with 1:10 mg TNL/mg splenocytes. These cells were further explored to determine the pathway by which activation is occurring, and it was observed that TNL are phagocytosed by DCs to activate NF-kB and c-Fos pathways, resulting in enhanced cytokine release after 24 h. An in vivo temporal analysis was performed in mice to understand the immune response at 1, 3, 7 and 10 days after one 100 μL dose of TNL consisting of 105 sonicated 4T1 cells via cardiac puncture and splenocyte and peripheral blood mononuclear cell (PBMC) analysis. Changes were observed for up to one week. A multiple dose study was performed comparing mice that were vaccinated with one dose of TNL administered every ten days for 3 doses total, as well as a PBS vehicle control. Survival for TNL-vaccinated mice was enhanced compared to the PBS control, and there was an average delay of 10 days in the onset of metastasis. The differences between the groups at the end of the study demonstrate the potential for TNL as a preventative therapeutic.
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Affiliation(s)
- Jenna A Dombroski
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, United States
| | - Abigail R Fabiano
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, United States
| | - Samantha V Knoblauch
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, United States
| | - Schyler J Rowland
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, United States
| | - Katherine N Gibson-Corley
- Department of Pathology, Microbiology and Immunology, Division of Comparative Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Michael R King
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, United States.
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3
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Volpini X, Natali L, Brugo MB, de la Cruz-Thea B, Baigorri RE, Cerbán FM, Fozzatti L, Motran CC, Musri MM. Trypanosoma cruzi Infection Promotes Vascular Remodeling and Coexpression of α-Smooth Muscle Actin and Macrophage Markers in Cells of the Aorta. ACS Infect Dis 2022; 8:2271-2290. [PMID: 36083791 DOI: 10.1021/acsinfecdis.2c00318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Chagas disease is an emerging global health problem; however, it remains neglected. Increased aortic stiffness (IAS), a predictor of cardiovascular events, has recently been reported in asymptomatic chronic Chagas patients. After vascular injury, smooth muscle cells (SMCs) can undergo alterations associated with phenotypic switch and transdifferentiation, promoting vascular remodeling and IAS. By studying different mouse aortic segments, we tested the hypothesis that Trypanosoma cruzi infection promotes vascular remodeling. Interestingly, the thoracic aorta was the most affected by the infection. Decreased expression of SMC markers and increased expression of proliferative markers were observed in the arteries of acutely infected mice. In acutely and chronically infected mice, we observed cells coexpressing SMC and macrophage (Mo) markers in the media and adventitia layers of the aorta, indicating that T. cruzi might induce cellular processes associated with SMC transdifferentiation into Mo-like cells or vice versa. In the adventitia, the Mo cell functional polarization was associated with an M2-like CD206+arginase-1+ phenotype despite the T. cruzi presence in the tissue. Only Mo-like cells in inflammatory foci were CD206+iNOS+. In addition to the disorganization of elastic fibers, we found thickening of the aortic layers during the acute and chronic phases of the disease. Our findings indicate that T. cruzi infection induces a vascular remodeling with SMC dedifferentiation and increased cell populations coexpressing α-SMA and Mo markers that could be associated with IAS promotion. These data highlight the importance of studying large vessel homeostasis in Chagas disease.
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Affiliation(s)
- Ximena Volpini
- Instituto de Investigaciones Médicas Mercedes y Martín Ferreyra. Consejo Nacional de Investigaciones Científicas y Tecnicas. Universidad Nacional de Córdoba (INIMEC-CONICET-UNC), Friuli 2434. Colinas de Velez Sarfield, Córdoba, PC X5016NST, Argentina.,Centro de Investigaciones en Bioquímica Clínica e Inmunología. Consejo Nacional de Investigaciones Científicas y Técnicas (CIBICI-CONICET), Haya de la Torre y Medina Allende. Ciudad Universitaria, Córdoba, PC X5000HUA, Argentina.,Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (FCQ-UNC). Ciudad Universitaria, Córdoba, PC X5000HUA, Argentina
| | - Lautaro Natali
- Instituto de Investigaciones Médicas Mercedes y Martín Ferreyra. Consejo Nacional de Investigaciones Científicas y Tecnicas. Universidad Nacional de Córdoba (INIMEC-CONICET-UNC), Friuli 2434. Colinas de Velez Sarfield, Córdoba, PC X5016NST, Argentina.,Centro de Investigaciones en Bioquímica Clínica e Inmunología. Consejo Nacional de Investigaciones Científicas y Técnicas (CIBICI-CONICET), Haya de la Torre y Medina Allende. Ciudad Universitaria, Córdoba, PC X5000HUA, Argentina
| | - Maria Belén Brugo
- Centro de Investigaciones en Bioquímica Clínica e Inmunología. Consejo Nacional de Investigaciones Científicas y Técnicas (CIBICI-CONICET), Haya de la Torre y Medina Allende. Ciudad Universitaria, Córdoba, PC X5000HUA, Argentina.,Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (FCQ-UNC). Ciudad Universitaria, Córdoba, PC X5000HUA, Argentina
| | - Benjamin de la Cruz-Thea
- Instituto de Investigaciones Médicas Mercedes y Martín Ferreyra. Consejo Nacional de Investigaciones Científicas y Tecnicas. Universidad Nacional de Córdoba (INIMEC-CONICET-UNC), Friuli 2434. Colinas de Velez Sarfield, Córdoba, PC X5016NST, Argentina
| | - Ruth Eliana Baigorri
- Centro de Investigaciones en Bioquímica Clínica e Inmunología. Consejo Nacional de Investigaciones Científicas y Técnicas (CIBICI-CONICET), Haya de la Torre y Medina Allende. Ciudad Universitaria, Córdoba, PC X5000HUA, Argentina.,Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (FCQ-UNC). Ciudad Universitaria, Córdoba, PC X5000HUA, Argentina
| | - Fabio Marcelo Cerbán
- Centro de Investigaciones en Bioquímica Clínica e Inmunología. Consejo Nacional de Investigaciones Científicas y Técnicas (CIBICI-CONICET), Haya de la Torre y Medina Allende. Ciudad Universitaria, Córdoba, PC X5000HUA, Argentina.,Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (FCQ-UNC). Ciudad Universitaria, Córdoba, PC X5000HUA, Argentina
| | - Laura Fozzatti
- Centro de Investigaciones en Bioquímica Clínica e Inmunología. Consejo Nacional de Investigaciones Científicas y Técnicas (CIBICI-CONICET), Haya de la Torre y Medina Allende. Ciudad Universitaria, Córdoba, PC X5000HUA, Argentina.,Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (FCQ-UNC). Ciudad Universitaria, Córdoba, PC X5000HUA, Argentina
| | - Claudia Cristina Motran
- Centro de Investigaciones en Bioquímica Clínica e Inmunología. Consejo Nacional de Investigaciones Científicas y Técnicas (CIBICI-CONICET), Haya de la Torre y Medina Allende. Ciudad Universitaria, Córdoba, PC X5000HUA, Argentina.,Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (FCQ-UNC). Ciudad Universitaria, Córdoba, PC X5000HUA, Argentina
| | - Melina Mara Musri
- Instituto de Investigaciones Médicas Mercedes y Martín Ferreyra. Consejo Nacional de Investigaciones Científicas y Tecnicas. Universidad Nacional de Córdoba (INIMEC-CONICET-UNC), Friuli 2434. Colinas de Velez Sarfield, Córdoba, PC X5016NST, Argentina.,Departamento de Fisiología, Facultad de Ciencias Exactas Físicas y Naturales. Universidad Nacional de Córdoba (FCEFyN-UNC). Av. Velez Sarfield 299, Centro, Córdoba, PC X5000JJC, Argentina
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Utility of Serum Ki-67 as a Marker for Malignancy in Dogs. Animals (Basel) 2022; 12:ani12101263. [PMID: 35625109 PMCID: PMC9138135 DOI: 10.3390/ani12101263] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 05/08/2022] [Accepted: 05/12/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Although serum tumour markers offer an uncomplicated, non-invasive examination method and possible therapeutic options, they are still rarely used in veterinary medicine. Our marker of interest, the Ki-67 protein, can only be detected in the active phases of the cell cycle. Therefore, it is a suitable marker for assessing the proliferating cell fraction of an organism and can thus provide information about potentially present, rapid-growing tumour tissue. The purpose of our study was to determine whether Ki-67 could be considered as a possible tumour marker in canine serum for veterinary medicine. We measured serum concentrations of Ki-67 in dogs with various malignant tumours, such as carcinomas, sarcomas, and lymphomas. In the dogs with malignant tumours we determined significantly higher serum Ki-67 concentrations compared with healthy dogs and dogs with non-malignant diseases. No significant difference in serum Ki-67 concentration was observed between the different types of cancer or between benign and malignant mammary tumours. Our investigations also included some inflammatory parameters measured in blood, such as neutrophils, lymphocytes, and monocytes, with mixed results. The results of our study suggest that Ki-67 may be useful as a potential serum tumour marker, providing information about the presence of malignant diseases in a dog. Abstract Tumour markers are scarcely used in veterinary medicine, although they are non-invasive, contribute to a faster diagnosis and new therapeutic options. The nuclear protein Ki-67 is absent in G0-phase but is detectable throughout all active phases of the cell cycle. Consequently, it is used as a marker for the proliferating cell fraction of a cell population and thus could indicate neoplastic tissue present. Our study is designed to show whether Ki-67 can be considered as a potential canine serum tumour marker for veterinary medicine. We measured serum concentrations of Ki-67 in dogs with various malignant tumours (carcinomas (n = 35); sarcomas (n = 26); lymphomas (n = 21)) using a commercially available quantitative sandwich ELISA from mybiosource. Dogs with malignant tumours showed significantly higher serum Ki-67 concentrations compared to healthy dogs (n = 19) and non-neoplastic diseased dogs (n = 26). No significant difference in serum Ki-67 concentration was detected between carcinoma, sarcoma, and lymphoma, nor between mammary adenocarcinoma and adenoma. In our investigations we also included some inflammatory parameters measured in blood, such as neutrophils, lymphocytes, and monocytes, and gained mixed results. The results of our study suggest that Ki-67 may be useful as a potential serum tumour marker, providing information about the presence of malignancies in a dog.
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5
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Nolan RP, Cavuoto KM, Patel N, Falcone MM, Liu Y, Liu X, Dubovy SR, Chang VS, Osigian CJ. Clinical Diagnosis and Histopathologic Features of a Synthetic Fiber Granuloma. J Pediatr Ophthalmol Strabismus 2020; 57:e92-e95. [PMID: 33320269 DOI: 10.3928/01913913-20200915-01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 07/17/2020] [Indexed: 11/20/2022]
Abstract
The authors report a case of a synthetic fiber granuloma to demonstrate the challenges in diagnosing these lesions and to highlight their histopathologic features. This is the first report in the literature to use histopatho-logic and immunofluorescence studies to characterize the subtype and distribution of macrophages in synthetic fiber granuloma. [J Pediatr Ophthalmol Strabismus. 2020;57:e92-e95.].
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6
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Zhang W, Dai L, Li X, Li Y, Hung Yap MK, Liu L, Deng H. SARI prevents ocular angiogenesis and inflammation in mice. J Cell Mol Med 2020; 24:4341-4349. [PMID: 32119762 PMCID: PMC7171405 DOI: 10.1111/jcmm.15096] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 10/22/2019] [Accepted: 11/26/2019] [Indexed: 02/05/2023] Open
Abstract
SARI (Suppressor of AP‐1, regulated by IFN‐β) is known to play an important role in some systemic disease processes such an inflammatory conditions and cancer. We hypothesize that SARI may also play a role in ocular diseases involving inflammation and neovascularization. To explore our hypothesis, further, we investigated an endotoxin‐induced uveitis (EIU) and experimental argon laser‐induced choroidal neovascularization (CNV) model in SARI wild‐type (SARIWT) and SARI‐deficient (SARI−/−) mice. Through imaging, morphological and immunohistochemical (IHC) studies, we found that SARI deficiency exacerbated the growth of CNV. More VEGF‐positive cells were presented in the retina of SARI−/− mice with CNV. Compared to SARIWT mice, more inflammatory cells infiltrated the ocular anterior segment and posterior segments in SARI−/− mice with EIU. Collectively, the results point to a potential dual functional role of SARI in inflammatory ocular diseases, suggesting that SARI could be a potential therapy target for ocular inflammation and neovascularization.
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Affiliation(s)
- Wenqiu Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.,Research Laboratory of Ophthalmology and Vision Sciences, West China Hospital, Sichuan University, Chengdu, China.,Department of Optometry and Visual Science, West China Hospital, Sichuan University, Chengdu, China
| | - Lei Dai
- State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xun Li
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.,Research Laboratory of Ophthalmology and Vision Sciences, West China Hospital, Sichuan University, Chengdu, China
| | - Yiming Li
- State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | | | - Longqian Liu
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.,Department of Optometry and Visual Science, West China Hospital, Sichuan University, Chengdu, China
| | - Hongxin Deng
- State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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7
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Kaiser U, Loeffler KU, Nadal J, Holz FG, Herwig-Carl MC. Polarization and Distribution of Tumor-Associated Macrophages and COX-2 Expression in Basal Cell Carcinoma of the Ocular Adnexae. Curr Eye Res 2018; 43:1126-1135. [PMID: 29775390 DOI: 10.1080/02713683.2018.1478980] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
PURPOSE Basal cell carcinoma (BCC) is a locally invasive skin tumor which can be subdivided into a circumscribed nodular and an invasive fibrosing subtype. There is increasing evidence that macrophages play an important role in interacting between tumor cells and their microenvironment, thereby affecting not only the invasive potential but also the patients' prognosis. Thus, we wanted to compare these two BCC variants with regard to tumor-related inflammation, COX-2 expression, distribution, and polarization of tumor-associated macrophages. MATERIAL AND METHODS 30 BCCs (nodular: n = 15; fibrosing: n = 15) of the ocular adnexae were investigated by histopathology and immunohistochemistry. The grade of inflammation was evaluated on hematoxylin and eosin stains (score: 0-3). Immunohistochemical stains for CD68 (macrophages), Ki67 (proliferative activity), and COX-2 as well as immunofluorescence stains for CD68 and CD163 (to distinguish M1 and M2 macrophage subtypes) were performed. SPSS was used for statistical analysis. RESULTS Fibrosing BCCs were predominantly located on the lower lid, while nodular BCCs showed a broader distribution (p = 0.013). The fibrosing BCC subtype was associated with a higher degree of inflammation (p < 0.001) and revealed a higher COX-2 immunoreactivity than nodular BCC (p = 0.012). COX-2-positive cells were predominantly located on the infiltrating edge of the tumor. Macrophage polarization was balanced regarding M1 and M2 macrophage subtypes. There was no difference in macrophage number (p = 0.389) or polarization (p = 0.161) between nodular and fibrosing BCC. CONCLUSIONS The findings indicate that COX-2 represents a factor for invasion of BCC. Macrophage polarization did not play a major role for aggressive behavior. However, other inflammatory components than tumor-associated macrophages seem to be involved in tissue destruction and thereby an invading growth pattern since fibrosing BCC revealed a significantly more intense inflammatory reaction in the surrounding tissue.
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Affiliation(s)
- Ute Kaiser
- a Department of Ophthalmology , University of Bonn , Bonn , Germany
| | - Karin U Loeffler
- a Department of Ophthalmology , University of Bonn , Bonn , Germany
| | - Jennifer Nadal
- b Institute of Medical Biometry, Informatics and Epidemiology , University of Bonn , Bonn , Germany
| | - Frank G Holz
- a Department of Ophthalmology , University of Bonn , Bonn , Germany
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8
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Krishna Y, McCarthy C, Kalirai H, Coupland SE. Inflammatory cell infiltrates in advanced metastatic uveal melanoma. Hum Pathol 2017; 66:159-166. [PMID: 28655639 DOI: 10.1016/j.humpath.2017.06.005] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2017] [Revised: 06/04/2017] [Accepted: 06/16/2017] [Indexed: 12/22/2022]
Abstract
Current treatments for metastatic uveal melanoma (mUM) are limited and rarely prolong patient survival. Immunotherapy trials for mUM are few and to date have demonstrated only marginal success. High densities of tumor-associated macrophages (TAMs) and infiltrating T lymphocytes (TILs) in primary UM are associated with poor prognosis. Little is known about the immune microenvironment of mUM. Our aim was to examine the presence and distribution of TAMs and TILs in mUM within the liver. Whole-tissue sections of liver mUM (n=35) were examined by immunohistochemistry. For TAMs, monoclonal antibodies against CD68 and CD163 were used. Macrophage density and morphology were scored using previous established systems. Density and spatial distribution of TILs were highlighted using antibodies against CD3 (pan-lymphocyte marker), CD4 (T-helper cells), and CD8 (T-cytotoxic cells). CD68+ and CD163+ TAMs were seen within the tumor in all 35 specimens; their density was "moderate" in 50% of cases and "few" in 43%, and the majority showed an "indeterminate" phenotype. CD3+ TILs were noted both within mUMs and surrounding the tumor. Of these, CD8+ TILs were "few" in number within mUM but were predominantly seen peritumorally at the tumor/normal liver interface, whereas CD4+ TILs showed a high perivascular density within mUM. CD68+ and CD163+ TAMs of "indeterminate" morphology were observed in mUM, suggesting a tendency toward the protumorigenic M2 phenotype. CD4+ TILs were seen within the mUM, whereas CD8+ TILs tended to be peritumoral. The biological and functional roles of inflammatory cells in mUM require further investigation to determine if they represent potential targets for future therapies in mUM.
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Affiliation(s)
- Yamini Krishna
- Department of Cellular Pathology, Royal Liverpool University Hospital, Liverpool, L7 8XP, UK
| | - Conni McCarthy
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, L7 8TX, UK
| | - Helen Kalirai
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, L7 8TX, UK
| | - Sarah E Coupland
- Department of Cellular Pathology, Royal Liverpool University Hospital, Liverpool, L7 8XP, UK; Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, L7 8TX, UK.
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9
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Luo J, Huang L, Chen Z, Zeng Z, Miyamoto T, Wu H, Zhang Z, Pan Z, Fujita N, Hikata T, Iwanami A, Tsuji T, Ishii K, Nakamura M, Matsumoto M, Watanabe K, Cao K. Increased sorbitol levels in the hypertrophic ligamentum flavum of diabetic patients with lumbar spinal canal stenosis. J Orthop Res 2017; 35:1058-1066. [PMID: 27208686 DOI: 10.1002/jor.23302] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 05/06/2016] [Indexed: 02/04/2023]
Abstract
The pathomechanism of the ligamentum flavum (LF) hypertrophy in diabetic patients with lumbar spinal canal stenosis (LSCS) remains unclear. A cross-sectional study was undertaken to investigate the mechanism of LF hypertrophy in these patients. Twenty-four diabetic and 20 normoglycemic patients with LSCS were enrolled in the study. The structure of the LF in the study subjects was evaluated using histological and immunohistochemical methods, and the levels of sorbitol, pro-inflammatory cytokines, and the fibrogenic factor, TGF-β1, in the LF were analyzed. In vitro experiments were performed using NIH3T3 fibroblasts to evaluate the effect of high-glucose conditions and an aldose reductase inhibitor on the cellular production of sorbitol, pro-inflammatory factors, and TGF-β1. We found that the LF of diabetic patients exhibited significantly higher levels of sorbitol and pro-inflammatory cytokines, TGF-β1 and of CD68-positive staining than that of the normoglycemic subjects. The diabetic LF was significantly thicker than that of the controls, and showed evidence of degeneration. The high glucose-cultured fibroblasts exhibited significantly higher levels of sorbitol, pro-inflammatory factors, and TGF-β1 compared to the low glucose-cultured cells, and these levels were dose-dependently reduced by treatment with the aldose reductase inhibitor. Taken together, our data suggests that increased sorbitol levels in the LF of diabetic patients results in increased production of pro-inflammatory and fibrogenic factor, which contribute to LF hypertrophy, and could increase the susceptibility of diabetic patients to LSCS. Furthermore, aldose reductase inhibition effectively reduced the levels of sorbitol and sorbitol-induced pro-inflammatory factor expression in high glucose-cultured fibroblasts. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1058-1066, 2017.
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Affiliation(s)
- Jiaquan Luo
- Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University, 17, Yongwai Street, East Lake District, Nanchang, #330006, China
| | - Lu Huang
- Department of Healthcare, Jiangxi Maternal and Child Health Hospital, Nanchang, China
| | - Zhuo Chen
- Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University, 17, Yongwai Street, East Lake District, Nanchang, #330006, China
| | - Zhaoxun Zeng
- Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University, 17, Yongwai Street, East Lake District, Nanchang, #330006, China
| | - Takeshi Miyamoto
- Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan
| | - Hao Wu
- Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan
| | - Zhongzu Zhang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University, 17, Yongwai Street, East Lake District, Nanchang, #330006, China
| | - Zhimin Pan
- Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University, 17, Yongwai Street, East Lake District, Nanchang, #330006, China
| | - Nobuyuki Fujita
- Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan
| | - Tomohiro Hikata
- Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan
| | - Akio Iwanami
- Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan
| | - Takashi Tsuji
- Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan
| | - Ken Ishii
- Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan
| | - Masaya Nakamura
- Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan
| | - Morio Matsumoto
- Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan
| | - Kota Watanabe
- Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan
| | - Kai Cao
- Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University, 17, Yongwai Street, East Lake District, Nanchang, #330006, China
- Department of Orthopedic Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo, #160-8582, Japan
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MIRAgel: the immunohistochemical expression of CD3, CD34, and CD68 in the surrounding capsule. Eye (Lond) 2016; 30:1381-1388. [PMID: 27341317 DOI: 10.1038/eye.2016.125] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Accepted: 05/04/2016] [Indexed: 12/16/2022] Open
Abstract
PurposeTo study the immunohistochemical features of the capsule tissue surrounding MIRAgel episcleral buckles.Patients and methodsThis Institutional interventional clinical cohort study examined a consecutive series of 21 referred patients who required MIRAgel removal from July 2009 to July 2013. All patients with hydrated and fragmented MIRAgel episcleral buckles were included in this study. Capsule biopsies from MIRAgel episcleral buckles were obtained from all patients. Capsule specimens of seven patients with extruded silicone bands were processed as controls. Paraffin-embedded specimens were examined using light microscopy and immunohistochemistry (via the PAP horseradish peroxidase technique) to detect the expression of CD3, CD20, CD34 and CD68, and S-100 protein.ResultsInflammation with granuloma, which was primarily related to sutures, was found in all (n=36) of the MIRAgel specimens and foreign body granulomas with multinucleated giant cells, histiocytes, and macrophages (CD68+ cells) surrounded the MIRAgel fragments. Average number of CD68+ cells was higher (P<0.001) for MIRAgel than for silicone rubber. The lymphocytic inflammatory infiltrate related to the MIRAgel fragments was CD3+ and CD20- (delayed T cell-mediated immune response). Moderate neoangiogenesis was indicated by the presence of CD34+ cells.ConclusionsThe immunohistochemical analysis revealed that the immune system is able to identify the fragments of MIRAgel (after its hydrolytic degradation) as a foreign body during a delayed T cell-mediated immune response. The phagocytosis by macrophages likely triggers and perpetuates local disease. Removal of MIRAgel explants before hydrolysis should be considered.
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Belhareth R, Mège JL. Macrophage populations and self-renewal: Changing the paradigm. World J Immunol 2015; 5:131-141. [DOI: 10.5411/wji.v5.i3.131] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 08/27/2015] [Accepted: 10/27/2015] [Indexed: 02/05/2023] Open
Abstract
The origin of macrophages has been considered since several decades to be a continuum from bone marrow (BM) to tissue via monocytes as precursors. The development of new tools such as genetic lineage tracing, parabiosis and BM chimeras changed the paradigm of macrophage origin. In steady state, most resident macrophages are of embryonic origin, whereas a monocyte origin remains prominent in pathological conditions. The findings of a proliferation of mature macrophages will oblige us to reappraise the relationship between proliferation and differentiation in macrophages. This review is based on the recent explosion of high impact articles on macrophage biology. It summarizes new data on the origin of macrophages and their self-renewal potential in steady states. While monocytes are required for intestinal macrophage development, the microglia is independent of monocyte influx and skin macrophages provide an excellent model of the balance between monocyte input and self-renewal. In addition, macrophage proliferation requires intrinsic and extrinsic factors including growth factors and cytokines. It also analyzes the impact of this new paradigm in human diseases such as athrosclerosis, cancer, infectious diseases and neurodegenerative diseases. In atherosclerosis, the finding of macrophage proliferation within the lesions will change our understanding of disease pathophysiology, this new paradigm may have therapeutical impact in the future.
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