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Zhao F, Lei C, Zhang Y, Wu S, Lin H, Chen DF, Lin C, Xiong K, Dai M, Zhang S, Li D, Liang Y. Analysis of uric acid and high-density lipoprotein levels in refractory posner-schlossman syndrome patients: a matched case-control study by the propensity score. BMC Ophthalmol 2024; 24:545. [PMID: 39716126 DOI: 10.1186/s12886-024-03814-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 12/17/2024] [Indexed: 12/25/2024] Open
Abstract
BACKGROUND Recent studies have indicated that oxidative stress is a crucial pathophysiological process in glaucoma. We hypothesized that Posner-Schlossman syndrome (PSS) is a vascular inflammation in the ciliary body due to oxidative stress and endothelial dysfunction. Thus, we investigated serum uric acid (UA) and lipid levels in patients with refractory PSS with the aim of providing basic evidence for the mechanism of PSS. METHODS This is a retrospective, case-control study. A total of 81 refractory PSS and 409 control participants were included in this study. Clinical and laboratory characteristics were reviewed using an electronic medical system. Propensity score-matched (PSM) analysis was performed to reduce demographic differences. The t-test, Mann-Whitney U test, and χ2 test were used to assess the differences between the PSS and control groups. Logistic regression analysis was used to identify the predictors of PSS. RESULTS The higher serum UA (364.14 ± 98.72µmol/L vs. 322.38 ± 72.09µmol/L), higher low-density lipoprotein (LDL) / High-density lipoprotein (HDL) ratio (2.50 ± 0.97 vs. 1.95 ± 0.72) and lower HDL (1.29 ± 0.32 mmol/L vs. 1.59 ± 0.38 mmol/L) can be noticed in refractory PSS than control group. Logistics regression identified UA > 420 µmol/L (OR = 4.461) and the HDL < 1.03 mmol/L (OR = 3.896) were the independent risk factors for refractory PSS. CONCLUSIONS Increasing serum UA and decreasing HDL levels were positively correlated with the incidence risk of refractory PSS. Further prospective longitudinal studies and animal models are needed.
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Affiliation(s)
- Fengping Zhao
- Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
- National Clinical Research Center for Ocular Diseases, Wenzhou, China
| | - Changrong Lei
- Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
- National Clinical Research Center for Ocular Diseases, Wenzhou, China
| | - Yue Zhang
- Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
- National Clinical Research Center for Ocular Diseases, Wenzhou, China
| | - Shuangqing Wu
- Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
| | - Haishuang Lin
- Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
- National Clinical Research Center for Ocular Diseases, Wenzhou, China
| | - De-Fu Chen
- Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
- National Clinical Research Center for Ocular Diseases, Wenzhou, China
| | - Chuanqi Lin
- Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
- National Clinical Research Center for Ocular Diseases, Wenzhou, China
| | - Kun Xiong
- Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
- National Clinical Research Center for Ocular Diseases, Wenzhou, China
| | - Mali Dai
- Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
- National Clinical Research Center for Ocular Diseases, Wenzhou, China
| | - Shaodan Zhang
- Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
- National Clinical Research Center for Ocular Diseases, Wenzhou, China
| | - Duo Li
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, Zhejiang, 325027, China.
| | - Yuanbo Liang
- Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
- National Clinical Research Center for Ocular Diseases, Wenzhou, China
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Santiso A, Heinemann A, Kargl J. Prostaglandin E2 in the Tumor Microenvironment, a Convoluted Affair Mediated by EP Receptors 2 and 4. Pharmacol Rev 2024; 76:388-413. [PMID: 38697857 DOI: 10.1124/pharmrev.123.000901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 11/15/2023] [Accepted: 11/20/2023] [Indexed: 05/05/2024] Open
Abstract
The involvement of the prostaglandin E2 (PGE2) system in cancer progression has long been recognized. PGE2 functions as an autocrine and paracrine signaling molecule with pleiotropic effects in the human body. High levels of intratumoral PGE2 and overexpression of the key metabolic enzymes of PGE2 have been observed and suggested to contribute to tumor progression. This has been claimed for different types of solid tumors, including, but not limited to, lung, breast, and colon cancer. PGE2 has direct effects on tumor cells and angiogenesis that are known to promote tumor development. However, one of the main mechanisms behind PGE2 driving cancerogenesis is currently thought to be anchored in suppressed antitumor immunity, thus providing possible therapeutic targets to be used in cancer immunotherapies. EP2 and EP4, two receptors for PGE2, are emerging as being the most relevant for this purpose. This review aims to summarize the known roles of PGE2 in the immune system and its functions within the tumor microenvironment. SIGNIFICANCE STATEMENT: Prostaglandin E2 (PGE2) has long been known to be a signaling molecule in cancer. Its presence in tumors has been repeatedly associated with disease progression. Elucidation of its effects on immunological components of the tumor microenvironment has highlighted the potential of PGE2 receptor antagonists in cancer treatment, particularly in combination with immune checkpoint inhibitor therapeutics. Adjuvant treatment could increase the response rates and the efficacy of immune-based therapies.
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Affiliation(s)
- Ana Santiso
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Akos Heinemann
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Julia Kargl
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
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Tai SB, Lee ECY, Lim BY, Kannan B, Lee JY, Guo Z, Ko TK, Ng CCY, Teh BT, Chan JY. Tumor-Infiltrating Mast Cells in Angiosarcoma Correlate With Immuno-Oncology Pathways and Adverse Clinical Outcomes. J Transl Med 2024; 104:100323. [PMID: 38218317 DOI: 10.1016/j.labinv.2024.100323] [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: 10/14/2023] [Revised: 12/22/2023] [Accepted: 12/27/2023] [Indexed: 01/15/2024] Open
Abstract
Recent studies have described several molecular subtypes and deregulation of immuno-oncologic signaling pathways in angiosarcoma. Interestingly, mast cells were enriched in subsets of angiosarcoma, although their significance remains unknown. In this study, we aim to verify this observation using immunohistochemistry (H scores) and NanoString transcriptomic profiling and explore the association between mast cells with clinical and biological features. In the study cohort (N = 60), H scores showed a significant moderate correlation with NanoString mast cell scores (r = 0.525; P < .001). Both H score and NanoString mast cell scores showed a significant positive correlation (P < .05) with head and neck location, nonepithelioid morphology, and lower tumor grade. Mast cell enrichment significantly correlated with higher NanoString regulatory T-cell scores (H score, r = 0.32; P = .01; NanoString mast cell score, r = 0.27; P = .04). NanoString mast cell scores positively correlated with signaling pathways relating to antigen presentation (r = 0.264; P = .0414) and negatively correlated with apoptosis (r = -0.366; P = .0040), DNA damage repair (r = -0.348; P = .0064), and cell proliferation (r = -0.542; P < .001). Interestingly, in the metastatic setting, patients with mast cell-enriched angiosarcoma showed poorer progression-free survival (median, 0.2 vs 0.4 years; hazard ratio = 3.05; P = .0489) along with a trend toward worse overall survival (median, 0.2 vs 0.6 years; hazard ratio, 2.86; P = .0574) compared with patients with mast cell-poor angiosarcoma. In conclusion, we demonstrated the presence of mast cells in human angiosarcoma and provided initial evidence of their potential clinical and biological significance. Future research will be required to elucidate their specific roles and mechanisms, which may uncover novel avenues for therapeutic intervention.
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Affiliation(s)
- Sarah Beishan Tai
- Department of Nuclear Medicine and Molecular Imaging, Singapore General Hospital, Singapore; Cancer Discovery Hub, National Cancer Centre Singapore, Singapore.
| | | | - Boon Yee Lim
- Cancer Discovery Hub, National Cancer Centre Singapore, Singapore
| | - Bavani Kannan
- Cancer Discovery Hub, National Cancer Centre Singapore, Singapore
| | - Jing Yi Lee
- Cancer Discovery Hub, National Cancer Centre Singapore, Singapore
| | - Zexi Guo
- Cancer Discovery Hub, National Cancer Centre Singapore, Singapore
| | - Tun Kiat Ko
- Cancer Discovery Hub, National Cancer Centre Singapore, Singapore
| | | | - Bin Tean Teh
- Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore; Duke-NUS Medical School, Singapore
| | - Jason Yongsheng Chan
- Cancer Discovery Hub, National Cancer Centre Singapore, Singapore; Duke-NUS Medical School, Singapore; Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
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Babalola KT, Arora M, Ganugula R, Agarwal SK, Mohan C, Kumar MNVR. Leveraging Lymphatic System Targeting in Systemic Lupus Erythematosus for Improved Clinical Outcomes. Pharmacol Rev 2024; 76:228-250. [PMID: 38351070 PMCID: PMC10877736 DOI: 10.1124/pharmrev.123.000938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 11/21/2023] [Accepted: 12/06/2023] [Indexed: 02/16/2024] Open
Abstract
The role of advanced drug delivery strategies in drug repositioning and minimizing drug attrition rates, when applied early in drug discovery, is poised to increase the translational impact of various therapeutic strategies in disease prevention and treatment. In this context, drug delivery to the lymphatic system is gaining prominence not only to improve the systemic bioavailability of various pharmaceutical drugs but also to target certain specific diseases associated with the lymphatic system. Although the role of the lymphatic system in lupus is known, very little is done to target drugs to yield improved clinical benefits. In this review, we discuss recent advances in drug delivery strategies to treat lupus, the various routes of drug administration leading to improved lymph node bioavailability, and the available technologies applied in other areas that can be adapted to lupus treatment. Moreover, this review also presents some recent findings that demonstrate the promise of lymphatic targeting in a preclinical setting, offering renewed hope for certain pharmaceutical drugs that are limited by efficacy in their conventional dosage forms. These findings underscore the potential and feasibility of such lymphatic drug-targeting approaches to enhance therapeutic efficacy in lupus and minimize off-target effects of the pharmaceutical drugs. SIGNIFICANCE STATEMENT: The World Health Organization estimates that there are currently 5 million humans living with some form of lupus. With limited success in lupus drug discovery, turning to effective delivery strategies with existing drug molecules, as well as those in the early stage of discovery, could lead to better clinical outcomes. After all, effective delivery strategies have been proven to improve treatment outcomes.
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Affiliation(s)
- K T Babalola
- The Center for Convergent Bioscience and Medicine (CCBM) (K.T.B., M.A., R.G., M.N.V.R.K.), Division of Translational Science and Medicine, College of Community Health Sciences (K.T.B., M.A., R.G., M.N.V.R.K.), Alabama Life Research Institute (K.T.B., M.A., R.G., M.N.V.R.K.), and Department of Biological Sciences (M.A., R.G., M.N.V.R.K.), The University of Alabama, Tuscaloosa, Alabama; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Biology of Inflammation Baylor College of Medicine, One Baylor Plaza, Houston, Texas (S.K.A.); Department of Biomedical Engineering, University of Houston, Houston, Texas (C.M.); Chemical and Biological Engineering, University of Alabama, Tuscaloosa, Alabama (M.N.V.R.K.); and Center for Free Radical Biology (M.N.V.R.K.) and Nephrology Research and Training Center, Division of Nephrology, Department of Medicine (M.N.V.R.K.), University of Alabama at Birmingham, Birmingham, Alabama
| | - M Arora
- The Center for Convergent Bioscience and Medicine (CCBM) (K.T.B., M.A., R.G., M.N.V.R.K.), Division of Translational Science and Medicine, College of Community Health Sciences (K.T.B., M.A., R.G., M.N.V.R.K.), Alabama Life Research Institute (K.T.B., M.A., R.G., M.N.V.R.K.), and Department of Biological Sciences (M.A., R.G., M.N.V.R.K.), The University of Alabama, Tuscaloosa, Alabama; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Biology of Inflammation Baylor College of Medicine, One Baylor Plaza, Houston, Texas (S.K.A.); Department of Biomedical Engineering, University of Houston, Houston, Texas (C.M.); Chemical and Biological Engineering, University of Alabama, Tuscaloosa, Alabama (M.N.V.R.K.); and Center for Free Radical Biology (M.N.V.R.K.) and Nephrology Research and Training Center, Division of Nephrology, Department of Medicine (M.N.V.R.K.), University of Alabama at Birmingham, Birmingham, Alabama
| | - R Ganugula
- The Center for Convergent Bioscience and Medicine (CCBM) (K.T.B., M.A., R.G., M.N.V.R.K.), Division of Translational Science and Medicine, College of Community Health Sciences (K.T.B., M.A., R.G., M.N.V.R.K.), Alabama Life Research Institute (K.T.B., M.A., R.G., M.N.V.R.K.), and Department of Biological Sciences (M.A., R.G., M.N.V.R.K.), The University of Alabama, Tuscaloosa, Alabama; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Biology of Inflammation Baylor College of Medicine, One Baylor Plaza, Houston, Texas (S.K.A.); Department of Biomedical Engineering, University of Houston, Houston, Texas (C.M.); Chemical and Biological Engineering, University of Alabama, Tuscaloosa, Alabama (M.N.V.R.K.); and Center for Free Radical Biology (M.N.V.R.K.) and Nephrology Research and Training Center, Division of Nephrology, Department of Medicine (M.N.V.R.K.), University of Alabama at Birmingham, Birmingham, Alabama
| | - S K Agarwal
- The Center for Convergent Bioscience and Medicine (CCBM) (K.T.B., M.A., R.G., M.N.V.R.K.), Division of Translational Science and Medicine, College of Community Health Sciences (K.T.B., M.A., R.G., M.N.V.R.K.), Alabama Life Research Institute (K.T.B., M.A., R.G., M.N.V.R.K.), and Department of Biological Sciences (M.A., R.G., M.N.V.R.K.), The University of Alabama, Tuscaloosa, Alabama; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Biology of Inflammation Baylor College of Medicine, One Baylor Plaza, Houston, Texas (S.K.A.); Department of Biomedical Engineering, University of Houston, Houston, Texas (C.M.); Chemical and Biological Engineering, University of Alabama, Tuscaloosa, Alabama (M.N.V.R.K.); and Center for Free Radical Biology (M.N.V.R.K.) and Nephrology Research and Training Center, Division of Nephrology, Department of Medicine (M.N.V.R.K.), University of Alabama at Birmingham, Birmingham, Alabama
| | - C Mohan
- The Center for Convergent Bioscience and Medicine (CCBM) (K.T.B., M.A., R.G., M.N.V.R.K.), Division of Translational Science and Medicine, College of Community Health Sciences (K.T.B., M.A., R.G., M.N.V.R.K.), Alabama Life Research Institute (K.T.B., M.A., R.G., M.N.V.R.K.), and Department of Biological Sciences (M.A., R.G., M.N.V.R.K.), The University of Alabama, Tuscaloosa, Alabama; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Biology of Inflammation Baylor College of Medicine, One Baylor Plaza, Houston, Texas (S.K.A.); Department of Biomedical Engineering, University of Houston, Houston, Texas (C.M.); Chemical and Biological Engineering, University of Alabama, Tuscaloosa, Alabama (M.N.V.R.K.); and Center for Free Radical Biology (M.N.V.R.K.) and Nephrology Research and Training Center, Division of Nephrology, Department of Medicine (M.N.V.R.K.), University of Alabama at Birmingham, Birmingham, Alabama
| | - M N V Ravi Kumar
- The Center for Convergent Bioscience and Medicine (CCBM) (K.T.B., M.A., R.G., M.N.V.R.K.), Division of Translational Science and Medicine, College of Community Health Sciences (K.T.B., M.A., R.G., M.N.V.R.K.), Alabama Life Research Institute (K.T.B., M.A., R.G., M.N.V.R.K.), and Department of Biological Sciences (M.A., R.G., M.N.V.R.K.), The University of Alabama, Tuscaloosa, Alabama; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Biology of Inflammation Baylor College of Medicine, One Baylor Plaza, Houston, Texas (S.K.A.); Department of Biomedical Engineering, University of Houston, Houston, Texas (C.M.); Chemical and Biological Engineering, University of Alabama, Tuscaloosa, Alabama (M.N.V.R.K.); and Center for Free Radical Biology (M.N.V.R.K.) and Nephrology Research and Training Center, Division of Nephrology, Department of Medicine (M.N.V.R.K.), University of Alabama at Birmingham, Birmingham, Alabama
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Yi M, Li T, Niu M, Mei Q, Zhao B, Chu Q, Dai Z, Wu K. Exploiting innate immunity for cancer immunotherapy. Mol Cancer 2023; 22:187. [PMID: 38008741 PMCID: PMC10680233 DOI: 10.1186/s12943-023-01885-w] [Citation(s) in RCA: 82] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 10/23/2023] [Indexed: 11/28/2023] Open
Abstract
Immunotherapies have revolutionized the treatment paradigms of various types of cancers. However, most of these immunomodulatory strategies focus on harnessing adaptive immunity, mainly by inhibiting immunosuppressive signaling with immune checkpoint blockade, or enhancing immunostimulatory signaling with bispecific T cell engager and chimeric antigen receptor (CAR)-T cell. Although these agents have already achieved great success, only a tiny percentage of patients could benefit from immunotherapies. Actually, immunotherapy efficacy is determined by multiple components in the tumor microenvironment beyond adaptive immunity. Cells from the innate arm of the immune system, such as macrophages, dendritic cells, myeloid-derived suppressor cells, neutrophils, natural killer cells, and unconventional T cells, also participate in cancer immune evasion and surveillance. Considering that the innate arm is the cornerstone of the antitumor immune response, utilizing innate immunity provides potential therapeutic options for cancer control. Up to now, strategies exploiting innate immunity, such as agonists of stimulator of interferon genes, CAR-macrophage or -natural killer cell therapies, metabolic regulators, and novel immune checkpoint blockade, have exhibited potent antitumor activities in preclinical and clinical studies. Here, we summarize the latest insights into the potential roles of innate cells in antitumor immunity and discuss the advances in innate arm-targeted therapeutic strategies.
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Affiliation(s)
- Ming Yi
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People's Republic of China
- Department of Breast Surgery, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310000, People's Republic of China
| | - Tianye Li
- Department of Gynecology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310000, People's Republic of China
| | - Mengke Niu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Qi Mei
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People's Republic of China
| | - Bin Zhao
- Department of Breast Surgery, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310000, People's Republic of China
| | - Qian Chu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
| | - Zhijun Dai
- Department of Breast Surgery, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310000, People's Republic of China.
| | - Kongming Wu
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People's Republic of China.
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
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Dileepan KN, Raveendran VV, Sharma R, Abraham H, Barua R, Singh V, Sharma R, Sharma M. Mast cell-mediated immune regulation in health and disease. Front Med (Lausanne) 2023; 10:1213320. [PMID: 37663654 PMCID: PMC10470157 DOI: 10.3389/fmed.2023.1213320] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 07/17/2023] [Indexed: 09/05/2023] Open
Abstract
Mast cells are important components of the immune system, and they perform pro-inflammatory as well as anti-inflammatory roles in the complex process of immune regulation in health and disease. Because of their strategic perivascular localization, sensitivity and adaptability to the microenvironment, and ability to release a variety of preformed and newly synthesized effector molecules, mast cells perform unique functions in almost all organs. Additionally, Mast cells express a wide range of surface and cytoplasmic receptors which enable them to respond to a variety of cytokines, chemicals, and pathogens. The mast cell's role as a cellular interface between external and internal environments as well as between vasculature and tissues is critical for protection and repair. Mast cell interactions with different immune and nonimmune cells through secreted inflammatory mediators may also turn in favor of disease promoting agents. First and forefront, mast cells are well recognized for their multifaceted functions in allergic diseases. Reciprocal communication between mast cells and endothelial cells in the presence of bacterial toxins in chronic/sub-clinical infections induce persistent vascular inflammation. We have shown that mast cell proteases and histamine induce endothelial inflammatory responses that are synergistically amplified by bacterial toxins. Mast cells have been shown to exacerbate vascular changes in normal states as well as in chronic or subclinical infections, particularly among cigarette smokers. Furthermore, a potential role of mast cells in SARS-CoV-2-induced dysfunction of the capillary-alveolar interface adds to the growing understanding of mast cells in viral infections. The interaction between mast cells and microglial cells in the brain further highlights their significance in neuroinflammation. This review highlights the significant role of mast cells as the interface that acts as sensor and early responder through interactions with cells in systemic organs and the nervous system.
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Affiliation(s)
- Kottarappat N. Dileepan
- Division of Allergy, Clinical Immunology and Rheumatology, Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, United States
| | - Vineesh V. Raveendran
- Division of Allergy, Clinical Immunology and Rheumatology, Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, United States
| | - Rishi Sharma
- Department of Medicine, School of Medicine, University of Missouri, Kansas City, MO, United States
| | - Harita Abraham
- Division of Allergy, Clinical Immunology and Rheumatology, Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, United States
| | - Rajat Barua
- Cardiology Section, Kansas City Veterans Affairs Medical Center, Kansas City, MO, United States
| | - Vikas Singh
- Neurology Section, Kansas City Veterans Affairs Medical Center, Kansas City, MO, United States
| | - Ram Sharma
- Research and Development Service, Kansas City Veterans Affairs Medical Center, Kansas City, MO, United States
| | - Mukut Sharma
- Research and Development Service, Kansas City Veterans Affairs Medical Center, Kansas City, MO, United States
- Midwest Veterans’ Biomedical Research Foundation (MVBRF), Kansas City VA Medical Center, Kansas, MO, United States
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Lauritano D, Mastrangelo F, D’Ovidio C, Ronconi G, Caraffa A, Gallenga CE, Frydas I, Kritas SK, Trimarchi M, Carinci F, Conti P. Activation of Mast Cells by Neuropeptides: The Role of Pro-Inflammatory and Anti-Inflammatory Cytokines. Int J Mol Sci 2023; 24:ijms24054811. [PMID: 36902240 PMCID: PMC10002992 DOI: 10.3390/ijms24054811] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 02/24/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Mast cells (MCs) are tissue cells that are derived from bone marrow stem cells that contribute to allergic reactions, inflammatory diseases, innate and adaptive immunity, autoimmunity, and mental disorders. MCs located near the meninges communicate with microglia through the production of mediators such as histamine and tryptase, but also through the secretion of IL-1, IL-6 and TNF, which can create pathological effects in the brain. Preformed chemical mediators of inflammation and tumor necrosis factor (TNF) are rapidly released from the granules of MCs, the only immune cells capable of storing the cytokine TNF, although it can also be produced later through mRNA. The role of MCs in nervous system diseases has been extensively studied and reported in the scientific literature; it is of great clinical interest. However, many of the published articles concern studies on animals (mainly rats or mice) and not on humans. MCs are known to interact with neuropeptides that mediate endothelial cell activation, resulting in central nervous system (CNS) inflammatory disorders. In the brain, MCs interact with neurons causing neuronal excitation with the production of neuropeptides and the release of inflammatory mediators such as cytokines and chemokines. This article explores the current understanding of MC activation by neuropeptide substance P (SP), corticotropin-releasing hormone (CRH), and neurotensin, and the role of pro-inflammatory cytokines, suggesting a therapeutic effect of the anti-inflammatory cytokines IL-37 and IL-38.
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Affiliation(s)
- Dorina Lauritano
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Filiberto Mastrangelo
- Department of Clinical and Experimental Medicine, School of Dentistry, University of Foggia, 71100 Foggia, Italy
| | - Cristian D’Ovidio
- Section of Legal Medicine, Department of Medicine and Aging Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
| | - Gianpaolo Ronconi
- Clinica dei Pazienti del Territorio, Fondazione Policlinico Gemelli, 00185 Rome, Italy
| | | | - Carla E. Gallenga
- Section of Ophthalmology, Department of Biomedical Sciences and Specialist Surgery, University of Ferrara, 44121 Ferrara, Italy
| | - Ilias Frydas
- Department of Parasitology, Aristotle University, 54124 Thessaloniki, Greece
| | - Spyros K. Kritas
- Department of Microbiology and Infectious Diseases, School of Veterinary Medicine, Aristotle University of Thessaloniki, 54124 Macedonia, Greece
| | - Matteo Trimarchi
- Centre of Neuroscience of Milan, Department of Medicine and Surgery, University of Milan, 20122 Milano, Italy
| | - Francesco Carinci
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Pio Conti
- Immunology Division, Postgraduate Medical School, University of Chieti, 66100 Chieti, Italy
- Correspondence:
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Zaitoun IS, Song YS, Zaitoun HB, Sorenson CM, Sheibani N. Assessment of Choroidal Vasculature and Innate Immune Cells in the Eyes of Albino and Pigmented Mice. Cells 2022; 11:3329. [PMID: 36291198 PMCID: PMC9600292 DOI: 10.3390/cells11203329] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/06/2022] [Accepted: 10/17/2022] [Indexed: 12/05/2022] Open
Abstract
The visualization of choroidal vasculature and innate immune cells in the eyes of pigmented mice has been challenging due to the presence of a retinal pigment epithelium (RPE) layer separating the choroid and retina. Here, we established methods for visualizing the choroidal macrophages, mast cells, and vasculature in eyes of albino and pigmented mice using cell type-specific staining. We were able to visualize the choroidal arterial and venous systems. An arterial circle around the optic nerve was found in mice similar to the Zinn-Haller arterial circle that exists in humans and primates. Three different structural patterns of choriocapillaris were observed throughout the whole choroid: honeycomb-like, maze-like, and finger-like patterns. Choroidal mast cells were relatively few but dense around the optic nerve. Mast cell distribution in the middle and periphery was different among strains. Macrophages were found in all layers of the choroid. Thus, utilizing the simple and reliable methods described herein will allow the evaluation of transgenic and preclinical mouse models of ocular diseases that affect the choroid, including age-related macular degeneration (AMD), diabetic choroidopathy, and retinopathy of prematurity. These studies will advance our understanding of the pathophysiology, and molecular and cellular mechanisms that can be targeted therapeutically, in these diseases.
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Affiliation(s)
- Ismail S. Zaitoun
- Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA
- McPherson Eye Research Institute, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA
| | - Yong-Seok Song
- Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA
- McPherson Eye Research Institute, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA
| | - Hammam B. Zaitoun
- Faculty of Medicine, Yarmouk University in Irbid, Irbid 21163, Jordan
| | - Christine M. Sorenson
- McPherson Eye Research Institute, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA
- Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA
| | - Nader Sheibani
- Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA
- McPherson Eye Research Institute, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA
- Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA
- Department of Biomedical Engineering, University of Wisconsin, Madison, WI 53706, USA
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9
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Norrby K. Do mast cells contribute to the continued survival of vertebrates? APMIS 2022; 130:618-624. [PMID: 35869669 PMCID: PMC9545593 DOI: 10.1111/apm.13264] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/20/2022] [Indexed: 11/30/2022]
Abstract
This study is an attempt to shed light on why the connective tissue mast cell (MC) is preserved in all species with a blood circulatory system, i.e., the vertebrates since >500 million years, which suggests that the MC performs as yet not understood indispensible life-promoting actions. The literature survey focuses on data in published papers on MC functions in immunological and nonimmunological reactions, host protection, pregnancy, inflammation, and wound healing. All data are thus accessible to the reader. The MC is a secretory cell with a unique mediator profile. A distinctive role for MCs is defined not only by their extensive mediator composition but also by their prominent ability to affect the vasculature to expedite selective cell recruitment and permeability changes and to set the stage for an appropriate acquired response. MCs, harboring a wide range of surface membrane receptors, are activated by the major female sex hormones as well as by diverse potentially adverse stimuli. MC activation/degranulation creates a presumably unique triad tissue response in physiological and pathological situations alike: extracellular matrix degradation and tissue remodeling, de novo cell proliferation, and de novo angiogenesis. As shown in the literature, MC-activation is crucial for successful female reproduction in the mouse, implying one of possibly several yet unidentified physiological roles of MCs. Moreover, the activated MC aids newborns to survive to reproductive age owing to its key beneficial actions in inflammation and wound healing. Thus, a not previously described life-perpetuating loop spanning generations are apparently formed, which, hypothetically, could contribute to the continued survival of the vertebrates.
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Affiliation(s)
- Klas Norrby
- Department of Pathology, Institute of Biomedicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
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10
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Rezaeiamiri E, Asadi M, Hosseini FS, Amanlou A, Dehpour AR, Amanlou M. Thebaine Derivatives as a New Regulator of Tumor Angiogenesis. Polycycl Aromat Compd 2022. [DOI: 10.1080/10406638.2021.1922471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- Elnaz Rezaeiamiri
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Asadi
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Faezeh Sadat Hosseini
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Arash Amanlou
- Faculty of Specialized Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Ahmad Reza Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Massoud Amanlou
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
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11
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Autoantibodies to IgE can induce the release of proinflammatory and vasoactive mediators from human cardiac mast cells. Clin Exp Med 2022:10.1007/s10238-022-00861-w. [PMID: 35879625 PMCID: PMC10390627 DOI: 10.1007/s10238-022-00861-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 06/30/2022] [Indexed: 11/03/2022]
Abstract
Mast cells are multifunctional immune cells with complex roles in tissue homeostasis and disease. Cardiac mast cells (HCMCs) are strategically located within the human myocardium, in atherosclerotic plaques, in proximity to nerves, and in the aortic valve. HCMCs express the high-affinity receptor (FcεRI) for IgE and can be activated by anti-IgE and anti-FcεRI. Autoantibodies to IgE and/or FcεRI have been found in the serum of patients with a variety of immune disorders. We have compared the effects of different preparations of IgG anti-IgE obtained from patients with atopic dermatitis (AD) with rabbit IgG anti-IgE on the release of preformed (histamine and tryptase) and lipid mediators [prostaglandin D2 (PGD2) and cysteinyl leukotriene C4 (LTC4)] from HCMCs. Functional human IgG anti-IgE from one out of six AD donors and rabbit IgG anti-IgE induced the release of preformed (histamine, tryptase) and de novo synthesized mediators (PGD2 and LTC4) from HCMCs. Human IgG anti-IgE was more potent than rabbit IgG anti-IgE in inducing proinflammatory mediators from HCMCs. Human monoclonal IgE was a competitive antagonist of both human and rabbit IgG anti-IgE. Although functional anti-IgE autoantibodies rarely occur in patients with AD, when present, they can powerfully activate the release of proinflammatory and vasoactive mediators from HCMCs.
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12
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Angiogenesis, Lymphangiogenesis, and Inflammation in Chronic Obstructive Pulmonary Disease (COPD): Few Certainties and Many Outstanding Questions. Cells 2022; 11:cells11101720. [PMID: 35626756 PMCID: PMC9139415 DOI: 10.3390/cells11101720] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 05/20/2022] [Accepted: 05/21/2022] [Indexed: 02/07/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation, predominantly affecting the lung parenchyma and peripheral airways, that results in progressive and irreversible airflow obstruction. COPD development is promoted by persistent pulmonary inflammation in response to several stimuli (e.g., cigarette smoke, bacterial and viral infections, air pollution, etc.). Angiogenesis, the formation of new blood vessels, and lymphangiogenesis, the formation of new lymphatic vessels, are features of airway inflammation in COPD. There is compelling evidence that effector cells of inflammation (lung-resident macrophages and mast cells and infiltrating neutrophils, eosinophils, basophils, lymphocytes, etc.) are major sources of a vast array of angiogenic (e.g., vascular endothelial growth factor-A (VEGF-A), angiopoietins) and/or lymphangiogenic factors (VEGF-C, -D). Further, structural cells, including bronchial and alveolar epithelial cells, endothelial cells, fibroblasts/myofibroblasts, and airway smooth muscle cells, can contribute to inflammation and angiogenesis in COPD. Although there is evidence that alterations of angiogenesis and, to a lesser extent, lymphangiogenesis, are associated with COPD, there are still many unanswered questions.
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13
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Meghnem D, Leong E, Pinelli M, Marshall JS, Di Cara F. Peroxisomes Regulate Cellular Free Fatty Acids to Modulate Mast Cell TLR2, TLR4, and IgE-Mediated Activation. Front Cell Dev Biol 2022; 10:856243. [PMID: 35756999 PMCID: PMC9215104 DOI: 10.3389/fcell.2022.856243] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 04/12/2022] [Indexed: 11/17/2022] Open
Abstract
Mast cells are specialized, tissue resident, immune effector cells able to respond to a wide range of stimuli. MCs are involved in the regulation of a variety of physiological functions, including vasodilation, angiogenesis and pathogen elimination. In addition, MCs recruit and regulate the functions of many immune cells such as dendritic cells, macrophages, T cells, B cells and eosinophils through their selective production of multiple cytokines and chemokines. MCs generate and release multi-potent molecules, such as histamine, proteases, prostanoids, leukotrienes, heparin, and many cytokines, chemokines, and growth factors through both degranulation dependent and independent pathways. Recent studies suggested that metabolic shifts dictate the activation and granule content secretion by MCs, however the metabolic signaling promoting these events is at its infancy. Lipid metabolism is recognized as a pivotal immunometabolic regulator during immune cell activation. Peroxisomes are organelles found across all eukaryotes, with a pivotal role in lipid metabolism and the detoxification of reactive oxygen species. Peroxisomes are one of the emerging axes in immunometabolism. Here we identified the peroxisome as an essential player in MCs activation. We determined that lack of functional peroxisomes in murine MCs causes a significant reduction of interleukin-6, Tumor necrosis factor and InterleukinL-13 following immunoglobulin IgE-mediated and Toll like receptor 2 and 4 activation compared to the Wild type (WT) BMMCs. We linked these defects in cytokine release to defects in free fatty acids homeostasis. In conclusion, our study identified the importance of peroxisomal fatty acids homeostasis in regulating mast cell-mediated immune functions.
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Affiliation(s)
- Dihia Meghnem
- Dalhousie Human Immunology and Inflammation Group, Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
- Department of Pediatrics, Nova Scotia Health Authority IWK, Halifax, NS, Canada
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Edwin Leong
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
| | - Marinella Pinelli
- Department of Pediatrics, Nova Scotia Health Authority IWK, Halifax, NS, Canada
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Jean S. Marshall
- Dalhousie Human Immunology and Inflammation Group, Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
- *Correspondence: Jean S. Marshall, ; Francesca Di Cara,
| | - Francesca Di Cara
- Department of Pediatrics, Nova Scotia Health Authority IWK, Halifax, NS, Canada
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
- *Correspondence: Jean S. Marshall, ; Francesca Di Cara,
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14
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Mast Cell–Tumor Interactions: Molecular Mechanisms of Recruitment, Intratumoral Communication and Potential Therapeutic Targets for Tumor Growth. Cells 2022; 11:cells11030349. [PMID: 35159157 PMCID: PMC8834237 DOI: 10.3390/cells11030349] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 01/08/2022] [Accepted: 01/13/2022] [Indexed: 12/13/2022] Open
Abstract
Mast cells (MCs) are tissue-resident immune cells that are important players in diseases associated with chronic inflammation such as cancer. Since MCs can infiltrate solid tumors and promote or limit tumor growth, a possible polarization of MCs to pro-tumoral or anti-tumoral phenotypes has been proposed and remains as a challenging research field. Here, we review the recent evidence regarding the complex relationship between MCs and tumor cells. In particular, we consider: (1) the multifaceted role of MCs on tumor growth suggested by histological analysis of tumor biopsies and studies performed in MC-deficient animal models; (2) the signaling pathways triggered by tumor-derived chemotactic mediators and bioactive lipids that promote MC migration and modulate their function inside tumors; (3) the possible phenotypic changes on MCs triggered by prevalent conditions in the tumor microenvironment (TME) such as hypoxia; (4) the signaling pathways that specifically lead to the production of angiogenic factors, mainly VEGF; and (5) the possible role of MCs on tumor fibrosis and metastasis. Finally, we discuss the novel literature on the molecular mechanisms potentially related to phenotypic changes that MCs undergo into the TME and some therapeutic strategies targeting MC activation to limit tumor growth.
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15
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Costa AC, Santos JMO, Gil da Costa RM, Medeiros R. Impact of immune cells on the hallmarks of cancer: A literature review. Crit Rev Oncol Hematol 2021; 168:103541. [PMID: 34801696 DOI: 10.1016/j.critrevonc.2021.103541] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 10/15/2021] [Accepted: 11/15/2021] [Indexed: 12/20/2022] Open
Abstract
Tumor-infiltrating immune cells (TIICs) are critical players in the tumor microenvironment, modulating cancer cell functions. TIICs are highly heterogenic and plastic and may either suppress cancers or provide support for tumor growth. A wide range of studies have shed light on how tumor-associated macrophages, dendritic cells, neutrophils, mast cells, natural killer cells and lymphocytes contribute for the establishment of several hallmarks of cancer and became the basis for successful immunotherapies. Many of those TIICs play pivotal roles in several hallmarks of cancer. This review contributes to elucidate the multifaceted roles of immune cells in cancer development, highlighting molecular components that constitute promising therapeutic targets. Additional studies are needed to clarify the relation between TIICs and hallmarks such as enabling replicative immortality, evading growth suppressors, sustaining proliferative signaling, resisting cell death and genome instability and mutation, to further explore their therapeutic potential and improve the outcomes of cancer patients.
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Affiliation(s)
- Alexandra C Costa
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; Faculty of Medicine of the University of Porto (FMUP), 4200-319, Porto, Portugal.
| | - Joana M O Santos
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; Faculty of Medicine of the University of Porto (FMUP), 4200-319, Porto, Portugal.
| | - Rui M Gil da Costa
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Inov4Agro, University of Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal; LEPABE - Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465, Porto, Portugal; Postgraduate Programme in Adult Health (PPGSAD), Department of Morphology, Federal University of Maranhão (UFMA), and UFMA University Hospital (HUUFMA), 65080-805, São Luís, Brazil.
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; Faculty of Medicine of the University of Porto (FMUP), 4200-319, Porto, Portugal; Virology Service, Portuguese Oncology Institute of Porto (IPO Porto), 4200-072, Porto, Portugal; CEBIMED, Faculty of Health Sciences of the Fernando Pessoa University, 4249-004, Porto, Portugal; Research Department of the Portuguese League Against Cancer-Regional Nucleus of the North (Liga Portuguesa Contra o Cancro-Núcleo Regional do Norte), 4200-177, Porto, Portugal.
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16
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Liu H, Yang Y. Identification of Mast Cell-Based Molecular Subtypes and a Predictive Signature in Clear Cell Renal Cell Carcinoma. Front Mol Biosci 2021; 8:719982. [PMID: 34646862 PMCID: PMC8503328 DOI: 10.3389/fmolb.2021.719982] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 09/13/2021] [Indexed: 12/31/2022] Open
Abstract
Background: Kidney renal clear cell carcinoma (KIRC) is a common malignant tumor of the urinary system. Surgery is the preferred treatment option; however, the rate of distant metastasis is high. Mast cells in the tumor microenvironment promote or inhibit tumorigenesis depending on the cancer type; however, their role in KIRC is not well-established. Here, we used a bioinformatics approach to evaluate the roles of mast cells in KIRC. Methods: To quantify mast cell abundance based on gene sets, a single-sample gene set enrichment analysis (ssGSEA) was utilized to analyze three datasets. Weighted correlation network analysis (WGCNA) was used to identify the genes most closely related to mast cells. To identify new molecular subtypes, the nonnegative matrix factorization algorithm was used. GSEA and least absolute shrinkage and selection operator (LASSO) Cox regression were used to identify genes with high prognostic value. A multivariate Cox regression analysis was performed to establish a prognostic model based on mast cell-related genes. Promoter methylation levels of mast cell-related genes and relationships between gene expression and survival were evaluated using the UALCAN and GEPIA databases. Results: A prolonged survival in KIRC was associated with a high mast cell abundance. KIRC was divided into two molecular subtypes (cluster 1 and cluster 2) based on mast cell-related genes. Genes in Cluster 1 were enriched for various functions related to cancer development, such as the TGFβ signaling pathway, renal cell carcinoma, and mTOR signaling pathway. Based on drug sensitivity predictions, sensitivity to doxorubicin was higher for cluster 2 than for cluster 1. By a multivariate Cox analysis, we established a clinical prognostic model based on eight mast cell-related genes. Conclusion: We identified eight mast cell-related genes and constructed a clinical prognostic model. These results improve our understanding of the roles of mast cells in KIRC and may contribute to personalized medicine.
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Affiliation(s)
- Hanxiang Liu
- Pediatric Urology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yi Yang
- Pediatric Urology, Shengjing Hospital of China Medical University, Shenyang, China
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17
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Ribatti D, Annese T, Tamma R. Adipocytes, mast cells and angiogenesis. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY 2021; 61:1051-1056. [PMID: 34171054 PMCID: PMC8343648 DOI: 10.47162/rjme.61.4.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
Healthy adipose tissue contains a wide variety of innate and adaptive immune cells, including macrophages, dendritic cells, mast cells, eosinophils, neutrophils, and lymphocytes. Numerous signaling molecules in the adipose microenvironment can positively or negatively modulate angiogenic processes, regulate the interaction between the vascular system and adipocytes, and participate in tumor progression. Mast cells are involved in the new formation or metabolism of fat, are present in abundant quantities in fatty tissue, among fat cells, and a number of mediators released from mast cells play a role in adipogenesis. Moreover, mast cells produce several pro-angiogenic factors and are involved in tumor angiogenesis. In this context, the angiogenic effect might be amplified when the adipocytes and mast cells act in concert, and treatment of adipose tissue- and mast cell-associated cancers with anti-angiogenic drugs may represent an alternative or adjuvant strategy for the treatment of these tumors.
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Affiliation(s)
- Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy;
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18
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Okumo T, Furuta A, Kimura T, Yusa K, Asano K, Sunagawa M. Inhibition of Angiogenic Factor Productions by Quercetin In Vitro and In Vivo. MEDICINES 2021; 8:medicines8050022. [PMID: 34065895 PMCID: PMC8150841 DOI: 10.3390/medicines8050022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 05/06/2021] [Accepted: 05/08/2021] [Indexed: 12/21/2022]
Abstract
Background: Angiogenesis is well known to be an important event in the tissue remodeling observed in allergic diseases. Although there is much evidence that quercetin, one of the most abundant dietary flavonoids, exerts anti-allergic effects in both human and experimental animal models of allergic diseases, the action of quercetin on angiogenesis has not been defined. Therefore, in this study, we first examined the action of quercetin on the secretion of angiogenic factors from murine mast cells in vitro. We also examined the action of quercetin on angiogenic factor secretion in the murine allergic rhinitis model in vivo. Methods: Mast cells (1 × 105 cells/mL) sensitized with ovalbumin (OVA)-specific murine IgE were stimulated with 10.0 ng/mL OVA in the presence or the absence of quercetin for 24 h. The concentrations of angiogenic factors, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor necrosis factor-α, IL-6 and IL-8 in the supernatants were examined by ELISA. BALB/c male mice immunized with OVA were challenged intranasally with OVA every other day, starting seven days after the final immunization. These mice were then orally administered quercetin once a day for five days, starting seven days after the final immunization. Clinical symptoms were assessed by counting the number of sneezes and nasal rubbing behaviors during the 10 min period just after OVA nasal provocation. The angiogenic factor concentrations in the nasal lavage fluids obtained 6 h after nasal antigenic provocation were examined by ELISA. Results: Quercetin significantly inhibited the production of angiogenetic factors induced by IgE-dependent mechanisms at 5.0 µM or more. Oral administration of 25.0 mg/kg quercetin into the mice also suppressed the appearance of angiogenetic factors in nasal lavage fluids, along with the attenuation of nasal symptoms. Conclusions: These results strongly suggest that the inhibitory action of quercetin on angiogenic factor secretion may be implicated in the therapeutic action of quercetin on allergic diseases, especially allergic rhinitis.
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Affiliation(s)
- Takayuki Okumo
- Department of Physiology, Showa University School of Medicine, Tokyo 142-8555, Japan; (T.O.); (T.K.); (K.Y.); (M.S.)
| | - Atsuko Furuta
- Department of Medical Education, Showa University School of Medicine, Tokyo 142-8555, Japan;
| | - Tarou Kimura
- Department of Physiology, Showa University School of Medicine, Tokyo 142-8555, Japan; (T.O.); (T.K.); (K.Y.); (M.S.)
| | - Kanako Yusa
- Department of Physiology, Showa University School of Medicine, Tokyo 142-8555, Japan; (T.O.); (T.K.); (K.Y.); (M.S.)
| | - Kazuhito Asano
- Faculty of Human Sciences, University of Human Arts and Sciences, Saitama 339-8555, Japan
- Correspondence: ; Tel.: +81-48-758-7111
| | - Masataka Sunagawa
- Department of Physiology, Showa University School of Medicine, Tokyo 142-8555, Japan; (T.O.); (T.K.); (K.Y.); (M.S.)
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Geindreau M, Ghiringhelli F, Bruchard M. Vascular Endothelial Growth Factor, a Key Modulator of the Anti-Tumor Immune Response. Int J Mol Sci 2021; 22:4871. [PMID: 34064508 PMCID: PMC8124522 DOI: 10.3390/ijms22094871] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/27/2021] [Accepted: 05/02/2021] [Indexed: 12/12/2022] Open
Abstract
During tumor growth, angiogenesis is required to ensure oxygen and nutrient transport to the tumor. Vascular endothelial growth factor (VEGF) is the major inducer of angiogenesis and appears to be a key modulator of the anti-tumor immune response. Indeed, VEGF modulates innate and adaptive immune responses through direct interactions and indirectly by modulating protein expressions on endothelial cells or vascular permeability. The inhibition of the VEGF signaling pathway is clinically approved for the treatment of several cancers. Therapies targeting VEGF can modulate the tumor vasculature and the immune response. In this review, we discuss the roles of VEGF in the anti-tumor immune response. In addition, we summarize therapeutic strategies based on its inhibition, and their clinical approval.
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Affiliation(s)
- Mannon Geindreau
- Faculté des Sciences de Santé, Université Bourgogne Franche-Comté, 21000 Dijon, France;
- Team “CAdIR”, CRI INSERM UMR1231 “Lipids, Nutrition and Cancer”, 21000 Dijon, France
- LipSTIC LabEx, 21000 Dijon, France;
| | - François Ghiringhelli
- LipSTIC LabEx, 21000 Dijon, France;
- Centre Georges François Leclerc, 21000 Dijon, France
| | - Mélanie Bruchard
- Faculté des Sciences de Santé, Université Bourgogne Franche-Comté, 21000 Dijon, France;
- Team “CAdIR”, CRI INSERM UMR1231 “Lipids, Nutrition and Cancer”, 21000 Dijon, France
- LipSTIC LabEx, 21000 Dijon, France;
- Centre Georges François Leclerc, 21000 Dijon, France
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20
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Mast Cells and Skin and Breast Cancers: A Complicated and Microenvironment-Dependent Role. Cells 2021; 10:cells10050986. [PMID: 33922465 PMCID: PMC8146516 DOI: 10.3390/cells10050986] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/18/2021] [Accepted: 04/20/2021] [Indexed: 12/24/2022] Open
Abstract
Mast cells are important sentinel cells in host defense against infection and major effector cells in allergic disease. The role of these cells in cancer settings has been widely debated. The diverse range of mast cell functions in both immunity and tissue remodeling events, such as angiogenesis, provides multiple opportunities for mast cells to modify the tumor microenvironment. In this review, we consider both skin and breast cancer settings to address the controversy surrounding the importance of mast cells in the host response to tumors. We specifically address the key mediators produced by mast cells which impact tumor development. The role of environmental challenges in modifying mast cell responses and opportunities to modify mast cell responses to enhance anti-tumor immunity are also considered. While the mast cell's role in many cancer contexts is complicated and poorly understood, the activities of these tissue resident and radioresistant cells can provide important opportunities to enhance anti-cancer responses and limit cancer development.
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21
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Marcella S, Petraroli A, Braile M, Parente R, Ferrara AL, Galdiero MR, Modestino L, Cristinziano L, Rossi FW, Varricchi G, Triggiani M, de Paulis A, Spadaro G, Loffredo S. Vascular endothelial growth factors and angiopoietins as new players in mastocytosis. Clin Exp Med 2021; 21:415-427. [PMID: 33687603 PMCID: PMC8266723 DOI: 10.1007/s10238-021-00693-0] [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: 12/18/2020] [Accepted: 02/08/2021] [Indexed: 12/27/2022]
Abstract
Mastocytosis is a disorder characterized by the abnormal proliferation and/or accumulation of mast cells in different organs. More than 90% of patients with systemic mastocytosis have a gain-of-function mutation in codon 816 of the KIT receptor on mast cells (MCs). The symptoms of mastocytosis patients are related to the MC-derived mediators that exert local and distant effects. MCs produce angiogenic and lymphangiogenic factors, including vascular endothelial growth factors (VEGFs) and angiopoietins (ANGPTs). Serum concentrations of VEGF-A, VEGF-C, VEGF-D, ANGPT1 and ANGPT2 were determined in 64 mastocytosis patients and 64 healthy controls. Intracellular concentrations and spontaneous release of these mediators were evaluated in the mast cell lines ROSAKIT WT and ROSA KIT D816V and in human lung mast cells (HLMCs). VEGF-A, ANGPT1, ANGPT2 and VEGF-C concentrations were higher in mastocytosis patients compared to controls. The VEGF-A, ANGPT2 and VEGF-C concentrations were correlated with the symptom severity. ANGPT1 concentrations were increased in all patients compared to controls. ANGPT2 levels were correlated with severity of clinical variants and with tryptase levels. VEGF-A, ANGPT1 and VEGF-C did not differ between indolent and advanced mastocytosis. ROSAKIT WT, ROSAKIT D816V and HLMCs contained and spontaneously released VEGFs and ANGPTs. Serum concentrations of VEGFs and ANGPTs are altered in mastocytosis patients.
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Affiliation(s)
- Simone Marcella
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy
| | - Angelica Petraroli
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy
| | - Mariantonia Braile
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy
| | - Roberta Parente
- Division of Allergy and Clinical Immunology, University of Salerno, 84084, Fisciano, SA, Italy
| | - Anne Lise Ferrara
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy.,Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, 80131, Naples, Italy
| | - Maria Rosaria Galdiero
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy.,Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, 80131, Naples, Italy
| | - Luca Modestino
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy
| | - Leonardo Cristinziano
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy
| | - Francesca Wanda Rossi
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy
| | - Gilda Varricchi
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy. .,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy. .,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy. .,Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, 80131, Naples, Italy.
| | - Massimo Triggiani
- Division of Allergy and Clinical Immunology, University of Salerno, 84084, Fisciano, SA, Italy
| | - Amato de Paulis
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy
| | - Giuseppe Spadaro
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy
| | - Stefania Loffredo
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy. .,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy. .,World Allergy Organization (WAO) Center of Excellence, 80131, Naples, Italy. .,Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, 80131, Naples, Italy.
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22
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Monteleone NJ, Lutz CS. miR-708-5p enhances erlotinib/paclitaxel efficacy and overcomes chemoresistance in lung cancer cells. Oncotarget 2020; 11:4699-4721. [PMID: 33473256 PMCID: PMC7771713 DOI: 10.18632/oncotarget.27840] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 11/23/2020] [Indexed: 12/16/2022] Open
Abstract
Lung cancer is a collection of aggressive tumors generally not diagnosed until late-stage, resulting in high mortality rates. The vast majority of non-small cell lung cancer (NSCLC) patients undergo combinatory chemotherapeutic treatment, which initially reduces tumor growth, but frequently becomes ineffective due to toxicity and resistance. Researchers have identified multiple signaling pathways involved in lung cancer chemoresistance, including cyclooxygenase-2 (COX-2)/microsomal prostaglandin E synthase-1 (mPGES-1) derived prostaglandin E2 (PGE2). While COX-2 inhibitors have shown promise in the clinic, their use is limited due to severe side effects. One novel approach to effectively suppress COX-2 signaling is through microRNA (miRNA). MiRNAs are small-noncoding RNAs commonly misexpressed in cancer. One tumor suppressive miRNA, miR-708-5p, has been shown to repress pro-resistant signaling pathways, including COX-2 and mPGES-1. Here, we demonstrate that chemotherapies reduce COX-2 expression, possibly through induction of miR-708-5p. Moreover, combination treatment of erlotinib (ERL) or paclitaxel (PAC) with miR-708-5p enhances COX-2 and mPGES-1 protein suppression. We also show that combination chemotherapeutic and miR-708-5p treatment intensifies the anti-proliferative and pro-apoptotic effects of ERL and PAC. We also created ERL and PAC resistant lung cancer cell lines, which have increased COX-2 expression and diminished miR-708-5p levels compared to naïve lung cancer cells. While ERL and PAC treatments do not alter resistant cell phenotype alone, combination treatment with miR-708-5p partially restores the chemotherapies' anti-proliferative effects and fully restores their pro-apoptotic qualities. These data suggest miR-708-5p may have potential combinatory therapeutic value to more efficaciously treat lung tumors while overcoming chemoresistance.
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Affiliation(s)
- Nicholas J Monteleone
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical & Health Sciences, New Jersey Medical School, School of Graduate Studies, Newark, NJ 07103, USA
| | - Carol S Lutz
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical & Health Sciences, New Jersey Medical School, School of Graduate Studies, Newark, NJ 07103, USA
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23
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Legere SA, Haidl ID, Castonguay MC, Brunt KR, Légaré JF, Marshall JS. Increased mast cell density is associated with decreased fibrosis in human atrial tissue. J Mol Cell Cardiol 2020; 149:15-26. [PMID: 32931784 DOI: 10.1016/j.yjmcc.2020.09.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 07/29/2020] [Accepted: 09/02/2020] [Indexed: 12/31/2022]
Abstract
Fibrotic remodelling of the atria is poorly understood and can be regulated by myocardial immune cell populations after injury. Mast cells are resident immune sentinel cells present in the heart that respond to tissue damage and have been linked to fibrosis in other settings. The role of cardiac mast cells in fibrotic remodelling in response to human myocardial injury is controversial. In this study, we sought to determine the association between mast cells, atrial fibrosis, and outcomes in a heterogeneous population of cardiac surgical patients, including a substantial proportion of coronary artery bypass grafting patients. Atrial appendage from patients was assessed for collagen and mast cell density by histology and by droplet digital polymerase chain reaction (ddPCR) for mast cell associated transcripts. Clinical variables and outcomes were also followed. Mast cells were detected in human atrial tissue at varying densities. Histological and ddPCR assessment of mast cells in atrial tissue were closely correlated. Patients with high mast cell density had less fibrosis and lower severity of heart failure classification or incidence mortality than patients with low mast cell content. Analysis of a homogeneous population of coronary artery bypass graft patients yielded similar observations. Therefore, evidence from this study suggests that increased atrial mast cell populations are associated with decreased clinical cardiac fibrotic remodelling and improved outcomes, in cardiac surgery patients.
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Affiliation(s)
- Stephanie A Legere
- Dalhousie University, Department of Microbiology and Immunology, Halifax, NS, Canada; Dalhousie Human Immunology and Inflammation Group, Dalhousie University, Halifax, NS, Canada; IMPART Investigator Team Canada, Canada
| | - Ian D Haidl
- Dalhousie University, Department of Microbiology and Immunology, Halifax, NS, Canada; Dalhousie Human Immunology and Inflammation Group, Dalhousie University, Halifax, NS, Canada
| | - Mathieu C Castonguay
- Department of Pathology and Laboratory Medicine, QEII Health Sciences Centre, Halifax, NS, Canada
| | - Keith R Brunt
- Dalhousie Medicine New Brunswick, Department of Pharmacology, Saint John, NB, Canada; New Brunswick Heart Centre, Saint John, NB, Canada; IMPART Investigator Team Canada, Canada
| | - Jean-François Légaré
- Dalhousie Human Immunology and Inflammation Group, Dalhousie University, Halifax, NS, Canada; Dalhousie Medicine New Brunswick, Department of Pharmacology, Saint John, NB, Canada; New Brunswick Heart Centre, Saint John, NB, Canada; IMPART Investigator Team Canada, Canada
| | - Jean S Marshall
- Dalhousie University, Department of Microbiology and Immunology, Halifax, NS, Canada; Dalhousie Human Immunology and Inflammation Group, Dalhousie University, Halifax, NS, Canada; IMPART Investigator Team Canada, Canada.
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24
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Monteleone NJ, Lutz CS. miR-708-5p targets oncogenic prostaglandin E2 production to suppress a pro-tumorigenic phenotype in lung cancer cells. Oncotarget 2020; 11:2464-2483. [PMID: 32655834 PMCID: PMC7335672 DOI: 10.18632/oncotarget.27614] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 05/14/2020] [Indexed: 12/13/2022] Open
Abstract
Many cancers maintain an inflammatory microenvironment to promote their growth. Lung cancer is of particular importance, as it is the deadliest cancer worldwide. One inflammatory pathway commonly dysregulated in cancer is the metabolism of arachidonic acid (AA) by Cyclooxygenase-2 (COX-2) and microsomal Prostaglandin E Synthase 1 (mPGES-1) into Prostaglandin E2 (PGE2). While researchers have identified PGE2's pro-tumorigenic functions, the mechanisms governing overexpression of COX-2 and mPGES-1 are incompletely understood. MicroRNAs (miRNAs) are important post-transcriptional regulators commonly dysregulated in cancer. Interestingly, miR-708-5p (miR-708) is predicted to target both COX-2 and mPGES-1. In this study, we show that high miR-708 expression is associated with survival rates in lung squamous cell carcinoma patients. miR-708 also represses PGE2 production by suppressing both COX-2 and mPGES-1 expression in lung cancer cells. miR-708 regulation of COX-2 and mPGES-1 is mediated through targeting of their 3' untranslated regions (UTRs). Moreover, miR-708 decreases proliferation, survival, and migration of lung cancer cells, which can be partially attributed to miR-708's inhibition of PGE2 signaling. Lastly, we identify novel miR-708 predicted targets and possible regulators of miR-708 expression in lung cancer. Collectively, these data demonstrate that dysregulated miR-708 expression contributes to exacerbated PGE2 production, leading to an enhanced pro-tumorigenic phenotype in lung cancer cells.
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Affiliation(s)
- Nicholas J. Monteleone
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical & Health Sciences, New Jersey Medical School, School of Graduate Studies, Newark, NJ 07103, USA
| | - Carol S. Lutz
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical & Health Sciences, New Jersey Medical School, School of Graduate Studies, Newark, NJ 07103, USA
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25
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HIV gp120 Induces the Release of Proinflammatory, Angiogenic, and Lymphangiogenic Factors from Human Lung Mast Cells. Vaccines (Basel) 2020; 8:vaccines8020208. [PMID: 32375243 PMCID: PMC7349869 DOI: 10.3390/vaccines8020208] [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: 04/03/2020] [Revised: 04/27/2020] [Accepted: 04/30/2020] [Indexed: 02/07/2023] Open
Abstract
Human lung mast cells (HLMCs) express the high-affinity receptor FcεRI for IgE and are involved in chronic pulmonary diseases occurring at high frequency among HIV-infected individuals. Immunoglobulin superantigens bind to the variable regions of either the heavy or light chain of immunoglobulins (Igs). Glycoprotein 120 (gp120) of HIV-1 is a typical immunoglobulin superantigen interacting with the heavy chain, variable 3 (VH3) region of human Igs. The present study investigated whether immunoglobulin superantigen gp120 caused the release of different classes of proinflammatory and immunoregulatory mediators from HLMCs. The results show that gp120 from different clades induced the rapid (30 min) release of preformed mediators (histamine and tryptase) from HLMCs. gp120 also caused the de novo synthesis of cysteinyl leukotriene C4 (LTC4) and prostaglandin D2 (PGD2) from HLMCs. Incubation (6 h) of HLMC with gp120 induced the release of angiogenic (VEGF-A) and lymphangiogenic (VEGF-C) factors from HLMCs. The activating property of gp120 was mediated through the interaction with IgE VH3+ bound to FcεRI. Our data indicate that HIV gp120 is a viral superantigen, which induces the release of different proinflammatory, angiogenic, and lymphangiogenic factors from HLMCs. These observations could contribute to understanding, at least in part, the pathophysiology of chronic pulmonary diseases in HIV-infected individuals.
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26
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Fusco R, Siracusa R, D’Amico R, Peritore AF, Cordaro M, Gugliandolo E, Crupi R, Impellizzeri D, Cuzzocrea S, Di Paola R. Melatonin Plus Folic Acid Treatment Ameliorates Reserpine-Induced Fibromyalgia: An Evaluation of Pain, Oxidative Stress, and Inflammation. Antioxidants (Basel) 2019; 8:antiox8120628. [PMID: 31817734 PMCID: PMC6943570 DOI: 10.3390/antiox8120628] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 11/27/2019] [Accepted: 12/05/2019] [Indexed: 12/11/2022] Open
Abstract
Background: Fibromyalgia is a chronic condition characterized by increased sensory perception of pain, neuropathic/neurodegenerative modifications, oxidative, and nitrosative stress. An appropriate therapy is hard to find, and the currently used treatments are able to target only one of these aspects. Methods: The aim of this study is to investigate the beneficial effects of melatonin plus folic acid administration in a rat model of reserpine-induced fibromyalgia. Sprague–Dawley male rats were injected with 1 mg/kg of reserpine for three consecutive days and later administered with melatonin, folic acid, or both for twenty-one days. Results: Administration of reserpine led to a significant decrease in the nociceptive threshold as well as a significant increase in depressive-like symptoms. These behavioral changes were accompanied by increased oxidative and nitrosative stress. Lipid peroxidation was significantly increased, as well as nitrotyrosine and PARP expression, while superoxide dismutase, nonprotein thiols, and catalase were significantly decreased. Endogenously produced oxidants species are responsible for mast cell infiltration, increased expression pro-inflammatory mediators, and microglia activation. Conclusion: Melatonin plus acid folic administration is able to ameliorate the behavioral defects, oxidative and nitrosative stress, mast cell infiltration, inflammatory mediators overexpression, and microglia activation induced by reserpine injection with more efficacy than their separate administration.
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Affiliation(s)
- Roberta Fusco
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy; (R.F.); (R.S.); (A.F.P.); (M.C.); (E.G.); (R.C.); (R.D.P.)
| | - Rosalba Siracusa
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy; (R.F.); (R.S.); (A.F.P.); (M.C.); (E.G.); (R.C.); (R.D.P.)
| | - Ramona D’Amico
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy; (R.F.); (R.S.); (A.F.P.); (M.C.); (E.G.); (R.C.); (R.D.P.)
| | - Alessio Filippo Peritore
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy; (R.F.); (R.S.); (A.F.P.); (M.C.); (E.G.); (R.C.); (R.D.P.)
| | - Marika Cordaro
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy; (R.F.); (R.S.); (A.F.P.); (M.C.); (E.G.); (R.C.); (R.D.P.)
| | - Enrico Gugliandolo
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy; (R.F.); (R.S.); (A.F.P.); (M.C.); (E.G.); (R.C.); (R.D.P.)
| | - Rosalia Crupi
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy; (R.F.); (R.S.); (A.F.P.); (M.C.); (E.G.); (R.C.); (R.D.P.)
| | - Daniela Impellizzeri
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy; (R.F.); (R.S.); (A.F.P.); (M.C.); (E.G.); (R.C.); (R.D.P.)
- Correspondence: (D.I.); (S.C.); Tel.: +39-90-6765208 (D.I. & S.C.)
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy; (R.F.); (R.S.); (A.F.P.); (M.C.); (E.G.); (R.C.); (R.D.P.)
- Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Blvd, St. Louis, MO 63104, USA
- Correspondence: (D.I.); (S.C.); Tel.: +39-90-6765208 (D.I. & S.C.)
| | - Rosanna Di Paola
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy; (R.F.); (R.S.); (A.F.P.); (M.C.); (E.G.); (R.C.); (R.D.P.)
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27
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Varricchi G, de Paulis A, Marone G, Galli SJ. Future Needs in Mast Cell Biology. Int J Mol Sci 2019; 20:E4397. [PMID: 31500217 PMCID: PMC6769913 DOI: 10.3390/ijms20184397] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 09/02/2019] [Accepted: 09/04/2019] [Indexed: 12/14/2022] Open
Abstract
The pathophysiological roles of mast cells are still not fully understood, over 140 years since their description by Paul Ehrlich in 1878. Initial studies have attempted to identify distinct "subpopulations" of mast cells based on a relatively small number of biochemical characteristics. More recently, "subtypes" of mast cells have been described based on the analysis of transcriptomes of anatomically distinct mouse mast cell populations. Although mast cells can potently alter homeostasis, in certain circumstances, these cells can also contribute to the restoration of homeostasis. Both solid and hematologic tumors are associated with the accumulation of peritumoral and/or intratumoral mast cells, suggesting that these cells can help to promote and/or limit tumorigenesis. We suggest that at least two major subsets of mast cells, MC1 (meaning anti-tumorigenic) and MC2 (meaning pro-tumorigenic), and/or different mast cell mediators derived from otherwise similar cells, could play distinct or even opposite roles in tumorigenesis. Mast cells are also strategically located in the human myocardium, in atherosclerotic plaques, in close proximity to nerves and in the aortic valve. Recent studies have revealed evidence that cardiac mast cells can participate both in physiological and pathological processes in the heart. It seems likely that different subsets of mast cells, like those of cardiac macrophages, can exert distinct, even opposite, effects in different pathophysiological processes in the heart. In this chapter, we have commented on possible future needs of the ongoing efforts to identify the diverse functions of mast cells in health and disease.
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Affiliation(s)
- Gilda Varricchi
- Department of Translational Medical Sciences (DISMET), University of Naples Federico II, 80138 Naples, Italy.
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, School of Medicine, 80138 Naples, Italy.
- WAO Center of Excellence, 80138 Naples, Italy.
| | - Amato de Paulis
- Department of Translational Medical Sciences (DISMET), University of Naples Federico II, 80138 Naples, Italy.
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, School of Medicine, 80138 Naples, Italy.
- WAO Center of Excellence, 80138 Naples, Italy.
| | - Gianni Marone
- Department of Translational Medical Sciences (DISMET), University of Naples Federico II, 80138 Naples, Italy.
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, School of Medicine, 80138 Naples, Italy.
- WAO Center of Excellence, 80138 Naples, Italy.
- Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOS), National Research Council (CNR), 80138 Naples, Italy.
| | - Stephen J Galli
- Departments of Pathology and of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5176, USA.
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28
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McHale C, Mohammed Z, Gomez G. Human Skin-Derived Mast Cells Spontaneously Secrete Several Angiogenesis-Related Factors. Front Immunol 2019; 10:1445. [PMID: 31293594 PMCID: PMC6603178 DOI: 10.3389/fimmu.2019.01445] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 06/10/2019] [Indexed: 12/12/2022] Open
Abstract
Mast cells are classically recognized as cells that cause IgE-mediated allergic reactions. However, their ability to store and secrete vascular endothelial growth factor (VEGF) suggests a role in vascular development and tumorigenesis. The current study sought to determine if other angiogenesis-related factors, in addition to VEGF, were also secreted by human tissue-derived mast cells. Using proteome array analysis and ELISA, we found that human skin-derived mast cells spontaneously secrete CXCL16, DPPIV, Endothelin-1, GM-CSF, IL-8, MCP-1, Pentraxin 3, Serpin E1, Serpin F1, TIMP-1, Thrombospondin-1, and uPA. We identified three groups based on their dependency for stem cell factor (SCF), which is required for mast cell survival: Endothelin-1, GM-CSF, IL-8, MCP-1, and VEGF (dependent); Pentraxin 3, Serpin E1, Serpin F1, TIMP-1, and Thrombospondin-1 (partly dependent); and CXCL16, DPPIV, and uPA (independent). Crosslinking of FcεRI with multivalent antigen enhanced the secretion of GM-CSF, Serpin E1, IL-8, and VEGF, and induced Amphiregulin and MMP-8 expression. Interestingly, FcεRI signals inhibited the spontaneous secretion of CXCL16, Endothelin-1, Serpin F1, Thrombospondin-1, MCP-1 and Pentraxin-3. Furthermore, IL-6, which we previously showed could induce VEGF, significantly enhanced MCP-1 secretion. Overall, this study identified several angiogenesis-related proteins that, in addition to VEGF, are spontaneously secreted at high concentrations from human skin-derived mast cells. These findings provide further evidence supporting an intrinsic role for mast cells in blood vessel formation.
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Affiliation(s)
- Cody McHale
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Zahraa Mohammed
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Gregorio Gomez
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, United States
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29
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Varricchi G, Rossi FW, Galdiero MR, Granata F, Criscuolo G, Spadaro G, de Paulis A, Marone G. Physiological Roles of Mast Cells: Collegium Internationale Allergologicum Update 2019. Int Arch Allergy Immunol 2019; 179:247-261. [PMID: 31137021 DOI: 10.1159/000500088] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 04/02/2019] [Indexed: 11/19/2022] Open
Abstract
Mast cells are immune cells which have a widespread distribution in nearly all tissues. These cells and their mediators are canonically viewed as primary effector cells in allergic disorders. However, in the last years, mast cells have gained recognition for their involvement in several physiological and pathological conditions. They are highly heterogeneous immune cells displaying a constellation of surface receptors and producing a wide spectrum of inflammatory and immunomodulatory mediators. These features enable the cells to act as sentinels in harmful situations as well as respond to metabolic and immune changes in their microenvironment. Moreover, they communicate with many immune and nonimmune cells implicated in several immunological responses. Although mast cells contribute to host responses in experimental infections, there is no satisfactory model to study how they contribute to infection outcome in humans. Mast cells modulate physiological and pathological angiogenesis and lymphangiogenesis, but their role in tumor initiation and development is still controversial. Cardiac mast cells store and release several mediators that can exert multiple effects in the homeostatic control of different cardiometabolic functions. Although mast cells and their mediators have been simplistically associated with detrimental roles in allergic disorders, there is increasing evidence that they can also have homeostatic or protective roles in several pathophysiological processes. These findings may reflect the functional heterogeneity of different subsets of mast cells.
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Affiliation(s)
- Gilda Varricchi
- Department of Translational Medical Sciences (DiSMeT), Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, Naples, Italy
| | - Francesca Wanda Rossi
- Department of Translational Medical Sciences (DiSMeT), Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, Naples, Italy
| | - Maria Rosaria Galdiero
- Department of Translational Medical Sciences (DiSMeT), Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, Naples, Italy
| | - Francescopaolo Granata
- Department of Translational Medical Sciences (DiSMeT), Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, Naples, Italy
| | - Gjada Criscuolo
- Department of Translational Medical Sciences (DiSMeT), Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, Naples, Italy
| | - Giuseppe Spadaro
- Department of Translational Medical Sciences (DiSMeT), Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, Naples, Italy
| | - Amato de Paulis
- Department of Translational Medical Sciences (DiSMeT), Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.,World Allergy Organization (WAO) Center of Excellence, Naples, Italy
| | - Gianni Marone
- Department of Translational Medical Sciences (DiSMeT), Naples, Italy, .,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy, .,World Allergy Organization (WAO) Center of Excellence, Naples, Italy, .,Institute of Endocrinology and Experimental Oncology (IEOS), CNR, Naples, Italy,
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30
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Sammarco G, Varricchi G, Ferraro V, Ammendola M, De Fazio M, Altomare DF, Luposella M, Maltese L, Currò G, Marone G, Ranieri G, Memeo R. Mast Cells, Angiogenesis and Lymphangiogenesis in Human Gastric Cancer. Int J Mol Sci 2019; 20:2106. [PMID: 31035644 PMCID: PMC6540185 DOI: 10.3390/ijms20092106] [Citation(s) in RCA: 135] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/15/2019] [Accepted: 04/19/2019] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer is diagnosed in nearly one million new patients each year and it remains the second leading cause of cancer-related deaths worldwide. Although gastric cancer represents a heterogeneous group of diseases, chronic inflammation has been shown to play a role in tumorigenesis. Cancer development is a multistep process characterized by genetic and epigenetic alterations during tumour initiation and progression. The stromal microenvironment is important in maintaining normal tissue homeostasis or promoting tumour development. A plethora of immune cells (i.e., lymphocytes, macrophages, mast cells, monocytes, myeloid-derived suppressor cells, Treg cells, dendritic cells, neutrophils, eosinophils, natural killer (NK) and natural killer T (NKT) cells) are components of gastric cancer microenvironment. Mast cell density is increased in gastric cancer and there is a correlation with angiogenesis, the number of metastatic lymph nodes and the survival of these patients. Mast cells exert a protumorigenic role in gastric cancer through the release of angiogenic (VEGF-A, CXCL8, MMP-9) and lymphangiogenic factors (VEGF-C and VEGF-F). Gastric mast cells express the programmed death ligands (PD-L1 and PD-L2) which are relevant as immune checkpoints in cancer. Several clinical undergoing trials targeting immune checkpoints could be an innovative therapeutic strategy in gastric cancer. Elucidation of the role of subsets of mast cells in different human gastric cancers will demand studies of increasing complexity beyond those assessing merely mast cell density and microlocalization.
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Affiliation(s)
- Giuseppe Sammarco
- Department of Health Science, General Surgery, Magna Graecia University, Medicine School of Germaneto, 88100 Catanzaro, Italy.
| | - Gilda Varricchi
- Department of Translational Medical Sciences (DISMET) and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131 Naples, Italy.
- WAO Center of Excellence, 80131 Naples, Italy.
| | - Valentina Ferraro
- Department of Biomedical Sciences and Human Oncology, Unit of Endocrine, Digestive and Emergency Surgery, Aldo Moro University, 74124 Bari, Italy.
| | - Michele Ammendola
- Department of Health Science, General Surgery, Magna Graecia University, Medicine School of Germaneto, 88100 Catanzaro, Italy.
| | - Michele De Fazio
- Department of Emergency and Organ Transplantation, Aldo Moro University, 74124 Bari, Italy.
| | | | - Maria Luposella
- Cardiovascular Disease Unit, San Giovanni di Dio Hospital, 88900 Crotone, Italy.
| | - Lorenza Maltese
- Pathology Unit, Pugliese-Ciaccio Hospital, 88100 Catanzaro, Italy.
| | - Giuseppe Currò
- Department of Health Science, General Surgery, Magna Graecia University, Medicine School of Germaneto, 88100 Catanzaro, Italy.
- Department of Human Pathology of Adult and Evolutive Age G. Barresi, University of Messina, 98122 Messina, Italy.
| | - Gianni Marone
- Department of Translational Medical Sciences (DISMET) and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131 Naples, Italy.
- WAO Center of Excellence, 80131 Naples, Italy.
- Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council (CNR), 80131 Naples, Italy.
| | - Girolamo Ranieri
- Interventional Oncology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, 74124 Bari, Italy.
| | - Riccardo Memeo
- Department of Emergency and Organ Transplantation, Aldo Moro University, 74124 Bari, Italy.
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31
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Varricchi G, Loffredo S, Borriello F, Pecoraro A, Rivellese F, Genovese A, Spadaro G, Marone G. Superantigenic Activation of Human Cardiac Mast Cells. Int J Mol Sci 2019; 20:ijms20081828. [PMID: 31013832 PMCID: PMC6514993 DOI: 10.3390/ijms20081828] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 04/09/2019] [Accepted: 04/10/2019] [Indexed: 02/06/2023] Open
Abstract
B cell superantigens, also called immunoglobulin superantigens, bind to the variable regions of either the heavy or light chain of immunoglobulins mirroring the lymphocyte-activating properties of classical T cell superantigens. Protein A of Staphylococcus aureus, protein L of Peptostreptococcus magnus, and gp120 of HIV are typical immunoglobulin superantigens. Mast cells are immune cells expressing the high-affinity receptor for IgE (FcεRI) and are strategically located in the human heart, where they play a role in several cardiometabolic diseases. Here, we investigated whether immunoglobulin superantigens induced the activation of human heart mast cells (HHMCs). Protein A induced the de novo synthesis of cysteinyl leukotriene C4 (LTC4) from HHMCs through the interaction with IgE VH3+ bound to FcεRI. Protein L stimulated the production of prostaglandin D2 (PGD2) from HHMCs through the interaction with κ light chains of IgE. HIV glycoprotein gp120 induced the release of preformed (histamine) and de novo synthesized mediators, such as cysteinyl leukotriene C4 (LTC4), angiogenic (VEGF-A), and lymphangiogenic (VEGF-C) factors by interacting with the VH3 region of IgE. Collectively, our data indicate that bacterial and viral immunoglobulin superantigens can interact with different regions of IgE bound to FcεRI to induce the release of proinflammatory, angiogenic, and lymphangiogenic factors from human cardiac mast cells.
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Affiliation(s)
- Gilda Varricchi
- Department of Translational Medical Sciences, University of Naples Federico II, 80100 Naples, Italy.
- Center for Basic and Clinical Immunology Research (CISI), 80100 Naples, Italy.
- World Allergy Organization (WAO) Center of Excellence, 80100 Naples, Italy.
| | - Stefania Loffredo
- Department of Translational Medical Sciences, University of Naples Federico II, 80100 Naples, Italy.
- Center for Basic and Clinical Immunology Research (CISI), 80100 Naples, Italy.
- World Allergy Organization (WAO) Center of Excellence, 80100 Naples, Italy.
| | - Francesco Borriello
- Department of Translational Medical Sciences, University of Naples Federico II, 80100 Naples, Italy.
- Center for Basic and Clinical Immunology Research (CISI), 80100 Naples, Italy.
- World Allergy Organization (WAO) Center of Excellence, 80100 Naples, Italy.
- Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, Boston, 02115 MA, USA.
| | - Antonio Pecoraro
- Department of Translational Medical Sciences, University of Naples Federico II, 80100 Naples, Italy.
| | - Felice Rivellese
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, E1 4NS London, UK.
| | - Arturo Genovese
- Department of Translational Medical Sciences, University of Naples Federico II, 80100 Naples, Italy.
- Center for Basic and Clinical Immunology Research (CISI), 80100 Naples, Italy.
- World Allergy Organization (WAO) Center of Excellence, 80100 Naples, Italy.
| | - Giuseppe Spadaro
- Department of Translational Medical Sciences, University of Naples Federico II, 80100 Naples, Italy.
- Center for Basic and Clinical Immunology Research (CISI), 80100 Naples, Italy.
- World Allergy Organization (WAO) Center of Excellence, 80100 Naples, Italy.
| | - Gianni Marone
- Department of Translational Medical Sciences, University of Naples Federico II, 80100 Naples, Italy.
- Center for Basic and Clinical Immunology Research (CISI), 80100 Naples, Italy.
- World Allergy Organization (WAO) Center of Excellence, 80100 Naples, Italy.
- Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore", National Research Council (CNR), 80100 Naples, Italy.
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32
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A Transcriptomic Insight into the Impact of Colon Cancer Cells on Mast Cells. Int J Mol Sci 2019; 20:ijms20071689. [PMID: 30987352 PMCID: PMC6480031 DOI: 10.3390/ijms20071689] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 03/27/2019] [Accepted: 04/01/2019] [Indexed: 12/13/2022] Open
Abstract
Mast cells (MCs) are one of the first immune cells recruited to a tumor. It is well recognized that MCs accumulate in colon cancer lesion and their density is associated with the clinical outcomes. However, the molecular mechanism of how colon cancer cells may modify MC function is still unclear. In this study, primary human MCs were generated from CD34+ progenitor cells and a 3D coculture model was developed to study the interplay between colon cancer cells and MCs. By comparing the transcriptomic profile of colon cancer-cocultured MCs versus control MCs, we identified a number of deregulated genes, such as MMP-2, VEGF-A, PDGF-A, COX2, NOTCH1 and ISG15, which contribute to the enrichment of cancer-related pathways. Intriguingly, pre-stimulation with a TLR2 agonist prior to colon cancer coculture induced upregulation of multiple interferon-inducible genes as well as MHC molecules in MCs. Our study provides an alternative approach to study the influence of colon cancer on MCs. The transcriptome signature of colon cancer-cocultured MCs may potentially reflect the mechanism of how colon cancer cells educate MCs to become pro-tumorigenic in the initial phase and how a subsequent inflammatory signal—e.g., TLR2 ligands—may modify their responses in the cancer milieu.
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Derakhshani A, Vahidian F, Alihasanzadeh M, Mokhtarzadeh A, Lotfi Nezhad P, Baradaran B. Mast cells: A double-edged sword in cancer. Immunol Lett 2019; 209:28-35. [PMID: 30905824 DOI: 10.1016/j.imlet.2019.03.011] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Accepted: 03/20/2019] [Indexed: 12/14/2022]
Abstract
Mast cells (MCs), a type of innate immune cells, are derived from myeloid stem cells, sometimes known as mastocytes or labrocytes, and contain many granules rich in histamine and heparin. The mentioned cells are able to release various mediators such as cytokines, leukotrienes, and a large number of proteases into the environment. Many studies and experiments have established the infiltration of MCs into the tumor site. However, the findings are highly controversial to determine whether these immune cells contribute to the growth and development of the tumor or cause anti-tumor immune responses. Various studies have revealed that MCs have a pro-tumorigenic or anti-tumorigenic role depending on the type of cancer, the degree of tumor progression, and the location of these immune cells in the tumor bulk. Although these types of immune cells cause angiogenesis and tumor progression in some cancers, they have a significant anti-tumor role in some other types of cancers. In general, although a number of studies have specified the protective role of MCs in cancers, the increased number of MCs in the blood and microenvironment of tumors, as well as the increased level of angiogenesis and tumor progression, has been indicated in another array of studies. The function of MCs against or in favor of the cancers still requires further investigations to more accurately and specifically determine the role of MCs in the cancers. The function of MCs in tumors and their various roles in case of exposure to the cancer cells have been addressed in the present review. The concluding section of the present study recommends a number of methods for modification of MCs in cancer immunotherapy.
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Affiliation(s)
- Afshin Derakhshani
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran; Cellular & Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Fatemeh Vahidian
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Alihasanzadeh
- Department of Immunology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parisa Lotfi Nezhad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Ribatti D, Tamma R, Vacca A. Mast Cells and Angiogenesis in Human Plasma Cell Malignancies. Int J Mol Sci 2019; 20:ijms20030481. [PMID: 30678047 PMCID: PMC6386864 DOI: 10.3390/ijms20030481] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 01/18/2019] [Accepted: 01/21/2019] [Indexed: 02/07/2023] Open
Abstract
Bone marrow angiogenesis plays an important role in the pathogenesis and progression of hematological malignancies. It is well known that tumor microenvironment promotes tumor angiogenesis, proliferation, invasion, and metastasis, and also mediates mechanisms of therapeutic resistance. An increased number of mast cells has been demonstrated in angiogenesis associated with hematological tumors. In this review we focused on the role of mast cells in angiogenesis in human plasma cell malignancies. In this context, mast cells might act as a new target for the adjuvant treatment of these tumors through the selective inhibition of angiogenesis, tissue remodeling and tumor-promoting molecules, permitting the secretion of cytotoxic cytokines and preventing mast cell-mediated immune suppression.
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Affiliation(s)
- Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, 70124 Bari, Italy.
| | - Roberto Tamma
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, 70124 Bari, Italy.
| | - Angelo Vacca
- Department of Biomedical Sciences, and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, 70124 Bari, Italy.
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35
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Abstract
Fibrosis is a medical condition characterized by an excessive deposition of extracellular matrix compounds such as collagen in tissues. Fibrotic lesions are present in many diseases and can affect all organs. The excessive extracellular matrix accumulation in these conditions can often have serious consequences and in many cases be life-threatening. A typical event seen in many fibrotic conditions is a profound accumulation of mast cells (MCs), suggesting that these cells can contribute to the pathology. Indeed, there is now substantialv evidence pointing to an important role of MCs in fibrotic disease. However, investigations from various clinical settings and different animal models have arrived at partly contradictory conclusions as to how MCs affect fibrosis, with many studies suggesting a detrimental role of MCs whereas others suggest that MCs can be protective. Here, we review the current knowledge of how MCs can affect fibrosis.
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Affiliation(s)
- Peter Bradding
- Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester, UK
| | - Gunnar Pejler
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.,Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden
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36
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Mukai K, Tsai M, Saito H, Galli SJ. Mast cells as sources of cytokines, chemokines, and growth factors. Immunol Rev 2019; 282:121-150. [PMID: 29431212 DOI: 10.1111/imr.12634] [Citation(s) in RCA: 499] [Impact Index Per Article: 83.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Mast cells are hematopoietic cells that reside in virtually all vascularized tissues and that represent potential sources of a wide variety of biologically active secreted products, including diverse cytokines and growth factors. There is strong evidence for important non-redundant roles of mast cells in many types of innate or adaptive immune responses, including making important contributions to immediate and chronic IgE-associated allergic disorders and enhancing host resistance to certain venoms and parasites. However, mast cells have been proposed to influence many other biological processes, including responses to bacteria and virus, angiogenesis, wound healing, fibrosis, autoimmune and metabolic disorders, and cancer. The potential functions of mast cells in many of these settings is thought to reflect their ability to secrete, upon appropriate activation by a range of immune or non-immune stimuli, a broad spectrum of cytokines (including many chemokines) and growth factors, with potential autocrine, paracrine, local, and systemic effects. In this review, we summarize the evidence indicating which cytokines and growth factors can be produced by various populations of rodent and human mast cells in response to particular immune or non-immune stimuli, and comment on the proven or potential roles of such mast cell products in health and disease.
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Affiliation(s)
- Kaori Mukai
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.,Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA, USA
| | - Mindy Tsai
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.,Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA, USA
| | - Hirohisa Saito
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health & Development, Tokyo, Japan
| | - Stephen J Galli
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.,Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA, USA.,Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
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37
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Varricchi G, Raap U, Rivellese F, Marone G, Gibbs BF. Human mast cells and basophils-How are they similar how are they different? Immunol Rev 2019; 282:8-34. [PMID: 29431214 DOI: 10.1111/imr.12627] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mast cells and basophils are key contributors to allergies and other inflammatory diseases since they are the most prominent source of histamine as well as numerous additional inflammatory mediators which drive inflammatory responses. However, a closer understanding of their precise roles in allergies and other pathological conditions has been marred by the considerable heterogeneity that these cells display, not only between mast cells and basophils themselves but also across different tissue locations and species. While both cell types share the ability to rapidly degranulate and release histamine following high-affinity IgE receptor cross-linking, they differ markedly in their ability to either react to other stimuli, generate inflammatory eicosanoids or release immunomodulating cytokines and chemokines. Furthermore, these cells display considerable pharmacological heterogeneity which has stifled attempts to develop more effective anti-allergic therapies. Mast cell- and basophil-specific transcriptional profiling, at rest and after activation by innate and adaptive stimuli, may help to unravel the degree to which these cells differ and facilitate a clearer understanding of their biological functions and how these could be targeted by new therapies.
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Affiliation(s)
- Gilda Varricchi
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, Naples, Italy.,WAO Center of Excellence, Naples, Italy
| | - Ulrike Raap
- Department of Dermatology and Allergology, University of Oldenburg, Oldenburg, Germany
| | - Felice Rivellese
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, Naples, Italy.,WAO Center of Excellence, Naples, Italy.,Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Gianni Marone
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, Naples, Italy.,WAO Center of Excellence, Naples, Italy.,Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOS), National Research Council (CNR), Naples, Italy
| | - Bernhard F Gibbs
- Department of Dermatology and Allergology, University of Oldenburg, Oldenburg, Germany
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Yu Y, Blokhuis B, Derks Y, Kumari S, Garssen J, Redegeld F. Human mast cells promote colon cancer growth via bidirectional crosstalk: studies in 2D and 3D coculture models. Oncoimmunology 2018; 7:e1504729. [PMID: 30377568 PMCID: PMC6205014 DOI: 10.1080/2162402x.2018.1504729] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 07/19/2018] [Accepted: 07/21/2018] [Indexed: 02/07/2023] Open
Abstract
Chronic inflammation drives the development of colorectal cancer (CRC), where tumor-infiltrating immune cells interact with cancer cells in a dynamic crosstalk. Mast cells (MC), one of earliest recruited immune cells, accumulate in CRC tissues and their density is correlated with cancer progression. However, the exact contribution of MC in CRC and their interaction with colon cancer cells is poorly understood. Here, we investigated the impact of primary human MC and their mediators on colon cancer growth using 2D and 3D coculture models. Primary human MC were generated from peripheral CD34+ stem cells. Transwell chambers were used to analyze MC chemotaxis to colon cancer. Colon cancer cells HT29 and Caco2 differentially recruited MC by releasing CCL15 or SCF, respectively. Using BrdU proliferation assays, we demonstrated that MC can directly support colon cancer proliferation and this effect was mediated by their cellular crosstalk. 3D coculture models with cancer spheroids further confirmed the pro-tumor effect of MC on colon cancer growth, where direct cell-cell contact is dispensable and increased production of multiple soluble mediators was detected. Moreover, TLR2 stimulation of MC promoted stronger growth of colon cancer spheroids. By examining the transcriptome profile of colon cancer-cocultured MC versus control MC, we identified several MC marker genes, which were deregulated in expression. Our study provides an advanced in vitro model to investigate the role of human MC in cancer. Our data support the detrimental role of MC in CRC development and provide a molecular insight into the cellular crosstalk between MC and colon cancer cells.
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Affiliation(s)
- Yingxin Yu
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Bart Blokhuis
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Yvonne Derks
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Sangeeta Kumari
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.,Department of Immunology, Nutricia Research, Utrecht, The Netherlands
| | - Frank Redegeld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
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39
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Varricchi G, Loffredo S, Galdiero MR, Marone G, Cristinziano L, Granata F, Marone G. Innate effector cells in angiogenesis and lymphangiogenesis. Curr Opin Immunol 2018; 53:152-160. [PMID: 29778674 DOI: 10.1016/j.coi.2018.05.002] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 05/02/2018] [Accepted: 05/03/2018] [Indexed: 12/12/2022]
Abstract
Angiogenesis and lymphangiogenesis are distinct and complex processes requiring a finely tuned balance between stimulatory and inhibitory signals. During adulthood, angiogenesis and lymphangiogenesis are activated at sites of tumor growth, tissue injury and remodeling, and chronic inflammation. Vascular endothelial growth factors (VEGFs), angiopoietin (ANGPTs) and a multitude of additional signaling molecules play distinct roles in the modulation of angiogenesis/lymphangiogenesis. VEGFs and ANGPTs activate specific tyrosine kinase receptor (e.g., VEGFR1, VEGFR-2, VEGFR-3 and TIE2 respectively), expressed on blood endothelial cells (angiogenesis) and lymphatic endothelial cells (lymphangiogenesis). Although tumor cells produce VEGFs and other proangiogenic mediators, tissue resident (e.g., macrophages, mast cells) and circulating immune cells (e.g., basophils, neutrophils, monocytes, eosinophils) are an important source of angiogenic/lymphangiogenic mediators in inflammation and in tumor microenvironment and at site of chronic inflammation. Certain immune cells can also release anti-angiogenic factors. Mast cells, basophils, neutrophils and presumably other immune cells are not only a source of angiogenic/lymphangiogenic molecules, but also their target. Cells of the immune system need consideration as major players and possible targets for therapeutic manipulation of angiogenesis/lymphangiogenesis in chronic inflammatory disorders and tumors.
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Affiliation(s)
- Gilda Varricchi
- Department of Traslational Medicine, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), Naples, Italy; World Allergy Organization (WAO), Center of Excellence, Naples, Italy.
| | - Stefania Loffredo
- Department of Traslational Medicine, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), Naples, Italy; World Allergy Organization (WAO), Center of Excellence, Naples, Italy
| | - Maria Rosaria Galdiero
- Department of Traslational Medicine, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), Naples, Italy; World Allergy Organization (WAO), Center of Excellence, Naples, Italy
| | - Giancarlo Marone
- Department of Public Health, Section of Hygiene, University of Naples Federico II, Naples, Italy; Monaldi Hospital Pharmacy, Naples, Italy
| | - Leonardo Cristinziano
- Department of Traslational Medicine, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), Naples, Italy
| | - Francescopaolo Granata
- Department of Traslational Medicine, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), Naples, Italy; World Allergy Organization (WAO), Center of Excellence, Naples, Italy
| | - Gianni Marone
- Department of Traslational Medicine, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), Naples, Italy; World Allergy Organization (WAO), Center of Excellence, Naples, Italy; Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore", National Research Council, Naples, Italy.
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40
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Opioids: Modulators of angiogenesis in wound healing and cancer. Oncotarget 2018; 8:25783-25796. [PMID: 28445930 PMCID: PMC5421968 DOI: 10.18632/oncotarget.15419] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 02/07/2017] [Indexed: 12/12/2022] Open
Abstract
Opioids are potent drugs that are widely used to control wound or cancer pain. Increasing evidence suggest that opioids mediate clinically relevant effects that go beyond their classical role as analgesics. Of note, opioids appear to modulate angiogenesis - a process that is critical in wound healing and cancer progression. In this review, we focus on pro- and anti-angiogenic facets of opioids that arise from the activation of individual opioid receptors and the usage of individual concentrations or application routes. We overview the still incompletely elucidated mechanisms of these angiogenic opioid actions. Moreover, we describe plausible opioids effects, which - although not primarily studied in the context of vessel formation - may be related to the opioid-driven processes of angiogenesis. Finally we discuss the use of opioids as an innovative therapeutic avenue for the treatment of chronic wounds and cancer.
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McHale C, Mohammed Z, Deppen J, Gomez G. Interleukin-6 potentiates FcεRI-induced PGD 2 biosynthesis and induces VEGF from human in situ-matured skin mast cells. Biochim Biophys Acta Gen Subj 2018; 1862:1069-1078. [PMID: 29410184 DOI: 10.1016/j.bbagen.2018.01.020] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Revised: 01/18/2018] [Accepted: 01/31/2018] [Indexed: 11/16/2022]
Abstract
BACKGROUND Interleukin-6 is a gp130 utilizing cytokine that is consistently associated with allergic diseases like asthma and urticaria in humans where mast cells are known to play a critical role. However, the role of IL-6 in allergic disease in not known. IL-6 was reported to enhance degranulation of in vitro-derived mast cells, but the effect of IL-6 on mediator release from human in situ-matured tissue-isolated mast cells had not been reported. METHODS Human mature mast cells were isolated and purified from normal skin tissue from different donors. The expression of surface-expressed IL-6 receptors was demonstrated by flow cytometry. The effect of IL-6 on FcεRI-induced degranulation, PGD2 biosynthesis, and cytokine production was determined with β‑hexosaminidase release assay, Western blotting, quantitative real-time PCR, and ELISA. The small molecule inhibitor of STAT-3, C188-9, was used to demonstrate STAT3 dependency. RESULTS IL-6 significantly potentiated FcεRI-induced PGD2 biosynthesis, but had no effect on degranulation. IL-6 also induced VEGF gene expression and protein secretion, and enhanced FcεRI-induced IL-8 production. Mechanistically, IL-6 enhanced FcεRI-induced COX‑2 expression, PGD2 biosynthesis, and VEGF production in a STAT3 dependent manner. CONCLUSION Here, we demonstrate that IL-6 is a potentiator of FcεRI-induced PGD2 biosynthesis, and can induce or enhance production of pro-angiogenesis factors VEGF and IL-8 from human in situ-matured skin mast cells. GENERAL SIGNIFICANCE These findings from this study indicate that IL-6 contributes to human allergic disease by enhancing the production of inflammatory PGD2 from tissue-resident mast cells. Moreover, the data suggest a novel role for IL-6 in mast cell-mediated angiogenesis.
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Affiliation(s)
- Cody McHale
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA.
| | - Zahraa Mohammed
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA.
| | - Juline Deppen
- Department of Biomedical Engineering, University of South Carolina School of Medicine, Columbia, SC, USA.
| | - Gregorio Gomez
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA.
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Oldford SA, Salsman SP, Portales-Cervantes L, Alyazidi R, Anderson R, Haidl ID, Marshall JS. Interferon α2 and interferon γ induce the degranulation independent production of VEGF-A and IL-1 receptor antagonist and other mediators from human mast cells. IMMUNITY INFLAMMATION AND DISEASE 2017; 6:176-189. [PMID: 29235261 PMCID: PMC5818443 DOI: 10.1002/iid3.211] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 11/07/2017] [Accepted: 11/20/2017] [Indexed: 01/05/2023]
Abstract
Background Mast cells are resident immune effector cells, often studied in the context of allergic disease. Found in substantial numbers at sites of potential infection they are increased at sites of angiogenesis and can be pivotal for the sensing and clearance of a variety of pathogens. Interferons (IFNs) are cytokines that are critical for host defence against intracellular pathogens. Increased levels of IFNs are observed during viral infection and in autoimmune diseases. IFNs are also widely used therapeutically and have been examined in the therapy of severe asthma. Objective To define the selective human mast cell cytokine and chemokine response following activation with type I or type II IFN's. Methods The ability of both IFNα2 and IFNγ to induce cytokine production by human cord blood‐derived mast cells was examined in vitro. Cytokine and chemokine production at 6 and 24 h was assessed by multiplex protein analysis. Degranulation was assessed by β‐hexosaminidase release. Mast cells were also treated with reovirus or respiratory syncytial virus and their production of CXCL10, IL‐1 receptor antagonist (IL‐1Ra), and vascular endothelial growth factor (VEGF) examined after 24 h. Results In addition to increased expression of classical IFN response genes, such as CXCL10, small but significant increases in CCL5 and IL‐17 production were observed following IFN activation. Notably, human mast cells produced both VEGF and IL‐1Ra in a dose dependent manner. These responses occurred in the absence of mast cell degranulation by a mechanism consistent with classical IFN signaling. Both reovirus and respiratory syncytial virus infection of mast cells, were also associated with IFN‐dependent IL‐1Ra expression. Conclusion and Clinical Relevance Our findings demonstrate that IFNs have profound impact on cytokine and chemokine expression by human mast cells, alone or in the context of viral infection. Mast cell VEGF and IL‐1Ra responses to IFNs could impact the regulation of local inflammatory responses and subsequent tissue remodeling.
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Affiliation(s)
- Sharon A Oldford
- Dalhousie Inflammation Group, Dalhousie University, Halifax, Nova Scotia, Canada.,Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.,Canadian Center for Vaccinology, IWK Health Centre, Halifax, Nova Scotia, Canada
| | - Suzanne P Salsman
- Dalhousie Inflammation Group, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Liliana Portales-Cervantes
- Dalhousie Inflammation Group, Dalhousie University, Halifax, Nova Scotia, Canada.,Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Raidan Alyazidi
- Dalhousie Inflammation Group, Dalhousie University, Halifax, Nova Scotia, Canada.,Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.,Faculty of Medicine, Department of Pediatrics, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
| | - Robert Anderson
- Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.,Canadian Center for Vaccinology, IWK Health Centre, Halifax, Nova Scotia, Canada.,Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Ian D Haidl
- Dalhousie Inflammation Group, Dalhousie University, Halifax, Nova Scotia, Canada.,Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Jean S Marshall
- Dalhousie Inflammation Group, Dalhousie University, Halifax, Nova Scotia, Canada.,Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.,Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
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Li C, Liu P, Song R, Zhang Y, Lei S, Wu S. Immune cells and autoantibodies in pulmonary arterial hypertension. Acta Biochim Biophys Sin (Shanghai) 2017; 49:1047-1057. [PMID: 29036539 DOI: 10.1093/abbs/gmx095] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Indexed: 12/19/2022] Open
Abstract
Analyses of immunity in pulmonary arterial hypertension (PAH) support the notion that maladaptation of the immune response exists. Altered immunity is an increasingly recognized feature of PAH. Indeed, a delicate balance between immunity and tolerance exists and any disturbance may result in chronic inflammation or autoimmunity. This is suggested by infiltration of various immune cells (e.g. macrophages, T and B lymphocytes) in remodeled pulmonary vessels. In addition, several types of autoantibodies directed against antinuclear antigens, endothelial cells (ECs) and fibroblasts have been found in idiopathic and systemic sclerosis-associated PAH. These autoantibodies may play an important role in EC apoptosis and in the expression of cell adhesion molecules. This review article provides an overview of immunity pathways highlighting their potential roles in pulmonary vascular remodeling in PAH and the possibility of future targeted therapy.
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Affiliation(s)
- Cheng Li
- Department of Respiratory Medicine, Second Xiangya Hospital, Central South University, Changsha, China
| | - Pingping Liu
- Department of Emergency, Hunan Children's Hospital, Changsha, China
| | - Rong Song
- Department of Respiratory Medicine, Second Xiangya Hospital, Central South University, Changsha, China
| | - Yiqing Zhang
- Department of Respiratory Medicine, Second Xiangya Hospital, Central South University, Changsha, China
| | - Si Lei
- Department of Respiratory Medicine, Second Xiangya Hospital, Central South University, Changsha, China
| | - Shangjie Wu
- Department of Respiratory Medicine, Second Xiangya Hospital, Central South University, Changsha, China
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The role of vascular endothelial growth factor-B in metabolic homoeostasis: current evidence. Biosci Rep 2017; 37:BSR20171089. [PMID: 28798193 PMCID: PMC5577206 DOI: 10.1042/bsr20171089] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 08/09/2017] [Accepted: 08/10/2017] [Indexed: 02/07/2023] Open
Abstract
It has been shown that adipose tissue and skeletal muscles in lean individuals respond to meal-induced hyperinsulinemia by increase in perfusion, the effect not observed in patients with metabolic syndrome. In conditions of hyperglycaemia and hypertriglyceridemia, this insufficient vascularization leads to the liberation of reactive oxygen species (ROS), and disruption of nitric oxide (NO) synthesis and endothelial signalling responsible for the uptake of circulating fatty acids (FAs), whose accumulation in skeletal muscles and adipose tissue is widely associated with the impairment of insulin signalling. While the angiogenic role of VEGF-A and its increased circulating concentrations in obesity have been widely confirmed, the data related to the metabolic role of VEGF-B are diverse. However, recent discoveries indicate that this growth factor may be a promising therapeutic agent in patients with metabolic syndrome. Preclinical studies agree over two crucial metabolic effects of VEGF-B: (i) regulation of FAs uptake and (ii) regulation of tissue perfusion via activation of VEGF-A/vascular endothelial growth factor receptor (VEGFR) 2 (VEGFR2) pathway. While in some preclinical high-fat diet studies, VEGF-B overexpression reverted glucose intolerance and stimulated fat burning, in others it further promoted accumulation of lipids and lipotoxicity. Data from clinical studies point out the changes in circulating or tissue expression levels of VEGF-B in obese compared with lean patients. Potentially beneficial effects of VEGF-B, achieved through enhanced blood flow (increased availability of insulin and glucose uptake in target organs) and decreased FAs uptake (prevention of lipotoxicity and improved insulin signalling), and its safety for clinical use, remain to be clarified through future translational research.
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Galdiero MR, Varricchi G, Seaf M, Marone G, Levi-Schaffer F, Marone G. Bidirectional Mast Cell-Eosinophil Interactions in Inflammatory Disorders and Cancer. Front Med (Lausanne) 2017; 4:103. [PMID: 28791287 PMCID: PMC5523083 DOI: 10.3389/fmed.2017.00103] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 06/26/2017] [Indexed: 12/19/2022] Open
Abstract
Human mast cells (MCs) and eosinophils were first described and named by Paul Ehrlich. These cells have distinct myeloid progenitors and differ morphologically, ultrastructurally, immunologically, biochemically, and pharmacologically. However, MCs and eosinophils play a pivotal role in several allergic disorders. In addition, these cells are involved in autoimmune disorders, cardiovascular diseases, and cancer. MCs are distributed throughout all normal human tissues, whereas eosinophils are present only in gastrointestinal tract, secondary lymphoid tissues, and adipose tissue, thymus, mammary gland, and uterus. However, in allergic disorders, MCs and eosinophils can form the "allergic effector unit." Moreover, in several tumors, MCs and eosinophils can be found in close proximity. Therefore, it is likely that MCs have the capacity to modulate eosinophil functions and vice versa. For example, interleukin 5, stem cell factor, histamine, platelet-activating factor (PAF), prostaglandin D2 (PGD2), cysteinyl leukotrienes, and vascular endothelial growth factors (VEGFs), produced by activated MCs, can modulate eosinophil functions through the engagement of specific receptors. In contrast, eosinophil cationic proteins such as eosinophil cationic protein and major basic protein (MBP), nerve growth factor, and VEGFs released by activated eosinophils can modulate MC functions. These bidirectional interactions between MCs and eosinophils might be relevant not only in allergic diseases but also in several inflammatory and neoplastic disorders.
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Affiliation(s)
- Maria Rosaria Galdiero
- Department of Translational Medical Sciences (DiSMeT), Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
| | - Gilda Varricchi
- Department of Translational Medical Sciences (DiSMeT), Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
| | - Mansour Seaf
- Pharmacology and Experimental Therapeutics Unit, Faculty of Medicine, School of Pharmacy, Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Giancarlo Marone
- Department of Public Health, University of Naples Federico II, Monaldi Hospital Pharmacy, Naples, Italy
| | - Francesca Levi-Schaffer
- Pharmacology and Experimental Therapeutics Unit, Faculty of Medicine, School of Pharmacy, Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Gianni Marone
- Department of Translational Medical Sciences (DiSMeT), Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
- Institute of Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS), National Research Council (CNR), Naples, Italy
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Varricchi G, Galdiero MR, Loffredo S, Marone G, Iannone R, Marone G, Granata F. Are Mast Cells MASTers in Cancer? Front Immunol 2017; 8:424. [PMID: 28446910 PMCID: PMC5388770 DOI: 10.3389/fimmu.2017.00424] [Citation(s) in RCA: 235] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 03/27/2017] [Indexed: 12/19/2022] Open
Abstract
Prolonged low-grade inflammation or smoldering inflammation is a hallmark of cancer. Mast cells form a heterogeneous population of immune cells with differences in their ultra-structure, morphology, mediator content, and surface receptors. Mast cells are widely distributed throughout all tissues and are stromal components of the inflammatory microenvironment that modulates tumor initiation and development. Although canonically associated with allergic disorders, mast cells are a major source of pro-tumorigenic (e.g., angiogenic and lymphangiogenic factors) and antitumorigenic molecules (e.g., TNF-α and IL-9), depending on the milieu. In certain neoplasias (e.g., gastric, thyroid and Hodgkin's lymphoma) mast cells play a pro-tumorigenic role, in others (e.g., breast cancer) a protective role, whereas in yet others they are apparently innocent bystanders. These seemingly conflicting results suggest that the role of mast cells and their mediators could be cancer specific. The microlocalization (e.g., peritumoral vs intratumoral) of mast cells is another important aspect in the initiation/progression of solid and hematologic tumors. Increasing evidence in certain experimental models indicates that targeting mast cells and/or their mediators represent a potential therapeutic target in cancer. Thus, mast cells deserve focused consideration also as therapeutic targets in different types of tumors. There are many unanswered questions that should be addressed before we understand whether mast cells are an ally, adversary, or innocent bystanders in human cancers.
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Affiliation(s)
- Gilda Varricchi
- Department of Translational Medical Sciences (DiSMeT), Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
| | - Maria Rosaria Galdiero
- Department of Translational Medical Sciences (DiSMeT), Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
| | - Stefania Loffredo
- Department of Translational Medical Sciences (DiSMeT), Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
| | - Giancarlo Marone
- Department of Public Health, University of Naples Federico II, Monaldi Hospital Pharmacy, Naples, Italy
| | - Raffaella Iannone
- Department of Translational Medical Sciences (DiSMeT), Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
| | - Gianni Marone
- Department of Translational Medical Sciences (DiSMeT), Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
- Institute of Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS), National Research Council (CNR), Naples, Italy
| | - Francescopaolo Granata
- Department of Translational Medical Sciences (DiSMeT), Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
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Theoharides TC. Neuroendocrinology of mast cells: Challenges and controversies. Exp Dermatol 2017; 26:751-759. [PMID: 28094875 DOI: 10.1111/exd.13288] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/27/2016] [Indexed: 12/21/2022]
Abstract
Mast cells (MC) are hemotopoietically derived tissue immune cells that are ubiquitous in the body, including neuroendocrine organs such as the hypothalamus, pineal, pituitary, ovaries, pancreas and uterus where their action is not well understood. Mast cells have historically been associated with allergies because of their rich content of histamine and tryptase, but more recently with regulation of immunity and inflammation due to their synthesis and release of numerous cytokines and chemokines. Mast cells are located perivascularly and express numerous receptors for diverse ligands such as allergens, pathogens, neurotransmitters, neuropeptides and hormones including acetylcholine, calcitonin gene-related peptide (CGRP), corticosteroids, corticotropin-releasing hormone (CRH), β-endorphin, epinephrine, 17β-oestradiol, gonadotrophins, hemokinin-A (HKA), leptin, melatonin, neurotensin (NT), parathyroid hormone (PTH), substance P (SP) and vasoactive intestinal peptide (VIP). Moreover, MC can synthesize and release most of their neurohormonal triggers, including adrenocorticotropin hormone (ACTH), CRH, endorphins, HKA, leptin, melatonin, NT, SP and VIP. Animal experiments have shown that diencephalic MC increase in number during courting in doves, while stimulation of brain and nasal MC leads to activation of the hypothalamic-pituitary-adrenal (HPA) axis. Recent evidence indicates that MC reactivity exhibits diurnal variations, and it is interesting that melatonin appears to regulate MC secretion. However, the way MC change their phenotype or secrete specific molecules selectively at different pathophysiological settings still remains unknown. Mast cells developed over 500 million years ago and may have served as the original prototype neuroimmunoendocrine cell and then evolved into a master regulator of such interactions, especially as most of the known diseases involve neuroinflammation that worsens with stress.
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Affiliation(s)
- Theoharis C Theoharides
- Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA.,Sackler School of Graduate Biomedical Sciences, Program in Pharmacology and Experimental Therapeutics, Tufts University, Boston, MA, USA.,Department of Internal Medicine, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USA.,Department of Psychiatry, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USA
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Mast cell phenotype, TNFα expression and degranulation status in non-small cell lung cancer. Sci Rep 2016; 6:38352. [PMID: 27922077 PMCID: PMC5138591 DOI: 10.1038/srep38352] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 11/08/2016] [Indexed: 12/29/2022] Open
Abstract
Mast cell infiltration of tumour islets represents a survival advantage in non-small cell lung cancer (NSCLC). The phenotype and activation status of these mast cells is unknown. We investigated the mast cell phenotype in terms of protease content (tryptase-only [MCT], tryptase + chymase [MCTC]) and tumour necrosis factor-alpha (TNFα) expression, and extent of degranulation, in NSCLC tumour stroma and islets. Surgically resected tumours from 24 patients with extended survival (ES; mean survival 86.5 months) were compared with 25 patients with poor survival (PS; mean survival 8.0 months) by immunohistochemistry. Both MCT and MCTC in tumour islets were higher in ES (20.0 and 5.6 cells/mm2 respectively) compared to PS patients (0.0 cells/mm2) (p < 0.0001). Both phenotypes expressed TNFα in the islets and stroma. In ES 44% of MCT and 37% of MCTC expressed TNFα in the tumour islets. MCT in the ES stroma were more degranulated than in those with PS (median degranulation index = 2.24 versus 1.73 respectively) (p = 0.0022), and ES islet mast cells (2.24 compared to 1.71, p < 0.0001). Since both MCT and MCTC infiltrating tumour islets in ES NSCLC patients express TNFα, the cytotoxic activity of this cytokine may confer improved survival in these patients. Manipulating mast cell microlocalisation and functional responses in NSCLC may offer a novel approach to the treatment of this disease.
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Barbosa-Lorenzi VC, Peyda S, Scheynius A, Nilsson G, Lunderius-Andersson C. Curdlan induces selective mast cell degranulation without concomitant release of LTC 4, IL-6 or CCL2. Immunobiology 2016; 222:647-650. [PMID: 27989425 DOI: 10.1016/j.imbio.2016.12.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 12/04/2016] [Indexed: 01/19/2023]
Abstract
Mast cells are sentinel cells with a tissue-specific localization in the interface between the host and the external environment. Their quick and selective response upon encountering pathogens is part of the innate host response and typically initiates the following adaptive immune response. Among several pattern recognition receptors (PRRs) involved in the recognition of pathogens by mast cells, the C-type lectin receptor Dectin-1 has been associated with the recognition of fungi. Our previous studies have shown that mast cells are the predominant cell type expressing Dectin-1 in human skin, and they also recognize and respond to Malassezia sympodialis by producing cytokines connected to the innate host response and upregulating the expression of Dectin-1. In the present study, we investigated mast cell responses to Curdlan, a β-glucan that acts as an agonist for the fungi receptor Dectin-1, and found a unique response pattern with induced degranulation, but surprisingly without synthesis of Leukotriene C4, IL-6 or CCL2. Since mast cells are the predominant Dectin-1 expressing cell in the human skin, this study suggests that mast cell degranulation in response to fungi is an important part of the first line of defense against these pathogens.
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Affiliation(s)
- Valéria C Barbosa-Lorenzi
- Clincial Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Simon Peyda
- Clincial Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Annika Scheynius
- Department of Clinical Science and Education, Karolinska Institutet, and Sachs' Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden
| | - Gunnar Nilsson
- Clincial Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Carolina Lunderius-Andersson
- Clincial Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
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Laakkonen JP, Lappalainen JP, Theelen TL, Toivanen PI, Nieminen T, Jauhiainen S, Kaikkonen MU, Sluimer JC, Ylä-Herttuala S. Differential regulation of angiogenic cellular processes and claudin-5 by histamine and VEGF via PI3K-signaling, transcription factor SNAI2 and interleukin-8. Angiogenesis 2016; 20:109-124. [DOI: 10.1007/s10456-016-9532-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 11/07/2016] [Indexed: 01/19/2023]
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