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Hung JH, Jain T, Khatri A, Nguyen BT, Nguyen CDT, Yavari N, Mobasserian A, Karaca I, Saeed Mohammadi S, Gupta AS, Or CMC, Akhavanrezayat A, Yasar C, Saengsirinavin AO, Than NTT, Anover FA, Elaraby O, El Feky D, Yoo WS, Zhang X, Thng ZX, Do DV, Nguyen QD. Inherited retinal disease-associated uveitis. Surv Ophthalmol 2025:S0039-6257(25)00057-8. [PMID: 40157547 DOI: 10.1016/j.survophthal.2025.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 03/18/2025] [Accepted: 03/24/2025] [Indexed: 04/01/2025]
Abstract
Inherited retinal diseases (IRDs) are genetic disorders characterized by progressive photoreceptor function loss, often leading to significant visual impairment. Uveitis has been increasingly recognized in the clinical course of some IRDs. Despite advances in understanding the genetic causes and pathophysiology of IRDs, gaps remain in understanding the roles of inflammation and autoimmunity in IRD and IRD-associated uveitis. This review discusses IRD-associated uveitis, including anterior, intermediate, posterior, and panuveitis, as well as complications such as cystoid macular edema and retinal vasculitis. In patients with IRD-associated uveitis, mutations affecting protein function in cilia or photoreceptor outer segments suggest a universal autoimmune mechanism triggered by the immunogenicity of shedding photoreceptor discs. Notably, in patients where uveitis is the initial sign, CRB1 mutations are often implicated, likely due to the compromised blood-retina barrier function or alterations in the external limiting membrane. Other mechanisms leading to uveitis preceding IRD diagnosis include ALPK1 mutations, which activate the proinflammatory NF-κB pathway, CAPN5 mutations, which lead to dysfunction of the innate and adaptive immune systems, and VCAN1 mutations, which elicit immunogenicity due to irregularities in vitreous modeling. Understanding these mechanisms could enhance the development of innovative treatments that target personalized inflammation pathways in IRDs.
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Affiliation(s)
- Jia-Horung Hung
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA; Department of Genomic Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Ophthalmology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Tanya Jain
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA; Dr. Shroff's Charity Eye Hospital, New Delhi, India
| | - Anadi Khatri
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA; Birat Eye Hospital, Biratnagar, Nepal; Gautam Buddha Eye care centre, Lumbini, Nepal
| | - Ba Trung Nguyen
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA; Department of Ophthalmology, Viet Nam National Children's Hospital, Ha Noi, Viet Nam
| | | | - Negin Yavari
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Azadeh Mobasserian
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Irmak Karaca
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA; John A. Moran Eye Center, University of Utah, Salt Lake City, UT, US
| | - S Saeed Mohammadi
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Ankur Sudhir Gupta
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Chi Mong Christopher Or
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Amir Akhavanrezayat
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Cigdem Yasar
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Aim-On Saengsirinavin
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA; Police General Hospital, Bangkok, Thailand
| | - Ngoc Trong Tuong Than
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Frances Andrea Anover
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA; Batangas Medical Center, Batangas, Philippines
| | - Osama Elaraby
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Dalia El Feky
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Woong-Sun Yoo
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA; Department of Ophthalmology, Gyeongsang National University College of Medicine, and Gyeongsang National University Hospital, Jinju, Republic of Korea
| | - Xiaoyan Zhang
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Zheng Xian Thng
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA; National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore
| | - Diana V Do
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Quan Dong Nguyen
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA.
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Zhong A, Sumaroka A, Tsui JC, O'Neil EC, Cideciyan AV, Datz E, Bedoukian EC, Aleman TS, Scoles D. Detailed structural abnormalities associated with a novel VCAN variant in a family with versican vitreoretinopathy. Ophthalmic Genet 2025:1-10. [PMID: 40140649 DOI: 10.1080/13816810.2025.2483421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 02/04/2025] [Accepted: 03/17/2025] [Indexed: 03/28/2025]
Abstract
PURPOSE To understand the retina micropathology in a family with a novel variant in VCAN. METHODS Two sisters ages 16 (proband) and 18 years old and their 48-year-old father underwent comprehensive ophthalmic evaluations. Multimodal imaging was performed with spectral domain optical coherence tomography, ultrawide field short-wavelength fundus autofluorescence, and pseudocolor imaging. RESULTS Cataracts were present in the sisters along with a penetrant retinal phenotype in all three patients with vitreoretinal ring opacities and traction, peripheral pigmentary clumps, lattice-like features, retinoschisis, foveal ectopia, and nasal displacement of vessels. There were regions with inner retinal thinning with spared outer retina, likely a consequence of vitreoretinal traction, that contrasted with large areas of profound photoreceptor degeneration, but with a rather normal or thickened inner retina. A previously unreported heterozygous variant in intron 7 of VCAN (c.4004-2A>C) segregated with the phenotype in the proband and her father. CONCLUSIONS Segregation of a versican-associated vitreoretinopathy supports the pathogenicity of the VCAN variant. The patterns of structural abnormalities support classical mechanisms of disease that involve local vitreoretinal traction, as well as possible alternative developmental and/or degenerative changes of the retina, RPE, and/or choroid that result from the primary molecular defect.
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Affiliation(s)
- Anny Zhong
- Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Alexander Sumaroka
- Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Jonathan C Tsui
- Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Ophthalmology, New Jersey Veterans Affairs Medical Center, East Orange, New Jersey, USA
| | - Erin C O'Neil
- Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Division of Ophthalmology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Artur V Cideciyan
- Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Emily Datz
- Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Emma C Bedoukian
- Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Tomas S Aleman
- Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Division of Ophthalmology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Drew Scoles
- Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Division of Ophthalmology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
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Xu Y, Benedikt J, Ye L. Hyaluronic Acid Interacting Molecules Mediated Crosstalk between Cancer Cells and Microenvironment from Primary Tumour to Distant Metastasis. Cancers (Basel) 2024; 16:1907. [PMID: 38791985 PMCID: PMC11119954 DOI: 10.3390/cancers16101907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/11/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024] Open
Abstract
Hyaluronic acid (HA) is a prominent component of the extracellular matrix, and its interactions with HA-interacting molecules (HAIMs) play a critical role in cancer development and disease progression. This review explores the multifaceted role of HAIMs in the context of cancer, focusing on their influence on disease progression by dissecting relevant cellular and molecular mechanisms in tumour cells and the tumour microenvironment. Cancer progression can be profoundly affected by the interactions between HA and HAIMs. They modulate critical processes such as cell adhesion, migration, invasion, and proliferation. The TME serves as a dynamic platform in which HAIMs contribute to the formation of a unique niche. The resulting changes in HA composition profoundly influence the biophysical properties of the TME. These modifications in the TME, in conjunction with HAIMs, impact angiogenesis, immune cell recruitment, and immune evasion. Therefore, understanding the intricate interplay between HAIMs and HA within the cancer context is essential for developing novel therapeutic strategies. Targeting these interactions offers promising avenues for cancer treatment, as they hold the potential to disrupt critical aspects of disease progression and the TME. Further research in this field is imperative for advancing our knowledge and the treatment of cancer.
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Affiliation(s)
- Yali Xu
- Cardiff China Medical Research Collaborative, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK;
- School of Engineering, Cardiff University, Cardiff CF24 3AA, UK;
| | | | - Lin Ye
- Cardiff China Medical Research Collaborative, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK;
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Buruiană A, Gheban BA, Gheban-Roșca IA, Georgiu C, Crișan D, Crișan M. The Tumor Stroma of Squamous Cell Carcinoma: A Complex Environment That Fuels Cancer Progression. Cancers (Basel) 2024; 16:1727. [PMID: 38730679 PMCID: PMC11083853 DOI: 10.3390/cancers16091727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 04/25/2024] [Accepted: 04/27/2024] [Indexed: 05/13/2024] Open
Abstract
The tumor microenvironment (TME), a complex assembly of cellular and extracellular matrix (ECM) components, plays a crucial role in driving tumor progression, shaping treatment responses, and influencing metastasis. This narrative review focuses on the cutaneous squamous cell carcinoma (cSCC) tumor stroma, highlighting its key constituents and their dynamic contributions. We examine how significant changes within the cSCC ECM-specifically, alterations in fibronectin, hyaluronic acid, laminins, proteoglycans, and collagens-promote cancer progression, metastasis, and drug resistance. The cellular composition of the cSCC TME is also explored, detailing the intricate interplay of cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), endothelial cells, pericytes, adipocytes, and various immune cell populations. These diverse players modulate tumor development, angiogenesis, and immune responses. Finally, we emphasize the TME's potential as a therapeutic target. Emerging strategies discussed in this review include harnessing the immune system (adoptive cell transfer, checkpoint blockade), hindering tumor angiogenesis, disrupting CAF activity, and manipulating ECM components. These approaches underscore the vital role that deciphering TME interactions plays in advancing cSCC therapy. Further research illuminating these complex relationships will uncover new avenues for developing more effective treatments for cSCC.
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Affiliation(s)
- Alexandra Buruiană
- Department of Pathology, Iuliu Haţieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.B.); (C.G.); (D.C.)
| | - Bogdan-Alexandru Gheban
- Department of Histology, Iuliu Haţieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
- Emergency Clinical County Hospital, 400347 Cluj-Napoca, Romania
| | - Ioana-Andreea Gheban-Roșca
- Department of Medical Informatics and Biostatistics, Iuliu Hațieganu University of Medicine and Pharmacy, 400129 Cluj-Napoca, Romania;
| | - Carmen Georgiu
- Department of Pathology, Iuliu Haţieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.B.); (C.G.); (D.C.)
| | - Doința Crișan
- Department of Pathology, Iuliu Haţieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.B.); (C.G.); (D.C.)
| | - Maria Crișan
- Department of Histology, Iuliu Haţieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
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Minns AF, Santamaria S. Determination of Versikine Levels by Enzyme-Linked Immunosorbent Assay (ELISA). Methods Mol Biol 2024; 2747:83-93. [PMID: 38038934 DOI: 10.1007/978-1-0716-3589-6_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Abstract
The proteoglycan versican plays multiple roles in cancer progression, from promoting cell invasion and proliferation to evasion of immune surveillance. Metalloproteinases of the A Disintegrin and Metalloproteinase with Thrombospondin-like motif (ADAMTS) family cleave versican at a specific Glu-Ala bond, thus releasing a bioactive fragment named versikine, whose biological function, still not entirely revealed, seems that of antagonizing the effects of the parental molecule. Here we describe an enzyme-linked immunosorbent assay (ELISA) that specifically detects versikine in media, pure component systems, and biological fluids using neoepitope antibodies. Such antibodies recognize their target proteolytic fragment but not the intact, parental molecule. Versikine fragments are captured by neoepitope antibodies and detected by antibodies directed against its N-terminal globular (G1) domain. The method here described can therefore be used to measure ADAMTS versicanase activity and provides a quantitative alternative to immunoblotting.
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Affiliation(s)
- Alexander Frederick Minns
- Department of Biochemical Sciences, School of Biosciences, Faculty of Health and Medical Sciences, Edward Jenner Building, University of Surrey, Surrey, UK
| | - Salvatore Santamaria
- Department of Biochemical Sciences, School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK.
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Papadas A, Huang Y, Cicala A, Dou Y, Fields M, Gibbons A, Hong D, Lagal DJ, Quintana V, Rizo A, Zomalan B, Asimakopoulos F. Emerging roles for tumor stroma in antigen presentation and anti-cancer immunity. Biochem Soc Trans 2023; 51:2017-2028. [PMID: 38031753 PMCID: PMC10754280 DOI: 10.1042/bst20221083] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 11/15/2023] [Accepted: 11/21/2023] [Indexed: 12/01/2023]
Abstract
Advances in immunotherapy in the last decade have revolutionized treatment paradigms across multiple cancer diagnoses. However, only a minority of patients derive durable benefit and progress with traditional approaches, such as cancer vaccines, remains unsatisfactory. A key to overcoming these barriers resides with a deeper understanding of tumor antigen presentation and the complex and dynamic heterogeneity of tumor-infiltrating antigen-presenting cells (APCs). Reminiscent of the 'second touch' hypothesis proposed by Klaus Ley for CD4+ T cell differentiation, the acquisition of full effector potential by lymph node- primed CD8+ T cells requires a second round of co-stimulation at the site where the antigen originated, i.e. the tumor bed. The tumor stroma holds a prime role in this process by hosting specialized APC niches, apparently distinct from tertiary lymphoid structures, that support second antigenic touch encounters and CD8+ T cell effector proliferation and differentiation. We propose that APC within second-touch niches become licensed for co-stimulation through stromal-derived instructive signals emulating embryonic or wound-healing provisional matrix remodeling. These immunostimulatory roles of stroma contrast with its widely accepted view as a physical and functional 'immune barrier'. Stromal control of antigen presentation makes evolutionary sense as the host stroma-tumor interface constitutes the prime line of homeostatic 'defense' against the emerging tumor. In this review, we outline how stroma-derived signals and cells regulate tumor antigen presentation and T-cell effector differentiation in the tumor bed. The re-definition of tumor stroma as immune rheostat rather than as inflexible immune barrier harbors significant untapped therapeutic opportunity.
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Affiliation(s)
- Athanasios Papadas
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, U.S.A
- Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, U.S.A
| | - Yun Huang
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, U.S.A
- Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, U.S.A
| | - Alexander Cicala
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, U.S.A
- Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, U.S.A
| | - Yaling Dou
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, U.S.A
- Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, U.S.A
| | - Matteo Fields
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, U.S.A
- Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, U.S.A
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Alicia Gibbons
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, U.S.A
- Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, U.S.A
| | - Duncan Hong
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, U.S.A
- Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, U.S.A
| | - Daniel J. Lagal
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, U.S.A
- Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, U.S.A
| | - Victoria Quintana
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, U.S.A
- Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, U.S.A
| | - Alejandro Rizo
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, U.S.A
- Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, U.S.A
| | - Brolyn Zomalan
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, U.S.A
- Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, U.S.A
| | - Fotis Asimakopoulos
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, U.S.A
- Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, U.S.A
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Amin A, Koul AM, Wani UM, Farooq F, Amin B, Wani Z, Lone A, Qadri A, Qadri RA. Dissection of paracrine/autocrine interplay in lung tumor microenvironment mimicking cancer cell-monocyte co-culture models reveals proteins that promote inflammation and metastasis. BMC Cancer 2023; 23:926. [PMID: 37784035 PMCID: PMC10544320 DOI: 10.1186/s12885-023-11428-7] [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: 03/03/2023] [Accepted: 09/21/2023] [Indexed: 10/04/2023] Open
Abstract
BACKGROUND Tumor cell-monocyte interactions play crucial roles in shaping up the pro-tumorigenic phenotype and functional output of tumor-associated macrophages. Within the tumor microenvironment, such heterotypic cell-cell interactions are known to occur via secretory proteins. Secretory proteins establish a diabolic liaison between tumor cells and monocytes, leading to their recruitment, subsequent polarization and consequent tumor progression. METHODS We co-cultured model lung adenocarcinoma cell line A549 with model monocytes, THP-1 to delineate the interactions between them. The levels of prototypical pro-inflammatory cytokines like TNF-𝛼, IL-6 and anti-inflammatory cytokines like IL-10 were measured by ELISA. Migration, invasion and attachment independence of lung cancer cells was assessed by wound healing, transwell invasion and colony formation assays respectively. The status of EMT was evaluated by immunofluorescence. Identification of secretory proteins differentially expressed in monocultures and co-culture was carried out using SILAC LC-MS/MS. Various insilico tools like Cytoscape, Reacfoam, CHAT and Kaplan-Meier plotter were utilized for association studies, pathway analysis, functional classification, cancer hallmark relevance and predicting the prognostic potential of the candidate secretory proteins respectively. RESULTS Co-culture of A549 and THP-1 cells in 1:10 ratio showed early release of prototypical pro-inflammatory cytokines TNF-𝛼 and IL-6, however anti-inflammatory cytokine, IL-10 was observed to be released at the highest time point. The conditioned medium obtained from this co-culture ratio promoted the migration, invasion and colony formation as well as the EMT of A549 cells. Co-culturing of A549 with THP-1 cells modulated the secretion of proteins involved in cell proliferation, migration, invasion, EMT, inflammation, angiogenesis and inhibition of apoptosis. Among these proteins Versican, Tetranectin, IGFBP2, TUBB4B, C2 and IFI30 were found to correlate with the inflammatory and pro-metastatic milieu observed in our experimental setup. Furthermore, dysregulated expression of these proteins was found to be associated with poor prognosis and negative disease outcomes in lung adenocarcinoma compared to other cancer types. Pharmacological interventions targeting these proteins may serve as useful therapeutic approaches in lung adenocarcinoma. CONCLUSION In this study, we have demonstrated that the lung cancer cell-monocyte cross-talk modulates the secretion of IFI30, RNH1, CLEC3B, VCAN, IGFBP2, C2 and TUBB4B favoring tumor growth and metastasis.
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Affiliation(s)
- Asif Amin
- Immunobiology Lab, Department of Biotechnology, University of Kashmir, Srinagar, J&K, 190006, India
| | - Aabid Mustafa Koul
- Immunobiology Lab, Department of Biotechnology, University of Kashmir, Srinagar, J&K, 190006, India
| | - Umer Majeed Wani
- Immunobiology Lab, Department of Biotechnology, University of Kashmir, Srinagar, J&K, 190006, India
| | - Faizah Farooq
- Immunobiology Lab, Department of Biotechnology, University of Kashmir, Srinagar, J&K, 190006, India
| | - Basit Amin
- Immunobiology Lab, Department of Biotechnology, University of Kashmir, Srinagar, J&K, 190006, India
| | - Zubair Wani
- Immunobiology Lab, Department of Biotechnology, University of Kashmir, Srinagar, J&K, 190006, India
| | - Asif Lone
- Department of Biotechnology, All India Institute of Medical Sciences, New Delhi, 110608, India
| | - Ayub Qadri
- Abdul Kalam Chair for Translational Research, Islamic University of Science and Technology, Awantipora, J&K, 192122, India
| | - Raies A Qadri
- Immunobiology Lab, Department of Biotechnology, University of Kashmir, Srinagar, J&K, 190006, India.
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Deb G, Cicala A, Papadas A, Asimakopoulos F. Matrix proteoglycans in tumor inflammation and immunity. Am J Physiol Cell Physiol 2022; 323:C678-C693. [PMID: 35876288 PMCID: PMC9448345 DOI: 10.1152/ajpcell.00023.2022] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 07/11/2022] [Accepted: 07/11/2022] [Indexed: 11/22/2022]
Abstract
Cancer immunoediting progresses through elimination, equilibrium, and escape. Each of these phases is characterized by breaching, remodeling, and rebuilding tissue planes and structural barriers that engage extracellular matrix (ECM) components, in particular matrix proteoglycans. Some of the signals emanating from matrix proteoglycan remodeling are readily co-opted by the growing tumor to sustain an environment of tumor-promoting and immune-suppressive inflammation. Yet other matrix-derived cues can be viewed as part of a homeostatic response by the host, aiming to eliminate the tumor and restore tissue integrity. These latter signals may be harnessed for therapeutic purposes to tip the polarity of the tumor immune milieu toward anticancer immunity. In this review, we attempt to showcase the importance and complexity of matrix proteoglycan signaling in both cancer-restraining and cancer-promoting inflammation. We propose that the era of matrix diagnostics and therapeutics for cancer is fast approaching the clinic.
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Affiliation(s)
- Gauri Deb
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, California
- Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, California
| | - Alexander Cicala
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, California
- Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, California
| | - Athanasios Papadas
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, California
- Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, California
| | - Fotis Asimakopoulos
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, California
- Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, California
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Crotty KM, Yeligar SM. Hyaladherins May be Implicated in Alcohol-Induced Susceptibility to Bacterial Pneumonia. Front Immunol 2022; 13:865522. [PMID: 35634317 PMCID: PMC9133445 DOI: 10.3389/fimmu.2022.865522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 04/15/2022] [Indexed: 11/13/2022] Open
Abstract
Although the epidemiology of bacterial pneumonia and excessive alcohol use is well established, the mechanisms by which alcohol induces risk of pneumonia are less clear. Patterns of alcohol misuse, termed alcohol use disorders (AUD), affect about 15 million people in the United States. Compared to otherwise healthy individuals, AUD increase the risk of respiratory infections and acute respiratory distress syndrome (ARDS) by 2-4-fold. Levels and fragmentation of hyaluronic acid (HA), an extracellular glycosaminoglycan of variable molecular weight, are increased in chronic respiratory diseases, including ARDS. HA is largely involved in immune-assisted wound repair and cell migration. Levels of fragmented, low molecular weight HA are increased during inflammation and decrease concomitant with leukocyte levels following injury. In chronic respiratory diseases, levels of fragmented HA and leukocytes remain elevated, inflammation persists, and respiratory infections are not cleared efficiently, suggesting a possible pathological mechanism for prolonged bacterial pneumonia. However, the role of HA in alcohol-induced immune dysfunction is largely unknown. This mini literature review provides insights into understanding the role of HA signaling in host immune defense following excessive alcohol use. Potential therapeutic strategies to mitigate alcohol-induced immune suppression in bacterial pneumonia and HA dysregulation are also discussed.
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Affiliation(s)
- Kathryn M Crotty
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, United States.,Atlanta Veterans Affairs Health Care System, Decatur, GA, United States
| | - Samantha M Yeligar
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, United States.,Atlanta Veterans Affairs Health Care System, Decatur, GA, United States
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10
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Papadas A, Cicala A, Kraus SG, Arauz G, Tong A, Deming D, Asimakopoulos F. Versican in Tumor Progression, Tumor–Host Interactions, and Cancer Immunotherapy. BIOLOGY OF EXTRACELLULAR MATRIX 2022:93-118. [DOI: 10.1007/978-3-030-99708-3_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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11
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Hirani P, Gauthier V, Allen CE, Wight TN, Pearce OMT. Targeting Versican as a Potential Immunotherapeutic Strategy in the Treatment of Cancer. Front Oncol 2021; 11:712807. [PMID: 34527586 PMCID: PMC8435723 DOI: 10.3389/fonc.2021.712807] [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: 05/21/2021] [Accepted: 08/11/2021] [Indexed: 12/25/2022] Open
Abstract
A growing body of literature links events associated with the progression and severity of immunity and inflammatory disease with the composition of the tissue extracellular matrix as defined by the matrisome. One protein in the matrisome that is common to many inflammatory diseases is the large proteoglycan versican, whose varied function is achieved through multiple isoforms and post-translational modifications of glycosaminoglycan structures. In cancer, increased levels of versican are associated with immune cell phenotype, disease prognosis and failure to respond to treatment. Whether these associations between versican expression and tumour immunity are the result of a direct role in the pathogenesis of tumours is not clear. In this review, we have focused on the role of versican in the immune response as it relates to tumour progression, with the aim of determining whether our current understanding of the immunobiology of versican warrants further study as a cancer immunotherapy target.
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Affiliation(s)
- Priyanka Hirani
- Centre for Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Valentine Gauthier
- Centre for Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Carys E Allen
- Centre for Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Thomas N Wight
- Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, United States
| | - Oliver M T Pearce
- Centre for Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
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12
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DeRogatis JM, Viramontes KM, Neubert EN, Tinoco R. PSGL-1 Immune Checkpoint Inhibition for CD4 + T Cell Cancer Immunotherapy. Front Immunol 2021; 12:636238. [PMID: 33708224 PMCID: PMC7940186 DOI: 10.3389/fimmu.2021.636238] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 01/04/2021] [Indexed: 01/15/2023] Open
Abstract
Immune checkpoint inhibition targeting T cells has shown tremendous promise in the treatment of many cancer types and are now standard therapies for patients. While standard therapies have focused on PD-1 and CTLA-4 blockade, additional immune checkpoints have shown promise in promoting anti-tumor immunity. PSGL-1, primarily known for its role in cellular migration, has also been shown to function as a negative regulator of CD4+ T cells in numerous disease settings including cancer. PSGL-1 is highly expressed on T cells and can engage numerous ligands that impact signaling pathways, which may modulate CD4+ T cell differentiation and function. PSGL-1 engagement in the tumor microenvironment may promote CD4+ T cell exhaustion pathways that favor tumor growth. Here we highlight that blocking the PSGL-1 pathway on CD4+ T cells may represent a new cancer therapy approach to eradicate tumors.
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Affiliation(s)
| | | | | | - Roberto Tinoco
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, United States
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13
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Papadas A, Arauz G, Cicala A, Wiesner J, Asimakopoulos F. Versican and Versican-matrikines in Cancer Progression, Inflammation, and Immunity. J Histochem Cytochem 2020; 68:871-885. [PMID: 32623942 PMCID: PMC7711242 DOI: 10.1369/0022155420937098] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 06/04/2020] [Indexed: 12/16/2022] Open
Abstract
Versican is an extracellular matrix proteoglycan with key roles in multiple facets of cancer development, ranging from proliferative signaling, evasion of growth-suppressor pathways, regulation of cell death, promotion of neoangiogenesis, and tissue invasion and metastasis. Multiple lines of evidence implicate versican and its bioactive proteolytic fragments (matrikines) in the regulation of cancer inflammation and antitumor immune responses. The understanding of the dynamics of versican deposition/accumulation and its proteolytic turnover holds potential for the development of novel immune biomarkers as well as approaches to reset the immune thermostat of tumors, thus promoting efficacy of modern immunotherapies. This article summarizes work from several laboratories, including ours, on the role of this central matrix proteoglycan in tumor progression as well as tumor-immune cell cross-talk.
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Affiliation(s)
- Athanasios Papadas
- Division of Blood and Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA
- Cellular & Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, WI
| | - Garrett Arauz
- Division of Blood and Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA
| | - Alexander Cicala
- Division of Blood and Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA
| | - Joshua Wiesner
- Division of Blood and Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA
| | - Fotis Asimakopoulos
- Division of Blood and Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA
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14
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Karakioulaki M, Papakonstantinou E, Stolz D. Extracellular matrix remodelling in COPD. Eur Respir Rev 2020; 29:29/158/190124. [PMID: 33208482 DOI: 10.1183/16000617.0124-2019] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 05/16/2020] [Indexed: 12/30/2022] Open
Abstract
The extracellular matrix (ECM) of the lung plays several important roles in lung function, as it offers a low resistant pathway that allows the exchange of gases, provides compressive strength and elasticity that supports the fragile alveolar-capillary intersection, controls the binding of cells with growth factors and cell surface receptors and acts as a buffer against retention of water.COPD is a chronic inflammatory respiratory condition, characterised by various conditions that result in progressive airflow limitation. At any stage in the course of the disease, acute exacerbations of COPD may occur and lead to accelerated deterioration of pulmonary function. A key factor of COPD is airway remodelling, which refers to the serious alterations of the ECM affecting airway wall thickness, resistance and elasticity. Various studies have shown that serum biomarkers of ECM turnover are significantly associated with disease severity in patients with COPD and may serve as potential targets to control airway inflammation and remodelling in COPD. Unravelling the complete molecular composition of the ECM in the diseased lungs will help to identify novel biomarkers for disease progression and therapy.
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Affiliation(s)
- Meropi Karakioulaki
- Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital, Basel, Switzerland
| | - Eleni Papakonstantinou
- Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital, Basel, Switzerland.,Dept of Pharmacology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Daiana Stolz
- Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital, Basel, Switzerland
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15
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Caruso FP, Garofano L, D'Angelo F, Yu K, Tang F, Yuan J, Zhang J, Cerulo L, Pagnotta SM, Bedognetti D, Sims PA, Suvà M, Su XD, Lasorella A, Iavarone A, Ceccarelli M. A map of tumor-host interactions in glioma at single-cell resolution. Gigascience 2020; 9:giaa109. [PMID: 33155039 PMCID: PMC7645027 DOI: 10.1093/gigascience/giaa109] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 08/08/2020] [Accepted: 09/17/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Single-cell RNA sequencing is the reference technique for characterizing the heterogeneity of the tumor microenvironment. The composition of the various cell types making up the microenvironment can significantly affect the way in which the immune system activates cancer rejection mechanisms. Understanding the cross-talk signals between immune cells and cancer cells is of fundamental importance for the identification of immuno-oncology therapeutic targets. RESULTS We present a novel method, single-cell Tumor-Host Interaction tool (scTHI), to identify significantly activated ligand-receptor interactions across clusters of cells from single-cell RNA sequencing data. We apply our approach to uncover the ligand-receptor interactions in glioma using 6 publicly available human glioma datasets encompassing 57,060 gene expression profiles from 71 patients. By leveraging this large-scale collection we show that unexpected cross-talk partners are highly conserved across different datasets in the majority of the tumor samples. This suggests that shared cross-talk mechanisms exist in glioma. CONCLUSIONS Our results provide a complete map of the active tumor-host interaction pairs in glioma that can be therapeutically exploited to reduce the immunosuppressive action of the microenvironment in brain tumor.
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Affiliation(s)
- Francesca Pia Caruso
- Department of Electrical Engineering and Information Technology (DIETI), University of Naples “Federico II”, Via Claudio 21, 80128 Naples, Italy
- Bioinformatics Lab, BIOGEM, Via Camporeale, 83031 Ariano Irpino, Italy
| | - Luciano Garofano
- Department of Electrical Engineering and Information Technology (DIETI), University of Naples “Federico II”, Via Claudio 21, 80128 Naples, Italy
- Institute for Cancer Genetics, Columbia University, 1130 St Nicholas Ave, New York, NY 10032, USA
| | - Fulvio D'Angelo
- Bioinformatics Lab, BIOGEM, Via Camporeale, 83031 Ariano Irpino, Italy
- Institute for Cancer Genetics, Columbia University, 1130 St Nicholas Ave, New York, NY 10032, USA
| | - Kai Yu
- Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, 5 Yiheyuan Rd, Haidian District, 100871 Beijing, China
| | - Fuchou Tang
- Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, 5 Yiheyuan Rd, Haidian District, 100871 Beijing, China
| | - Jinzhou Yuan
- Department of Science and Technologies, Università degli Studi del Sannio, Via de Sanctis, 82100 Benevento, Italy
- Cancer Program, Sidra Medicine, Al Luqta Street, Zone 52, Education City, 26999, Doha Qatar
| | - Jing Zhang
- Institute for Cancer Genetics, Columbia University, 1130 St Nicholas Ave, New York, NY 10032, USA
| | - Luigi Cerulo
- Bioinformatics Lab, BIOGEM, Via Camporeale, 83031 Ariano Irpino, Italy
- Department of Science and Technologies, Università degli Studi del Sannio, Via de Sanctis, 82100 Benevento, Italy
| | - Stefano M Pagnotta
- Department of Science and Technologies, Università degli Studi del Sannio, Via de Sanctis, 82100 Benevento, Italy
| | - Davide Bedognetti
- Cancer Program, Sidra Medicine, Al Luqta Street, Zone 52, Education City, 26999, Doha Qatar
- Department of Internal Medicine and Medical Specialties (Di.M.I.), University of Genoa, Viale Benedetto XV 10, 16132 Genoa, Italy
| | - Peter A Sims
- Department of Systems Biology, Columbia University Irving Medical Center, 1130 St Nicholas Ave, New York , NY 10032, USA
- Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, 1130 St Nicholas Ave, New York, NY 10032, USA
| | - Mario Suvà
- Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, 55 Fruit St, Boston, MA 02114, USA
- Broad Institute of Harvard and MIT, 415 Main St, Cambridge, MA 02142, USA
| | - Xiao-Dong Su
- Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, 5 Yiheyuan Rd, Haidian District, 100871 Beijing, China
| | - Anna Lasorella
- Institute for Cancer Genetics, Columbia University, 1130 St Nicholas Ave, New York, NY 10032, USA
- Department of Pathology and Cell Biology, Columbia University Medical Center, 1130 St Nicholas Ave, New York , NY 10032 USA
| | - Antonio Iavarone
- Institute for Cancer Genetics, Columbia University, 1130 St Nicholas Ave, New York, NY 10032, USA
- Department of Pathology and Cell Biology, Columbia University Medical Center, 1130 St Nicholas Ave, New York , NY 10032 USA
- Department of Neurology, Columbia University Medical Center, 1130 St Nicholas Ave, New York, NY 10032, USA
| | - Michele Ceccarelli
- Department of Electrical Engineering and Information Technology (DIETI), University of Naples “Federico II”, Via Claudio 21, 80128 Naples, Italy
- Bioinformatics Lab, BIOGEM, Via Camporeale, 83031 Ariano Irpino, Italy
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16
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Proteoglycans in the Pathogenesis of Hormone-Dependent Cancers: Mediators and Effectors. Cancers (Basel) 2020; 12:cancers12092401. [PMID: 32847060 PMCID: PMC7563227 DOI: 10.3390/cancers12092401] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/16/2020] [Accepted: 08/18/2020] [Indexed: 12/21/2022] Open
Abstract
Hormone-dependent cancers exhibit high morbidity and mortality. In spite of advances in therapy, the treatment of hormone-dependent cancers remains an unmet health need. The tumor microenvironment (TME) exhibits unique characteristics that differ among various tumor types. It is composed of cancerous, non-cancerous, stromal, and immune cells that are surrounded and supported by components of the extracellular matrix (ECM). Therefore, the interactions among cancer cells, stromal cells, and components of the ECM determine cancer progression and response to therapy. Proteoglycans (PGs), hybrid molecules consisting of a protein core to which sulfated glycosaminoglycan chains are bound, are significant components of the ECM that are implicated in all phases of tumorigenesis. These molecules, secreted by both the stroma and cancer cells, are crucial signaling mediators that modulate the vital cellular pathways implicated in gene expression, phenotypic versatility, and response to therapy in specific tumor types. A plethora of deregulated signaling pathways contributes to the growth, dissemination, and angiogenesis of hormone-dependent cancers. Specific inputs from the endocrine and immune systems are some of the characteristics of hormone-dependent cancer pathogenesis. Importantly, the mechanisms involved in various aspects of cancer progression are executed in the ECM niche of the TME, and the PG components crucially mediate these processes. Here, we comprehensively discuss the mechanisms through which PGs affect the multifaceted aspects of hormone-dependent cancer development and progression, including cancer metastasis, angiogenesis, immunobiology, autophagy, and response to therapy.
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17
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Gerashchenko TS, Zolotaryova SY, Kiselev AM, Tashireva LA, Novikov NM, Krakhmal NV, Cherdyntseva NV, Zavyalova MV, Perelmuter VM, Denisov EV. The Activity of KIF14, Mieap, and EZR in a New Type of the Invasive Component, Torpedo-Like Structures, Predetermines the Metastatic Potential of Breast Cancer. Cancers (Basel) 2020; 12:E1909. [PMID: 32679794 PMCID: PMC7409151 DOI: 10.3390/cancers12071909] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/29/2020] [Accepted: 07/13/2020] [Indexed: 12/29/2022] Open
Abstract
Intratumor morphological heterogeneity reflects patterns of invasive growth and is an indicator of the metastatic potential of breast cancer. In this study, we used this heterogeneity to identify molecules associated with breast cancer invasion and metastasis. The gene expression microarray data were used to identify genes differentially expressed between solid, trabecular, and other morphological arrangements of tumor cells. Immunohistochemistry was applied to evaluate the association of the selected proteins with metastasis. RNA-sequencing was performed to analyze the molecular makeup of metastatic tumor cells. High frequency of metastases and decreased metastasis-free survival were detected in patients either with positive expression of KIF14 or Mieap or negative expression of EZR at the tips of the torpedo-like structures in breast cancers. KIF14- and Mieap-positive and EZR-negative cells were mainly detected in the torpedo-like structures of the same breast tumors; however, their transcriptomic features differed. KIF14-positive cells showed a significant upregulation of genes involved in ether lipid metabolism. Mieap-positive cells were enriched in genes involved in mitophagy. EZR-negative cells displayed upregulated genes associated with phagocytosis and the chemokine-mediated signaling pathway. In conclusion, the positive expression of KIF14 and Mieap and negative expression of EZR at the tips of the torpedo-like structures are associated with breast cancer metastasis.
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Affiliation(s)
- Tatiana S. Gerashchenko
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia; (T.S.G.); (S.Y.Z.); (A.M.K.); (N.M.N.)
| | - Sofia Y. Zolotaryova
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia; (T.S.G.); (S.Y.Z.); (A.M.K.); (N.M.N.)
| | - Artem M. Kiselev
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia; (T.S.G.); (S.Y.Z.); (A.M.K.); (N.M.N.)
- Institute of Cytology, Russian Academy of Sciences, 194064 Saint Petersburg, Russia
| | - Liubov A. Tashireva
- Department of General and Molecular Pathology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia; (L.A.T.); (M.V.Z.); (V.M.P.)
| | - Nikita M. Novikov
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia; (T.S.G.); (S.Y.Z.); (A.M.K.); (N.M.N.)
| | - Nadezhda V. Krakhmal
- Department of Pathological Anatomy, Siberian State Medical University, 634050 Tomsk, Russia;
| | - Nadezhda V. Cherdyntseva
- Laboratory of Molecular Oncology and Immunology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia;
| | - Marina V. Zavyalova
- Department of General and Molecular Pathology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia; (L.A.T.); (M.V.Z.); (V.M.P.)
- Department of Pathological Anatomy, Siberian State Medical University, 634050 Tomsk, Russia;
| | - Vladimir M. Perelmuter
- Department of General and Molecular Pathology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia; (L.A.T.); (M.V.Z.); (V.M.P.)
| | - Evgeny V. Denisov
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia; (T.S.G.); (S.Y.Z.); (A.M.K.); (N.M.N.)
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18
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Roedig H, Damiescu R, Zeng-Brouwers J, Kutija I, Trebicka J, Wygrecka M, Schaefer L. Danger matrix molecules orchestrate CD14/CD44 signaling in cancer development. Semin Cancer Biol 2020; 62:31-47. [PMID: 31412297 DOI: 10.1016/j.semcancer.2019.07.026] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 07/29/2019] [Accepted: 07/30/2019] [Indexed: 02/06/2023]
Abstract
The tumor matrix together with inflammation and autophagy are crucial regulators of cancer development. Embedded in the tumor stroma are numerous proteoglycans which, in their soluble form, act as danger-associated molecular patterns (DAMPs). By interacting with innate immune receptors, the Toll-like receptors (TLRs), DAMPs autonomously trigger aseptic inflammation and can regulate autophagy. Biglycan, a known danger proteoglycan, can regulate the cross-talk between inflammation and autophagy by evoking a switch between pro-inflammatory CD14 and pro-autophagic CD44 co-receptors for TLRs. Thus, these novel mechanistic insights provide some explanation for the plethora of reports indicating that the same matrix-derived DAMP acts either as a promoter or suppressor of tumor growth. In this review we will summarize and critically discuss the role of the matrix-derived DAMPs biglycan, hyaluronan, and versican in regulating the TLR-, CD14- and CD44-signaling dialogue between inflammation and autophagy with particular emphasis on cancer development.
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Affiliation(s)
- Heiko Roedig
- Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe University, Frankfurt am Main, Germany
| | - Roxana Damiescu
- Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe University, Frankfurt am Main, Germany
| | - Jinyang Zeng-Brouwers
- Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe University, Frankfurt am Main, Germany
| | - Iva Kutija
- Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe University, Frankfurt am Main, Germany
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, University Clinic Frankfurt, Germany
| | - Malgorzata Wygrecka
- Department of Biochemistry, Faculty of Medicine, Universities of Giessen and Marburg Lung Center, Giessen, Germany
| | - Liliana Schaefer
- Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe University, Frankfurt am Main, Germany.
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19
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Troidl K, Schubert C, Vlacil AK, Chennupati R, Koch S, Schütt J, Oberoi R, Schaper W, Schmitz-Rixen T, Schieffer B, Grote K. The Lipopeptide MALP-2 Promotes Collateral Growth. Cells 2020; 9:cells9040997. [PMID: 32316253 PMCID: PMC7227808 DOI: 10.3390/cells9040997] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 04/14/2020] [Indexed: 12/19/2022] Open
Abstract
Beyond their role in pathogen recognition and the initiation of immune defense, Toll-like receptors (TLRs) are known to be involved in various vascular processes in health and disease. We investigated the potential of the lipopeptide and TLR2/6 ligand macrophage activating protein of 2-kDA (MALP-2) to promote blood flow recovery in mice. Hypercholesterolemic apolipoprotein E (Apoe)-deficient mice were subjected to microsurgical ligation of the femoral artery. MALP-2 significantly improved blood flow recovery at early time points (three and seven days), as assessed by repeated laser speckle imaging, and increased the growth of pre-existing collateral arteries in the upper hind limb, along with intimal endothelial cell proliferation in the collateral wall and pericollateral macrophage accumulation. In addition, MALP-2 increased capillary density in the lower hind limb. MALP-2 enhanced endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) release from endothelial cells and improved the experimental vasorelaxation of mesenteric arteries ex vivo. In vitro, MALP-2 led to the up-regulated expression of major endothelial adhesion molecules as well as their leukocyte integrin receptors and consequently enhanced the endothelial adhesion of leukocytes. Using the experimental approach of femoral artery ligation (FAL), we achieved promising results with MALP-2 to promote peripheral blood flow recovery by collateral artery growth.
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Affiliation(s)
- Kerstin Troidl
- Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany; (R.C.); (W.S.)
- Department of Vascular and Endovascular Surgery, University Hospital Frankfurt, 60488 Frankfurt, Germany; (C.S.); (T.S.-R.)
- Correspondence:
| | - Christian Schubert
- Department of Vascular and Endovascular Surgery, University Hospital Frankfurt, 60488 Frankfurt, Germany; (C.S.); (T.S.-R.)
| | - Ann-Kathrin Vlacil
- Cardiology and Angiology, Philipps-University Marburg, 35043 Marburg, Germany; (A.-K.V.); (S.K.); (J.S.); (R.O.); (B.S.); (K.G.)
| | - Ramesh Chennupati
- Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany; (R.C.); (W.S.)
| | - Sören Koch
- Cardiology and Angiology, Philipps-University Marburg, 35043 Marburg, Germany; (A.-K.V.); (S.K.); (J.S.); (R.O.); (B.S.); (K.G.)
| | - Jutta Schütt
- Cardiology and Angiology, Philipps-University Marburg, 35043 Marburg, Germany; (A.-K.V.); (S.K.); (J.S.); (R.O.); (B.S.); (K.G.)
| | - Raghav Oberoi
- Cardiology and Angiology, Philipps-University Marburg, 35043 Marburg, Germany; (A.-K.V.); (S.K.); (J.S.); (R.O.); (B.S.); (K.G.)
| | - Wolfgang Schaper
- Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany; (R.C.); (W.S.)
| | - Thomas Schmitz-Rixen
- Department of Vascular and Endovascular Surgery, University Hospital Frankfurt, 60488 Frankfurt, Germany; (C.S.); (T.S.-R.)
| | - Bernhard Schieffer
- Cardiology and Angiology, Philipps-University Marburg, 35043 Marburg, Germany; (A.-K.V.); (S.K.); (J.S.); (R.O.); (B.S.); (K.G.)
| | - Karsten Grote
- Cardiology and Angiology, Philipps-University Marburg, 35043 Marburg, Germany; (A.-K.V.); (S.K.); (J.S.); (R.O.); (B.S.); (K.G.)
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20
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Santamaria S. ADAMTS-5: A difficult teenager turning 20. Int J Exp Pathol 2020; 101:4-20. [PMID: 32219922 DOI: 10.1111/iep.12344] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 12/28/2019] [Accepted: 01/19/2020] [Indexed: 12/13/2022] Open
Abstract
A Disintegrin And Metalloproteinase with ThromboSpondin motif (ADAMTS)-5 was identified in 1999 as one of the enzymes responsible for cleaving aggrecan, the major proteoglycan in articular cartilage. Studies in vitro, ex vivo and in vivo have validated ADAMTS-5 as a target in osteoarthritis (OA), a disease characterized by extensive degradation of aggrecan. For this reason, it attracted the interest of many research groups aiming to develop a therapeutic treatment for OA patients. However, ADAMTS-5 proteoglycanase activity is not only involved in the dysregulated aggrecan proteolysis, which occurs in OA, but also in the physiological turnover of other related proteoglycans. In particular, versican, a major ADAMTS-5 substrate, plays an important structural role in heart and blood vessels and its proteolytic processing by ADAMTS-5 must be tightly regulated. On the occasion of the 20th anniversary of the discovery of ADAMTS-5, this review looks at the evidence for its detrimental role in OA, as well as its physiological turnover of cardiovascular proteoglycans. Moreover, the other potential functions of this enzyme are highlighted. Finally, challenges and emerging trends in ADAMTS-5 research are discussed.
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Wight TN, Kang I, Evanko SP, Harten IA, Chang MY, Pearce OMT, Allen CE, Frevert CW. Versican-A Critical Extracellular Matrix Regulator of Immunity and Inflammation. Front Immunol 2020; 11:512. [PMID: 32265939 PMCID: PMC7105702 DOI: 10.3389/fimmu.2020.00512] [Citation(s) in RCA: 167] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 03/06/2020] [Indexed: 12/13/2022] Open
Abstract
The extracellular matrix (ECM) proteoglycan, versican increases along with other ECM versican binding molecules such as hyaluronan, tumor necrosis factor stimulated gene-6 (TSG-6), and inter alpha trypsin inhibitor (IαI) during inflammation in a number of different diseases such as cardiovascular and lung disease, autoimmune diseases, and several different cancers. These interactions form stable scaffolds which can act as "landing strips" for inflammatory cells as they invade tissue from the circulation. The increase in versican is often coincident with the invasion of leukocytes early in the inflammatory process. Versican interacts with inflammatory cells either indirectly via hyaluronan or directly via receptors such as CD44, P-selectin glycoprotein ligand-1 (PSGL-1), and toll-like receptors (TLRs) present on the surface of immune and non-immune cells. These interactions activate signaling pathways that promote the synthesis and secretion of inflammatory cytokines such as TNFα, IL-6, and NFκB. Versican also influences inflammation by interacting with a variety of growth factors and cytokines involved in regulating inflammation thereby influencing their bioavailability and bioactivity. Versican is produced by multiple cell types involved in the inflammatory process. Conditional total knockout of versican in a mouse model of lung inflammation demonstrated significant reduction in leukocyte invasion into the lung and reduced inflammatory cytokine expression. While versican produced by stromal cells tends to be pro-inflammatory, versican expressed by myeloid cells can create anti-inflammatory and immunosuppressive microenvironments. Inflammation in the tumor microenvironment often contains elevated levels of versican. Perturbing the accumulation of versican in tumors can inhibit inflammation and tumor progression in some cancers. Thus versican, as a component of the ECM impacts immunity and inflammation through regulating immune cell trafficking and activation. Versican is emerging as a potential target in the control of inflammation in a number of different diseases.
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Affiliation(s)
- Thomas N. Wight
- Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, United States
| | - Inkyung Kang
- Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, United States
| | - Stephen P. Evanko
- Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, United States
| | - Ingrid A. Harten
- Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, United States
| | - Mary Y. Chang
- Division of Pulmonary/Critical Care Medicine, Center for Lung Biology, University of Washington School of Medicine, Seattle, WA, United States
| | - Oliver M. T. Pearce
- Centre for the Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Carys E. Allen
- Centre for the Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Charles W. Frevert
- Division of Pulmonary/Critical Care Medicine, Center for Lung Biology, University of Washington School of Medicine, Seattle, WA, United States
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22
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Hatano S, Watanabe H. Regulation of Macrophage and Dendritic Cell Function by Chondroitin Sulfate in Innate to Antigen-Specific Adaptive Immunity. Front Immunol 2020; 11:232. [PMID: 32194548 PMCID: PMC7063991 DOI: 10.3389/fimmu.2020.00232] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 01/28/2020] [Indexed: 12/11/2022] Open
Abstract
Chondroitin sulfate (CS), a type of glycosaminoglycan (GAG), is a linear acidic polysaccharide comprised of repeating disaccharides, modified with sulfate groups at various positions. Except for hyaluronan (HA), GAGs are covalently bound to core proteins, forming proteoglycans (PGs). With highly negative charges, GAGs interact with a variety of physiologically active molecules, including cytokines, chemokines, and growth factors, and control cell behavior during development and in the progression of diseases, including cancer, infections, and inflammation. Heparan sulfate (HS), another type of GAG, and HA are well reported as regulators for leukocyte migration at sites of inflammation. There have been many reports on the regulation of immune cell function by HS and HA; however, regulation of immune cells by CS has not yet been fully understood. This article focuses on the regulatory function of CS in antigen-presenting cells, including macrophages and dendritic cells, and refers to CSPGs, such as versican and biglycan, and the cell surface proteoglycan, syndecan.
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Affiliation(s)
- Sonoko Hatano
- Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Japan
| | - Hideto Watanabe
- Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Japan
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23
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Papadas A, Asimakopoulos F. Versican in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1272:55-72. [PMID: 32845502 DOI: 10.1007/978-3-030-48457-6_4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Versican is an extracellular matrix proteoglycan with nonredundant roles in diverse biological and cellular processes, ranging from embryonic development to adult inflammation and cancer. Versican is essential for cardiovascular morphogenesis, neural crest migration, and skeletal development during embryogenesis. In the adult, versican acts as an inflammation "amplifier" and regulator of immune cell activation and cytokine production. Increased versican expression has been observed in a wide range of malignant tumors and has been associated with poor patient outcomes. The main sources of versican production in the tumor microenvironment include accessory cells (myeloid cells and stromal components) and, in some contexts, the tumor cells themselves. Versican has been implicated in several classical hallmarks of cancer such as proliferative signaling, evasion of growth suppressor signaling, resistance to cell death, angiogenesis, and tissue invasion and metastasis. More recently, versican has been implicated in escape from tumor immune surveillance, e.g., through dendritic cell dysfunction. Versican's multiple contributions to benign and malignant biological processes are further diversified through the generation of versican-derived bioactive proteolytic fragments (matrikines), with versikine being the most studied to date. Versican and versican-derived matrikines hold promise as targets in the management of inflammatory and malignant conditions as well as in the development of novel predictive and prognostic biomarkers.
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Affiliation(s)
- Athanasios Papadas
- Department of Medicine, Division of Blood and Marrow Transplantation, University of California San Diego (UCSD), Moores Cancer Center, La Jolla, CA, USA. .,University of Wisconsin-Madison, Cellular and Molecular Pathology Program, Madison, WI, USA.
| | - Fotis Asimakopoulos
- Department of Medicine, Division of Blood and Marrow Transplantation, University of California San Diego (UCSD), Moores Cancer Center, La Jolla, CA, USA
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24
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Groux-Degroote S, Cavdarli S, Uchimura K, Allain F, Delannoy P. Glycosylation changes in inflammatory diseases. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2019; 119:111-156. [PMID: 31997767 DOI: 10.1016/bs.apcsb.2019.08.008] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Glycosylation is one of the most important modifications of proteins and lipids, and cell surface glycoconjugates are thought to play important roles in a variety of biological functions including cell-cell and cell-substrate interactions, bacterial adhesion, cell immunogenicity and cell signaling. Alterations of glycosylation are observed in a number of inflammatory diseases. Pro-inflammatory cytokines have been shown to modulate cell surface glycosylation by regulating the expression of glycosyltransferases and sulfotransferases involved in the biosynthesis of glycan chains, inducing the expression of specific carbohydrate antigens at the cell surface that can be recognized by different types of lectins or by bacterial adhesins, contributing to the development of diseases. Glycosylation can also regulate biological functions of immune cells by recruiting leukocytes to inflammation sites with pro- or anti-inflammatory effects. Cell surface proteoglycans provide a large panel of binding sites for many mediators of inflammation, and regulate their bio-availability and functions. In this review, we summarize the current knowledge of the glycosylation changes occurring in mucin type O-linked glycans, glycosaminoglycans, as well as in glycosphingolipids, with a particular focus on cystic fibrosis and neurodegenerative diseases, and their consequences on cell interactions and disease progression.
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Affiliation(s)
- Sophie Groux-Degroote
- University Lille, CNRS, UMR 8576 - UGSF - Unite de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France
| | - Sumeyye Cavdarli
- University Lille, CNRS, UMR 8576 - UGSF - Unite de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France
| | - Kenji Uchimura
- University Lille, CNRS, UMR 8576 - UGSF - Unite de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France
| | - Fabrice Allain
- University Lille, CNRS, UMR 8576 - UGSF - Unite de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France
| | - Philippe Delannoy
- University Lille, CNRS, UMR 8576 - UGSF - Unite de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France
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25
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Islam S, Chuensirikulchai K, Khummuang S, Keratibumrungpong T, Kongtawelert P, Kasinrerk W, Hatano S, Nagamachi A, Honda H, Watanabe H. Accumulation of versican facilitates wound healing: Implication of its initial ADAMTS-cleavage site. Matrix Biol 2019; 87:77-93. [PMID: 31669737 DOI: 10.1016/j.matbio.2019.10.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Revised: 10/20/2019] [Accepted: 10/21/2019] [Indexed: 11/16/2022]
Abstract
Versican is a large chondroitin sulfate/dermatan sulfate proteoglycan in the extracellular matrix, and is expressed at high levels in tissues during development and remodeling in pathological conditions. Its core protein is cleaved at a region close to the N-terminal end of CSβ domain by several members of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family, i.e., ADAMTS-1, 4, 5, 9, 15, and 20. Here, using a CRISPR/Cas9 system, we generated knock-in mice (V1R), which express an ADAMTS cleavage-resistant versican. Some V1R homozygote mice, termed R/R, exhibit syndactyly and organ hemorrhage. In wound healing experiments, R/R wound shows accumulation of versican and activated TGFβ-signaling in the early stage, leading to faster healing than wild type wound. Immunostaining for Ki67, CD31, smooth muscle α-actin, periostin demonstrates higher levels of overall cell proliferation and an increased number of endothelial cells and myofibroblasts. Immunostaining for CD11b and qRT-PCR for macrophage markers revealed increased levels of inflammatory cell infiltration, especially those of M1 macrophages. Cultured R/R dermal fibroblasts revealed increased deposition of versican, type I and III collagens, and hyaluronan, and upregulation of Smad2/3 signaling. Taken together, these results demonstrate that the cleavage site determines versican turnover and that versican plays a central role in the provisional matrix during the wound repair.
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Affiliation(s)
- Shamima Islam
- Institute for Molecular Science of Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan
| | - Kantinan Chuensirikulchai
- Institute for Molecular Science of Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan; Biomedical Technology Research Center, Division of Clinical Immunology, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Saichit Khummuang
- Institute for Molecular Science of Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan; Biomedical Technology Research Center, Division of Clinical Immunology, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Tanyaporn Keratibumrungpong
- Institute for Molecular Science of Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan; Thailand Excellence Center for Tissue Engineering and Stem Cells, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Prachya Kongtawelert
- Thailand Excellence Center for Tissue Engineering and Stem Cells, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Watchara Kasinrerk
- Biomedical Technology Research Center, Division of Clinical Immunology, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Sonoko Hatano
- Institute for Molecular Science of Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan
| | - Akiko Nagamachi
- Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan
| | - Hiroaki Honda
- Field of Human Disease Models, Major in Advanced Life Sciences and Medicine, Institute of Laboratory Animals, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Hideto Watanabe
- Institute for Molecular Science of Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan.
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26
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Cherfils-Vicini J, Iltis C, Cervera L, Pisano S, Croce O, Sadouni N, Győrffy B, Collet R, Renault VM, Rey-Millet M, Leonetti C, Zizza P, Allain F, Ghiringhelli F, Soubeiran N, Shkreli M, Vivier E, Biroccio A, Gilson E. Cancer cells induce immune escape via glycocalyx changes controlled by the telomeric protein TRF2. EMBO J 2019; 38:embj.2018100012. [PMID: 31000523 DOI: 10.15252/embj.2018100012] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 03/10/2019] [Accepted: 03/15/2019] [Indexed: 12/15/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with strong immunosuppressive activity that promote tumor growth. In this study, we describe a mechanism by which cancer cells control MDSCs in human cancers by upregulating TRF2, a protein required for telomere stability. Specifically, we showed that the TRF2 upregulation in cancer cells has extratelomeric roles in activating the expression of a network of genes involved in the biosynthesis of heparan sulfate proteoglycan, leading to profound changes in glycocalyx length and stiffness, as revealed by atomic force microscopy. This TRF2-dependent regulation facilitated the recruitment of MDSCs, their activation via the TLR2/MyD88/IL-6/STAT3 pathway leading to the inhibition of natural killer recruitment and cytotoxicity, and ultimately tumor progression and metastasis. The clinical relevance of these findings is supported by our analysis of cancer cohorts, which showed a correlation between high TRF2 expression and MDSC infiltration, which was inversely correlated with overall patient survival.
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Affiliation(s)
- Julien Cherfils-Vicini
- Université Côte d'Azur, Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (INSERM) U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
| | - Charlene Iltis
- Université Côte d'Azur, Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (INSERM) U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
| | - Ludovic Cervera
- Université Côte d'Azur, Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (INSERM) U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
| | - Sabrina Pisano
- Université Côte d'Azur, Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (INSERM) U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
| | - Olivier Croce
- Université Côte d'Azur, Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (INSERM) U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
| | - Nori Sadouni
- Université Côte d'Azur, Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (INSERM) U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
| | - Balázs Győrffy
- MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary.,2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Romy Collet
- Université Côte d'Azur, Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (INSERM) U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
| | - Valérie M Renault
- Université Côte d'Azur, Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (INSERM) U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
| | - Martin Rey-Millet
- Université Côte d'Azur, Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (INSERM) U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
| | - Carlo Leonetti
- IRCCS-Regina Elena National Cancer Institute, Rome, Italy
| | - Pasquale Zizza
- IRCCS-Regina Elena National Cancer Institute, Rome, Italy
| | - Fabrice Allain
- CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, University of Lille, Villeneuve d'Ascq, Lille, France
| | - Francois Ghiringhelli
- INSERM, U866, UFR des Sciences de Sante, Universite de Bourgogne-Franche Comte, Dijon, France.,Centre Georges François Leclerc, Dijon, France
| | - Nicolas Soubeiran
- Université Côte d'Azur, Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (INSERM) U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
| | - Marina Shkreli
- Université Côte d'Azur, Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (INSERM) U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
| | - Eric Vivier
- Aix Marseille Univ, APHM, CNRS, INSERM, CIML, Hôpital de la Timone, Marseille-Immunopole, Marseille, France.,Innate Pharma Research Laboratories, Innate Pharma, Marseille, France
| | | | - Eric Gilson
- Université Côte d'Azur, Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (INSERM) U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France .,Department of Medical Genetics, Archet 2 Hospital, CHU of Nice, FHU Oncoage, Nice, France
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27
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Biglycan is a new high-affinity ligand for CD14 in macrophages. Matrix Biol 2019; 77:4-22. [DOI: 10.1016/j.matbio.2018.05.006] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 05/15/2018] [Accepted: 05/15/2018] [Indexed: 02/06/2023]
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28
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Nahon JE, Hoekstra M, Havik SR, Van Santbrink PJ, Dallinga-Thie GM, Kuivenhoven JA, Geerling JJ, Van Eck M. Proteoglycan 4 regulates macrophage function without altering atherosclerotic lesion formation in a murine bone marrow-specific deletion model. Atherosclerosis 2018; 274:120-127. [DOI: 10.1016/j.atherosclerosis.2018.05.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 05/01/2018] [Accepted: 05/02/2018] [Indexed: 11/15/2022]
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29
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Chen Y, Yousaf MN, Mehal WZ. Role of sterile inflammation in fatty liver diseases. LIVER RESEARCH 2018. [DOI: 10.1016/j.livres.2018.02.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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30
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Frevert CW, Felgenhauer J, Wygrecka M, Nastase MV, Schaefer L. Danger-Associated Molecular Patterns Derived From the Extracellular Matrix Provide Temporal Control of Innate Immunity. J Histochem Cytochem 2018; 66:213-227. [PMID: 29290139 DOI: 10.1369/0022155417740880] [Citation(s) in RCA: 119] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
It is evident that components of the extracellular matrix (ECM) act as danger-associated molecular patterns (DAMPs) through direct interactions with pattern recognition receptors (PRRs) including Toll-like receptors (TLRs) and inflammasomes. Through these interactions, ECM-derived DAMPs autonomously trigger sterile inflammation or prolong pathogen-induced responses through the production of proinflammatory mediators and the recruitment of leukocytes to sites of injury and infection. Recent research, however, suggests that ECM-derived DAMPs are additionally involved in the resolution and fine-tuning of inflammation by orchestrating the production of anti-inflammatory mediators that are required for the resolution of tissue inflammation and the transition to acquired immunity. Thus, in this review, we discuss the current knowledge of the interplay between ECM-derived DAMPs and the innate immune signaling pathways that are activated to provide temporal control of innate immunity.
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Affiliation(s)
- Charles W Frevert
- Center for Lung Biology, University of Washington, Seattle, Washington
| | | | - Malgorzata Wygrecka
- Department of Biochemistry, Faculty of Medicine, Universities of Giessen and Marburg Lung Center, Giessen, Germany
| | - Madalina V Nastase
- Pharmazentrum Frankfurt/ZAFES, Institut für Allgemeine Pharmakologie und Toxikologie, Frankfurt am Main, Germany.,National Institute for Chemical-Pharmaceutical Research and Development, Bucharest, Romania
| | - Liliana Schaefer
- Pharmazentrum Frankfurt/ZAFES, Institut für Allgemeine Pharmakologie und Toxikologie, Frankfurt am Main, Germany
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31
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Abstract
PURPOSE OF REVIEW The present review explores the mechanisms of superficial intimal erosion, a common cause of thrombotic complications of atherosclerosis. RECENT FINDINGS Human coronary artery atheroma that give rise to thrombosis because of erosion differ diametrically from those associated with fibrous cap rupture. Eroded lesions characteristically contain few inflammatory cells, abundant extracellular matrix, and neutrophil extracellular traps (NETs). Innate immune mechanisms such as engagement of Toll-like receptor 2 (TLR2) on cultured endothelial cells can impair their viability, attachment, and ability to recover a wound. Hyaluronan fragments may serve as endogenous TLR2 ligands. Mouse experiments demonstrate that flow disturbance in arteries with neointimas tailored to resemble features of human eroded plaques disturbs endothelial cell barrier function, impairs endothelial cell viability, recruits neutrophils, and provokes endothelial cells desquamation, NET formation, and thrombosis in a TLR2-dependent manner. SUMMARY Mechanisms of erosion have received much less attention than those that provoke plaque rupture. Intensive statin treatment changes the characteristic of plaques that render them less susceptible to rupture. Thus, erosion may contribute importantly to the current residual burden of risk. Understanding the mechanisms of erosion may inform the development and deployment of novel therapies to combat the remaining atherothrombotic risk in the statin era.
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Affiliation(s)
- Thibaut Quillard
- Department of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Grégory Franck
- Department of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Thomas Mawson
- Department of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Eduardo Folco
- Department of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Peter Libby
- Department of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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33
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Abedelhaffez AS, El-Aziz EAA, Aziz MAA, Ahmed AM. Lung injury induced by Bisphenol A: A food contaminant, is ameliorated by selenium supplementation. PATHOPHYSIOLOGY 2017; 24:81-89. [DOI: 10.1016/j.pathophys.2017.02.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 01/27/2017] [Accepted: 02/04/2017] [Indexed: 12/16/2022] Open
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34
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Wight TN, Frevert CW, Debley JS, Reeves SR, Parks WC, Ziegler SF. Interplay of extracellular matrix and leukocytes in lung inflammation. Cell Immunol 2017; 312:1-14. [PMID: 28077237 PMCID: PMC5290208 DOI: 10.1016/j.cellimm.2016.12.003] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 12/21/2016] [Accepted: 12/22/2016] [Indexed: 12/13/2022]
Abstract
During inflammation, leukocytes influx into lung compartments and interact with extracellular matrix (ECM). Two ECM components, versican and hyaluronan, increase in a range of lung diseases. The interaction of leukocytes with these ECM components controls leukocyte retention and accumulation, proliferation, migration, differentiation, and activation as part of the inflammatory phase of lung disease. In addition, bronchial epithelial cells from asthmatic children co-cultured with human lung fibroblasts generate an ECM that is adherent for monocytes/macrophages. Macrophages are present in both early and late lung inflammation. Matrix metalloproteinase 10 (MMP10) is induced in alveolar macrophages with injury and infection and modulates macrophage phenotype and their ability to degrade collagenous ECM components. Collectively, studies outlined in this review highlight the importance of specific ECM components in the regulation of inflammatory events in lung disease. The widespread involvement of these ECM components in the pathogenesis of lung inflammation make them attractive candidates for therapeutic intervention.
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Affiliation(s)
- Thomas N Wight
- Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
| | - Charles W Frevert
- Department of Comparative Medicine, University of Washington, Seattle, WA, USA
| | - Jason S Debley
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, and Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA
| | - Stephen R Reeves
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, and Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA
| | - William C Parks
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Steven F Ziegler
- Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
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35
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Wight TN. Provisional matrix: A role for versican and hyaluronan. Matrix Biol 2016; 60-61:38-56. [PMID: 27932299 DOI: 10.1016/j.matbio.2016.12.001] [Citation(s) in RCA: 161] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 11/22/2016] [Accepted: 12/01/2016] [Indexed: 12/19/2022]
Abstract
Hyaluronan and versican are extracellular matrix (ECM) components that are enriched in the provisional matrices that form during the early stages of development and disease. These two molecules interact to create pericellular "coats" and "open space" that facilitate cell sorting, proliferation, migration, and survival. Such complexes also impact the recruitment of leukocytes during development and in the early stages of disease. Once thought to be inert components of the ECM that help hold cells together, it is now quite clear that they play important roles in controlling cell phenotype, shaping tissue response to injury and maintaining tissue homeostasis. Conversion of hyaluronan-/versican-enriched provisional matrix to collagen-rich matrix is a "hallmark" of tissue fibrosis. Targeting the hyaluronan and versican content of provisional matrices in a variety of diseases including, cardiovascular disease and cancer, is becoming an attractive strategy for intervention.
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Affiliation(s)
- Thomas N Wight
- Matrix Biology Program, Benaroya Research Institute, 1201 9th Avenue, Seattle, WA 98101, United States.
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Kang I, Harten IA, Chang MY, Braun KR, Sheih A, Nivison MP, Johnson PY, Workman G, Kaber G, Evanko SP, Chan CK, Merrilees MJ, Ziegler SF, Kinsella MG, Frevert CW, Wight TN. Versican Deficiency Significantly Reduces Lung Inflammatory Response Induced by Polyinosine-Polycytidylic Acid Stimulation. J Biol Chem 2016; 292:51-63. [PMID: 27895126 DOI: 10.1074/jbc.m116.753186] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 11/10/2016] [Indexed: 12/16/2022] Open
Abstract
Viral infection is an exacerbating factor contributing to chronic airway diseases, such as asthma, via mechanisms that are still unclear. Polyinosine-polycytidylic acid (poly(I:C)), a Toll-like receptor 3 (TLR3) agonist used as a mimetic to study viral infection, has been shown to elicit inflammatory responses in lungs and to exacerbate pulmonary allergic reactions in animal models. Previously, we have shown that poly(I:C) stimulates lung fibroblasts to accumulate an extracellular matrix (ECM), enriched in hyaluronan (HA) and its binding partner versican, which promotes monocyte adhesion. In the current study, we aimed to determine the in vivo role of versican in mediating inflammatory responses in poly(I:C)-induced lung inflammation using a tamoxifen-inducible versican-deficient mouse model (Vcan-/- mice). In C57Bl/6 mice, poly(I:C) instillation significantly increased accumulation of versican and HA, especially in the perivascular and peribronchial regions, which were enriched in infiltrating leukocytes. In contrast, versican-deficient (Vcan-/-) lungs did not exhibit increases in versican or HA in these regions and had strikingly reduced numbers of leukocytes in the bronchoalveolar lavage fluid and lower expression of inflammatory chemokines and cytokines. Poly(I:C) stimulation of lung fibroblasts isolated from control mice generated HA-enriched cable structures in the ECM, providing a substrate for monocytic cells in vitro, whereas lung fibroblasts from Vcan-/- mice did not. Moreover, increases in proinflammatory cytokine expression were also greatly attenuated in the Vcan-/- lung fibroblasts. These findings provide strong evidence that versican is a critical inflammatory mediator during poly(I:C)-induced acute lung injury and, in association with HA, generates an ECM that promotes leukocyte infiltration and adhesion.
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Affiliation(s)
| | | | - Mary Y Chang
- the Department of Comparative Medicine and Center for Lung Biology, University of Washington, Seattle, Washington 98109, and
| | | | - Alyssa Sheih
- Immunology Program, Benaroya Research Institute, Seattle, Washington 98101
| | | | | | | | | | | | | | - Mervyn J Merrilees
- the Department of Anatomy and Medical Imaging, School of Medical Sciences, University of Auckland, Auckland 1010, New Zealand
| | - Steven F Ziegler
- Immunology Program, Benaroya Research Institute, Seattle, Washington 98101
| | | | - Charles W Frevert
- the Department of Comparative Medicine and Center for Lung Biology, University of Washington, Seattle, Washington 98109, and
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McMahon M, Ye S, Izzard L, Dlugolenski D, Tripp RA, Bean AGD, McCulloch DR, Stambas J. ADAMTS5 Is a Critical Regulator of Virus-Specific T Cell Immunity. PLoS Biol 2016; 14:e1002580. [PMID: 27855162 PMCID: PMC5113859 DOI: 10.1371/journal.pbio.1002580] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Accepted: 10/25/2016] [Indexed: 01/09/2023] Open
Abstract
The extracellular matrix (ECM) provides physical scaffolding for cellular constituents and initiates biochemical and biomechanical cues that are required for physiological activity of living tissues. The ECM enzyme ADAMTS5, a member of the ADAMTS (A Disintegrin-like and Metalloproteinase with Thrombospondin-1 motifs) protein family, cleaves large proteoglycans such as aggrecan, leading to the destruction of cartilage and osteoarthritis. However, its contribution to viral pathogenesis and immunity is currently undefined. Here, we use a combination of in vitro and in vivo models to show that ADAMTS5 enzymatic activity plays a key role in the development of influenza-specific immunity. Influenza virus infection of Adamts5-/- mice resulted in delayed virus clearance, compromised T cell migration and immunity and accumulation of versican, an ADAMTS5 proteoglycan substrate. Our research emphasises the importance of ADAMTS5 expression in the control of influenza virus infection and highlights the potential for development of ADAMTS5-based therapeutic strategies to reduce morbidity and mortality. The extracellular matrix enzyme ADAMTS5 enhances the clearance of viruses by facilitating migration of T lymphocytes to the periphery following influenza virus infection. Movement of immune cells is critical for effective clearance of pathogens. The response to influenza virus infection requires immune cell trafficking between the lung, mediastinal lymph node and other peripheral lymphoid organs such as the spleen. We set out to assess the contribution of a specific extracellular matrix enzyme, ADAMTS5, to migration of lymphocytes and overall pathogenesis following infection. In our studies, we demonstrate that mice lacking Adamts5 have fewer influenza-specific lymphocytes in the lung and spleen following infection. These observations correlated with an accumulation of influenza-specific lymphocytes in the mediastinal lymph node and increased virus titres. This work suggests that ADAMTS5 is necessary for immune cell migration to the periphery, where lymphocyte function is required to fight infection.
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Affiliation(s)
- Meagan McMahon
- School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
| | - Siying Ye
- School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
| | - Leonard Izzard
- School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
| | | | - Ralph A. Tripp
- College of Veterinary Medicine, University of Georgia, Athens, Georgia, United States of America
| | - Andrew G. D. Bean
- Australian Animal Health Laboratory, CSIRO, East Geelong, Victoria, Australia
| | | | - John Stambas
- School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
- * E-mail:
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Yakubenko VP, Byzova TV. Biological and pathophysiological roles of end-products of DHA oxidation. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1862:407-415. [PMID: 27713004 DOI: 10.1016/j.bbalip.2016.09.022] [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: 05/25/2016] [Revised: 09/28/2016] [Accepted: 09/29/2016] [Indexed: 01/20/2023]
Abstract
BACKGROUND Polyunsaturated fatty acids (PUFA) are known to be present and/or enriched in vegetable and fish oils. Among fatty acids, n-3 PUFA are generally considered to be protective in inflammation-related diseases. The guidelines for substituting saturated fatty acids for PUFAs have been highly publicized for decades by numerous health organizations. Recently, however, the beneficial properties of n-3 PUFA are questioned by detailed analyses of multiple randomized controlled clinical trials. The reported heterogeneity of results is likely due not only to differential effects of PUFAs on various pathological processes in humans, but also to the wide spectrum of PUFA's derived products generated in vivo. SCOPE OF REVIEW The goal of this review is to discuss the studies focused on well-defined end-products of PUFAs oxidation, their generation, presence in various pathological and physiological conditions, their biological activities and known receptors. Carboxyethylpyrrole (CEP), a DHA-derived oxidized product, is especially emphasized due to recent data demonstrating its pathophysiological significance in many inflammation-associated diseases, including atherosclerosis, hyperlipidemia, thrombosis, macular degeneration, and tumor progression. MAJOR CONCLUSIONS CEP is a product of radical-based oxidation of PUFA that forms adducts with proteins and lipids in blood and tissues, generating new powerful ligands for TLRs and scavenger receptors. The interaction of CEP with these receptors affects inflammatory response, angiogenesis, and wound healing. GENERAL SIGNIFICANCE The detailed understanding of CEP-mediated cellular responses may provide a basis for the development of novel therapeutic strategies and dietary recommendations.
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Affiliation(s)
- Valentin P Yakubenko
- Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States; Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Tatiana V Byzova
- Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States.
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Xu L, Xue T, Zhang J, Qu J. Knockdown of versican V1 induces a severe inflammatory response in LPS-induced acute lung injury via the TLR2-NF-κB signaling pathway in C57BL/6J mice. Mol Med Rep 2016; 13:5005-12. [PMID: 27109786 PMCID: PMC4878555 DOI: 10.3892/mmr.2016.5168] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 03/29/2016] [Indexed: 01/08/2023] Open
Abstract
The versican family is important in the modulation of inflammation, however, the role of versican V1 (V1) in lipo-polysaccharide (LPS)-induced acute lung injury (ALI) and the underlying mechanisms remain to be elucidated. To investigate this, the present study performed experiments in male C57BL/6J mice, which were randomly divided into a normal control group (control; n=6), an LPS-stimulated ALI group (LPS; n=6), a scramble small interfering (si)RNA group (scramble; n=6), a V1-siRNA group (V1-siRNA; n=6), a scramble siRNA and LPS-stimulated group (scramble+LPS; n=6) and a V1-siRNA and LPS-stimulated group (V1-siRNA+LPS; n=6). On day 1, the mice were anesthetized, and 5 nmol scramble siRNA or V1-siRNA were administered intratracheally. On day 3, LPS (1 mg/kg) or phosphate-buffered saline (50 µl per mouse) were injected intratracheally. All the mice were anesthetized and sacrificed on day 4, and samples were collected and analyzed. The mRNA and protein expression levels were examined using reverse transcription-quantitative polymerase chain reaction analysis, immunohistochemical staining and western blot analysis. ALI was evaluated based on lung injury scores, cell counts and total protein concentrations in the bronchoalveolar lavage fluid (BALF). Inflammatory mediators were detected using an enzyme-linked immunosorbend assay. V1 was increased by LPS in the mouse ALI model, whereas specific V1 knockdown induced higher lung injury scores, and higher total cell counts and protein concentrations in the BALF. Tumor necrosis factor-α (TNF)-α was upregulated, and interleukin-6 exhibited an increasing trend. The expression of toll-like receptor 2 (TLR2), but not TLR4, increased, and the nuclear factor (NF)-κB pathway subunit, P65, was phosphorylated. Taken together, the expression of V1 was upregulated by LPS, and V1 inhibition resulted in the aggravation of LPS-induced ALI via the activation of TLR2-NF-κB and release of TNF-α.
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Affiliation(s)
- Lulu Xu
- Department of Pulmonary Medicine, Huadong Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Tao Xue
- Department of Neurology, Yan'an University Affiliated Hospital, Yan'an, Shanxi 716000, P.R. China
| | - Jing Zhang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Jieming Qu
- Department of Pulmonary Medicine, Huadong Hospital, Fudan University, Shanghai 200040, P.R. China
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Versican: a novel modulator of hepatic fibrosis. J Transl Med 2016; 96:361-74. [PMID: 26752747 DOI: 10.1038/labinvest.2015.152] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 10/29/2015] [Accepted: 11/02/2015] [Indexed: 01/17/2023] Open
Abstract
Little is known about the deposition and turnover of proteoglycans in liver fibrosis, despite their abundance in the extracellular matrix. Versican plays diverse roles in modulating cell behavior in other fibroproliferative diseases, but remains poorly described in the liver. Hepatic fibrosis was induced by carbon tetrachloride treatment of C57BL/6 mice over 4 weeks followed by recovery over a 28-day period. Primary mouse hepatic stellate cells (HSCs) were activated in culture and versican was transiently knocked down in human (LX2) and mouse HSCs. Expression of versican, A Disintegrin-like and Metalloproteinase with Thrombospondin-1 motifs (ADAMTS)-1, -4, -5, -8, -9, -15, and -20, and markers of fibrogenesis were studied using immunohistochemistry, real-time quantitative PCR, and western blotting. Immunohistochemistry showed increased expression of versican in cirrhotic human livers and the mouse model of fibrosis. Carbon tetrachloride treatment led to significant increases in versican expression and the proteoglycanases ADAMTS-5, -9, -15, and -20, alongside TNF-α, α-smooth muscle actin (α-SMA), collagen-1, and TGF-β expression. During recovery, expression of many of these genes returned to control levels. However, expression of ADAMTS-5, -8, -9, and -15 showed delayed increases in expression at 28 days of recovery, which corresponded with decreases in versican V0 and V1 cleavage products (G1-DPEAAE(1401) and G1-DPEAAE(441)). Activation of primary HSCs in vitro significantly increased versican, α-SMA, and collagen-1 expression. Transient knockdown of versican in HSCs led to decreases in markers of fibrogenesis and reduced cell proliferation, without inducing apoptosis. Versican expression increases during HSC activation and liver fibrosis, and proteolytic processing occurs during the resolution of fibrosis. Knockdown studies in vitro suggest a possible role of versican in modulating hepatic fibrogenesis.
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Lopes JAG, Borges-Canha M, Pimentel-Nunes P. Innate immunity and hepatocarcinoma: Can toll-like receptors open the door to oncogenesis? World J Hepatol 2016; 8:162-182. [PMID: 26839640 PMCID: PMC4724579 DOI: 10.4254/wjh.v8.i3.162] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Accepted: 12/08/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocarcinoma (HCC) is a highly prevalent cancer worldwide and its inflammatory background was established long ago. Recent studies have shown that innate immunity is closely related to the HCC carcinogenesis. An effective innate immunity response relies on the toll-like receptors (TLR) found in several different liver cells which, through different ligands and many signaling pathways can elicit, not only a pro-inflammatory but also an oncogenic or anti-oncogenic response. Our aim was to study the role of TLRs in the liver oncogenesis and as a consequence their value as potential therapeutic targets. We performed a systematic review of PubMed searching for original articles studying the relationship between HCC and TLRs until March 2015. TLR2 appears to be a fundamental stress-sensor as its absence reveals an augmented tendency to accumulate DNA-damages and to cell survival. However, pathways are still not fully understood as TLR2 up-regulation was also associated to enhanced tumorigenesis. TLR3 has a well-known protective role influencing crucial processes like angiogenesis, cell growth or proliferation. TLR4 works as an interesting epithelial-mesenchymal transition’s inducer and a promoter of cell survival probably inducing HCC carcinogenesis even though an anti-cancer role has already been observed. TLR9’s influence on carcinogenesis is also controversial and despite a potential anti-cancer capacity, a pro-tumorigenic role is more likely. Genetic polymorphisms in some TLRs have been found and its influence on the risk of HCC has been reported. As therapeutic targets, TLRs are already in use and have a great potential. In conclusion, TLRs have been shown to be an interesting influence on the HCC’s microenvironment, with TLR3 clearly determining an anti-tumour influence. TLR4 and TLR9 are considered to have a positive relationship with tumour development even though, in each of them anti-tumorigenic signals have been described. TLR2 presents a more ambiguous role, possibly depending on the stage of the inflammation-HCC axis.
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Feldman N, Rotter-Maskowitz A, Okun E. DAMPs as mediators of sterile inflammation in aging-related pathologies. Ageing Res Rev 2015; 24:29-39. [PMID: 25641058 DOI: 10.1016/j.arr.2015.01.003] [Citation(s) in RCA: 201] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Revised: 12/29/2014] [Accepted: 01/19/2015] [Indexed: 12/20/2022]
Abstract
Accumulating evidence indicates that aging is associated with a chronic low-level inflammation, termed sterile-inflammation. Sterile-inflammation is a form of pathogen-free inflammation caused by mechanical trauma, ischemia, stress or environmental conditions such as ultra-violet radiation. These damage-related stimuli induce the secretion of molecular agents collectively termed danger-associated molecular patterns (DAMPs). DAMPs are recognized by virtue of specialized innate immune receptors, such as toll-like receptors (TLRs) and NOD-like receptor family, pyrin domain containing 3 (NLRP3). These receptors initiate signal transduction pathways, which typically drive inflammation in response to microbe-associated molecular patterns (MAMPs) and/or DAMPs. This review summarizes the current knowledge on DAMPs-mediated sterile-inflammation, its associated downstream signaling, and discusses the possibility that DAMPs activating TLRs or NLRP3 complex mediate sterile inflammation during aging and in aging-related pathologies.
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Affiliation(s)
- Noa Feldman
- The Mina and Everard Goodman Faculty of Life Sciences, The Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat-Gan 5290002, Israel
| | - Aviva Rotter-Maskowitz
- The Mina and Everard Goodman Faculty of Life Sciences, The Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat-Gan 5290002, Israel
| | - Eitan Okun
- The Mina and Everard Goodman Faculty of Life Sciences, The Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat-Gan 5290002, Israel.
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Kang I, Barth JL, Sproul EP, Yoon DW, Workman GA, Braun KR, Argraves WS, Wight TN. Expression of V3 Versican by Rat Arterial Smooth Muscle Cells Promotes Differentiated and Anti-inflammatory Phenotypes. J Biol Chem 2015; 290:21629-41. [PMID: 26152723 DOI: 10.1074/jbc.m115.657486] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Indexed: 01/03/2023] Open
Abstract
Arterial smooth muscle cells (ASMCs) undergo phenotypic changes during development and pathological processes in vivo and during cell culture in vitro. Our previous studies demonstrated that retrovirally mediated expression of the versican V3 splice variant (V3) by ASMCs retards cell proliferation and migration in vitro and reduces neointimal thickening and macrophage and lipid accumulation in animal models of vascular injury and atherosclerosis. However, the molecular pathways induced by V3 expression that are responsible for these changes are not yet clear. In this study, we employed a microarray approach to examine how expression of V3 induced changes in gene expression and the molecular pathways in rat ASMCs. We found that forced expression of V3 by ASMCs affected expression of 521 genes by more than 1.5-fold. Gene ontology analysis showed that components of the extracellular matrix were the most significantly affected by V3 expression. In addition, genes regulating the formation of the cytoskeleton, which also serve as markers of contractile smooth muscle cells (SMCs), were significantly up-regulated. In contrast, components of the complement system, chemokines, chemokine receptors, and transcription factors crucial for regulating inflammatory processes were among the genes most down-regulated. Consistently, we found that the level of myocardin, a key transcription factor promoting contractile SMC phenotype, was greatly increased, and the proinflammatory transcription factors NFκB1 and CCAAT/enhancer-binding protein β were significantly attenuated in V3-expressing SMCs. Overall, these findings demonstrate that V3 expression reprograms ASMCs promoting differentiated and anti-inflammatory phenotypes.
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Affiliation(s)
- Inkyung Kang
- From the Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101 and
| | - Jeremy L Barth
- the Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, South Carolina 29425
| | - Erin P Sproul
- the Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, South Carolina 29425
| | - Dong Won Yoon
- From the Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101 and
| | - Gail A Workman
- From the Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101 and
| | - Kathleen R Braun
- From the Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101 and
| | - W Scott Argraves
- the Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, South Carolina 29425
| | - Thomas N Wight
- From the Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101 and
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Fujii K, Karpova MB, Asagoe K, Georgiev O, Dummer R, Urosevic-Maiwald M. Versican upregulation in Sézary cells alters growth, motility and resistance to chemotherapy. Leukemia 2015; 29:2024-32. [DOI: 10.1038/leu.2015.103] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Revised: 03/13/2015] [Accepted: 04/07/2015] [Indexed: 01/08/2023]
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Wang Z, Li Z, Wang Y, Cao D, Wang X, Jiang M, Li M, Yan X, Li Y, Liu Y, Luo F. Versican silencing improves the antitumor efficacy of endostatin by alleviating its induced inflammatory and immunosuppressive changes in the tumor microenvironment. Oncol Rep 2015; 33:2981-91. [PMID: 25872924 DOI: 10.3892/or.2015.3903] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 03/17/2015] [Indexed: 02/05/2023] Open
Abstract
The systematic application of antiangiogenic therapy remains an issue of concern, mainly due to the hypoxic and inflammatory changes in the tumor microenvironment elicited by antiangiogenic therapy. Versican, a 'bridge' connecting inflammation with tumor progression as well as playing a central role in the generation of an inflammatory tumor microenvironment is a promising candidate for the intervention of inflammatory changes in the tumor microenvironment elicited by antiangiogenic therapy. To examine this hypothesis, a short-hairpin RNA targeting versican (shVCAN) was designed and shVCAN stable-transfected B16F1 and Lewis lung carcinoma (LLC) cell lines were established. Simultaneously, the established B16F1 and LLC tumor models were used to investigate the effect of versican silencing on the tumor burden of mice. The results showed that, versican silencing exerted an inhibitory effect on the proliferative and migratory ability of B16F1 cells, but did not affect LLC cells. Endostatin exhibited modest inhibition of tumor growth in tumor-bearing mice. Versican silencing alone effectively suppressed orthotopic tumor growth and significantly prolonged survival time of mice more effectively when combined with endostatin. Endostatin elicited inflammatory and immunosuppressive changes in the tumor microenvironment, including an accumulation of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and inflammatory cytokines. In addition, NF-κB and HIF-1α were overexpressed in the tumor. Versican silencing improved the antitumor efficacy of endostatin by alleviating its induced changes in the tumor microenvironment. Thus, versican silencing in the tumor microenvironment offers a promising approach to reverse the tumor refractoriness to antiangiogenic therapies.
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Affiliation(s)
- Zi Wang
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China
| | - Zhixi Li
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China
| | - Yuyi Wang
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China
| | - Dan Cao
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China
| | - Xia Wang
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China
| | - Ming Jiang
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China
| | - Mei Li
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China
| | - Xi Yan
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China
| | - Yan Li
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China
| | - Yanyang Liu
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China
| | - Feng Luo
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China
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Andersson-Sjöland A, Hallgren O, Rolandsson S, Weitoft M, Tykesson E, Larsson-Callerfelt AK, Rydell-Törmänen K, Bjermer L, Malmström A, Karlsson JC, Westergren-Thorsson G. Versican in inflammation and tissue remodeling: the impact on lung disorders. Glycobiology 2014; 25:243-51. [PMID: 25371494 PMCID: PMC4310351 DOI: 10.1093/glycob/cwu120] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Versican is a proteoglycan that has many different roles in tissue homeostasis and inflammation. The biochemical structure comprises four different types of the core protein with attached glycosaminoglycans (GAGs) that can be sulfated to various extents and has the capacity to regulate differentiation of different cell types, migration, cell adhesion, proliferation, tissue stabilization and inflammation. Versican's regulatory properties are of importance during both homeostasis and changes that lead to disease progression. The GAGs that are attached to the core protein are of the chondroitin sulfate/dermatan sulfate type and are known to be important in inflammation through interactions with cytokines and growth factors. For a more complex understanding of versican, it is of importance to study the tissue niche, where the wound healing process in both healthy and diseased conditions take place. In previous studies, our group has identified changes in the amount of the multifaceted versican in chronic lung disorders such as asthma, chronic obstructive pulmonary disease, and bronchiolitis obliterans syndrome, which could be a result of pathologic, transforming growth factor β driven, on-going remodeling processes. Reversely, the context of versican in its niche is of great importance since versican has been reported to have a beneficial role in other contexts, e.g. emphysema. Here we explore the vast mechanisms of versican in healthy lung and in lung disorders.
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Affiliation(s)
| | - Oskar Hallgren
- Lung Biology Lung Medicine and Allergology, Skåne University Hospital, Lund University, Lund 221 84, Sweden
| | | | | | - Emil Tykesson
- Lung Biology Matrix Biology, Department of Experimental Medical Sciences, BMC D12, Lund University, Lund 221 84, Sweden
| | | | | | - Leif Bjermer
- Lung Medicine and Allergology, Skåne University Hospital, Lund University, Lund 221 84, Sweden
| | - Anders Malmström
- Lung Medicine and Allergology, Skåne University Hospital, Lund University, Lund 221 84, Sweden
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Versican and the control of inflammation. Matrix Biol 2014; 35:152-61. [PMID: 24513039 DOI: 10.1016/j.matbio.2014.01.015] [Citation(s) in RCA: 169] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 01/25/2014] [Accepted: 01/25/2014] [Indexed: 12/14/2022]
Abstract
Versican is an extracellular matrix (ECM) proteoglycan that interacts with cells by binding to non-integrin and integrin receptors and to other ECM components that associate with the cell surface. Recent studies have shown also that versican interacts with myeloid and lymphoid cells promoting their adhesion and production of inflammatory cytokines. Versican is produced by stromal cells, as well as leukocytes, and is markedly increased in inflammation. Inflammatory agonists, such as double-stranded RNA mimetics (e.g., poly I:C), stimulate stromal cells, smooth muscle cells and fibroblasts, to produce fibrillar ECMs enriched in versican and hyaluronan (HA) that interact with leukocytes promoting their adhesion. Interference with the incorporation of versican into this ECM blocks monocyte adhesion and dampens the inflammatory response. Tumor cells also express elevated levels of versican which interact with myeloid cells to promote an inflammatory response, through stimulating cytokine release, and metastasis. In addition, myeloid cells, such as macrophages in tumors, synthesize versican which affects tumor cell phenotypes, inflammation, and subsequent metastasis. Versican, by binding to hyaluronan, influences T lymphocyte phenotypes and in part controls the ability of these cells to synthesize and secrete cytokines that influence the immune response. Collectively, these studies indicate that versican as an ECM molecule plays a central role in inflammation and as a result it is emerging as a potential target promising wide therapeutic benefits.
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Abstract
Toll-like receptors (TLRs) are pattern recognition receptors that play an important role in host defence by recognizing pathogen-associated molecular patterns (PAMP). Recent studies indicate that TLR signalling plays an important role in progression of chronic liver diseases. Ongoing clinical trials suggest that therapeutic manipulation of TLR pathways may offer novel means of reversing chronic liver diseases. Upon activation by their respective ligands, TLRs initiate an intracellular pro-inflammatory/anti-inflammatory signalling cascade via recruitment of various adaptor proteins. TLR associated signalling pathways are tightly regulated to keep a check on inappropriate production of pro-inflammatory cytokines and interferons thereby preventing various autoimmune and inflammatory processes. Herein, we review the current state of knowledge of hepatic distribution, signalling pathways and therapeutic modulation of TLRs in chronic liver diseases.
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Affiliation(s)
- Vivek Kesar
- Department of Medicine, Recanati/Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Lenox Hill Hospital, New York, NY, USA
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Versican and the regulation of cell phenotype in disease. Biochim Biophys Acta Gen Subj 2014; 1840:2441-51. [PMID: 24401530 DOI: 10.1016/j.bbagen.2013.12.028] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 12/23/2013] [Indexed: 12/22/2022]
Abstract
BACKGROUND Versican is an extracellular matrix (ECM) proteoglycan that is present in the pericellular environment of most tissues and increases in many different diseases. Versican interacts with cells to influence the ability of cells to proliferate, migrate, adhere and assemble an ECM. SCOPE OF REVIEW The structure of the versican molecule is briefly reviewed and studies highlighting those factors that promote versican synthesis and degradation and their impact on cell phenotype in disease are discussed. Particular attention is given to vascular disease, but other diseases where versican is important are covered as well, most notably different forms of cancers. Attention is given to mechanisms(s) by which versican influences cell behaviors through either direct or indirect processes. Versican produced by either stromal cells or myeloid cells can have a major impact influencing immunity and inflammation. Finally, studies controlling versican accumulation that either delay or inhibit the progression of disease will be highlighted. MAJOR CONCLUSIONS Versican is one component of the ECM that can influence the ability of cells to proliferate, migrate, adhere, and remodel the ECM. Targeting versican as a way to control cell phenotype offers a novel approach in the treatment of disease. SIGNIFICANCE ECM molecules such as versican contribute to the structural integrity of tissues and interact with cells through direct and indirect means to regulate, in part, cellular events that form the basis of disease. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.
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Gao D, Li S. Stimuli-induced organ-specific injury enhancement of organotropic metastasis in a spatiotemporal regulation. Pathol Oncol Res 2013; 20:27-42. [PMID: 24357158 DOI: 10.1007/s12253-013-9734-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Accepted: 12/05/2013] [Indexed: 12/11/2022]
Abstract
The relationship between inflammation and tumorigenesis has been established. Recently, inflammation is also reported to be a drive force for cancer metastasis. Further evidences show that various stimuli directly induced-injury in a specific organ can also promote metastasis in this organ, which include epidemiological reports, clinical series and experimental studies. Each type of cancer has preferential sites for metastasis, which is also due to inflammatory factors that are released by primary cancer to act on these sites and indirectly induce injuries on them. Host factors such as stress,fever can also influence distant metastasis in a specific site through stimulation of immune and inflammatory effects. The five aspects support an idea that specific-organ injury directly induced by various stimuli or indirectly induced by primary tumor or host factors activation of proinflammatory modulators can promote metastasis in this organ through a spatiotemporal regulation, which has important implications for personalized prediction, prevention and management of cancer metastasis.
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Affiliation(s)
- Dongwei Gao
- , 536 Hospital of PLA, 29# Xiadu street, Xining, 810007, Qinghai Province, People's Republic of China,
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