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International Heart Journal 2019
Topics: Thrombospondins
PubMed: 30890685
DOI: 10.1536/ihj.19-042 -
Matrix Biology : Journal of the... Jan 2019Thrombospondin-4 (TSP-4) belongs to the thrombospondin protein family that consists of five highly homologous members. A number of novel functions have been recently... (Review)
Review
Thrombospondin-4 (TSP-4) belongs to the thrombospondin protein family that consists of five highly homologous members. A number of novel functions have been recently assigned to TSP-4 in cardiovascular and nervous systems, inflammation, cancer, and the motor unit, which have attracted attention to this extracellular matrix (ECM) protein. These newly discovered functions set TSP-4 apart from other thrombospondins. For example, TSP-4 promotes angiogenesis while other TSPs either prevent it or have no effect on new blood vessel growth; TSP-4 reduces fibrosis and collagen production while TSP-1 and TSP-2 promote fibrosis in several organs; unlike other TSPs, TSP-4 appears to have some structural functions in ECM. The current information about TSP-4 functions in different organs and physiological systems suggests that this evolutionary conserved protein is a major regulator of the extracellular matrix (ECM) organization and production and tissue remodeling during the embryonic development and response to injury. In this review article, we summarize the properties and functions of TSP-4 and discuss its role in tissue remodeling.
Topics: Blood Vessels; Extracellular Matrix; Extracellular Matrix Proteins; Fibrosis; Gene Expression Regulation, Developmental; Humans; Neovascularization, Pathologic; Thrombospondin 1; Thrombospondins
PubMed: 29138119
DOI: 10.1016/j.matbio.2017.11.006 -
Advances in Experimental Medicine and... 2020Thrombospondins (TSPs) are multifaceted proteins that contribute to physiologic as well as pathologic conditions. Due to their multiple receptor-binding domains, TSPs... (Review)
Review
Thrombospondins (TSPs) are multifaceted proteins that contribute to physiologic as well as pathologic conditions. Due to their multiple receptor-binding domains, TSPs display both oncogenic and tumor-suppressive qualities and are thus essential components of the extracellular matrix. Known for their antiangiogenic capacity, TSPs are an important component of the tumor microenvironment. The N- and C-terminal domains of TSP are, respectively, involved in cell adhesion and spreading, an important feature of wound healing as well as cancer cell migration. Previously known for the activation of TGF-β to promote tumor growth and inflammation, TSP-1 has recently been found to be transcriptionally induced by TGF-β, implying the presence of a possible feedback loop. TSP-1 is an endogenous inhibitor of T cells and also mediates its immunosuppressive effects via induction of Tregs. Given the diverse roles of TSPs in the tumor microenvironment, many therapeutic strategies have utilized TSP-mimetic peptides or antibody blockade as anti-metastatic approaches. This chapter discusses the diverse structural domains, functional implications, and anti-metastatic therapies in the context of the role of TSP in the tumor microenvironment.
Topics: Angiogenesis Inhibitors; Cell Movement; Humans; Neoplasms; Thrombospondins; Transforming Growth Factor beta; Tumor Microenvironment
PubMed: 32845506
DOI: 10.1007/978-3-030-48457-6_8 -
American Journal of Respiratory and... Mar 2022
Topics: Bronchopulmonary Dysplasia; Humans; Infant, Newborn; Infant, Premature; Thrombospondins
PubMed: 35120300
DOI: 10.1164/rccm.202201-0101ED -
Medicine Apr 2023The degeneration of articular cartilage tissue is the most common cause of articular cartilage diseases such as osteoarthritis. There are limitations in chondrocyte... (Review)
Review
The degeneration of articular cartilage tissue is the most common cause of articular cartilage diseases such as osteoarthritis. There are limitations in chondrocyte self-renewal and conventional treatments. During cartilage regeneration and repair, growth factors are typically used to induce cartilage differentiation in stem cells. The role of thrombospondin-2 in cartilage formation has received much attention in recent years. This paper reviews the role of thrombospondin-2 in cartilage regeneration and the important role it plays in protecting cartilage from damage caused by inflammation or trauma and in the regenerative repair of cartilage by binding to different receptors and activating different intracellular signaling pathways. These studies provide new ideas for cartilage repair in clinical settings.
Topics: Humans; Regeneration; Cartilage, Articular; Chondrocytes; Cartilage Diseases; Thrombospondins
PubMed: 37115081
DOI: 10.1097/MD.0000000000033651 -
Nephrology, Dialysis, Transplantation :... Jul 2017Most therapeutic attempts to prevent the progression of kidney diseases have been based on interventions to inhibit the production of transforming growth factor-β... (Review)
Review
Most therapeutic attempts to prevent the progression of kidney diseases have been based on interventions to inhibit the production of transforming growth factor-β (TGF-β). Thrombospondins (TSPs) play an important role in activating TGF-β. In the healthy kidney, two TSPs are expressed, TSP1 and TSP2, which exert contrasting effects. While TSP1 is a major activator of TGF-β in renal cells and exerts pro-inflammatory effects both in vitro and in vivo, TSP2 lacks the ability for TGF-β activation but regulates matrix remodeling and inflammation in experimental kidney disease. The effects of TSPs in the kidney have been mostly investigated by using the murine model of unilateral ureteral obstruction. In this model, TSP1 expression is increased along with the development of interstitial fibrosis and TGF-β. Relief of the obstruction gradually improves renal function and decreases the expression in TSP1 and TGF-β1. Several inhibitors of TSP1 prevented progressive interstitial fibrosis in murine models of ureteral obstruction, suggesting that control of latent TGF-β activation by inhibiting TSP1 might represent a novel potential target for preventing renal interstitial fibrosis. However, further studies are needed to assess whether TSP1-mediated TGF-β activation can be safely used in humans. In fact, TSPs normally act to suppress tumors in vivo. Moreover, TGF-β can exert a pivotal function in the immune system, as it may induce the production of regulatory T cells and suppress B cell responses. Knowledge of the molecular mechanisms involved in TGF-β regulation may help in finding effective treatments of tissue fibrosis, cancer and autoimmune disease.
Topics: Animals; Humans; Kidney Diseases; Thrombospondins; Transforming Growth Factor beta1
PubMed: 28088772
DOI: 10.1093/ndt/gfw431 -
American Journal of Physiology. Cell... Sep 2022Matricellular proteins comprise a diverse group of molecular entities secreted into the extracellular space. They interact with the extracellular matrix (ECM),... (Review)
Review
Matricellular proteins comprise a diverse group of molecular entities secreted into the extracellular space. They interact with the extracellular matrix (ECM), integrins, and other cell-surface receptors, and can alter matrix strength, cell attachment to the matrix, and cell-cell adhesion. A founding member of this group is thrombospondin-1 (TSP-1), a high molecular-mass homotrimeric glycoprotein. Given the importance of the matrix and ECM remodeling in the lung following injury, TSP-1 has been implicated in a number of lung pathologies. This review examines the role of TSP-1 as a damage controller in the context of lung inflammation, injury resolution, and repair in noninfectious and infectious models. This review also discusses the potential role of TSP-1 in human diseases as it relates to lung inflammation and injury.
Topics: Cell Adhesion; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Pneumonia; Thrombospondin 1; Thrombospondins
PubMed: 35912991
DOI: 10.1152/ajpcell.00182.2022 -
Microvascular Research 2007Thrombospondins (TSPs) are a family of extracellular matrix proteins that regulate tissue genesis and remodeling. TSP-1 plays a pivotal role in the regulation of both... (Review)
Review
Thrombospondins (TSPs) are a family of extracellular matrix proteins that regulate tissue genesis and remodeling. TSP-1 plays a pivotal role in the regulation of both physiological and pathological angiogenesis. The inhibitory effects of TSP-1 on angiogenesis have been established in numerous experimental models. Among other TSP members, TSP-2 has equivalent domain structure as TSP-1 and shares most functions of TSP-1. The mechanisms by which TSP-1 and -2 inhibit angiogenesis can be broadly characterized as direct effects on vascular endothelial cells and indirect effects on the various angiogenic regulators. The fact that TSP-1 and -2 are potent endogenous angiogenic inhibitors has prompted studies to explore their therapeutic applications, and detailed understanding of the mechanisms of action of TSP-1 and -2 has facilitated the design of therapeutic strategies to optimize these activities. The therapeutic effects can be achieved by up-regulation of endogenous TSPs, or by the delivery of recombinant proteins or synthetic peptides that contain sequences from the angiogenic domain of TSP-1. In this article, we review the progress in thrombospondin-based antiangiogenic therapy and discuss the perspectives on the significant challenges that remain.
Topics: Angiogenesis Inhibitors; Animals; Endothelial Cells; Endothelium, Vascular; Humans; Neovascularization, Pathologic; Thrombospondins
PubMed: 17559888
DOI: 10.1016/j.mvr.2007.04.007 -
Seminars in Cell & Developmental Biology Mar 2024Thrombospondins (TSPs) have numerous different roles in cancer, regulating the behavior of cancer cells and non-neoplastic cells, and defining the responses of tumor... (Review)
Review
Thrombospondins (TSPs) have numerous different roles in cancer, regulating the behavior of cancer cells and non-neoplastic cells, and defining the responses of tumor cells to environmental changes, thorough their ability to orchestrate cellular and molecular interactions in the tumor microenvironment (TME). As a result of these activities, TSPs can also control drug delivery and activity, tumor response and resistance to therapies, with different outcomes depending on the nature of TSP-interacting cell types, receptors, and ligands, in a highly context-dependent manner. This review, focusing primarily on TSP-1, discusses the effects of TSPs on tumor response to chemotherapy, antiangiogenic, low-dose metronomic chemotherapy, immunotherapy, and radiotherapy, by analyzing TSP activity on different cell compartments - tumor cells, vascular endothelial cells and immune cells. We review evidence of the value of TSPs, specifically TSP-1 and TSP-2, as biomarkers of prognosis and tumor response to therapy. Finally, we examine possible approaches to develop TSP-based compounds as therapeutic tools to potentiate the efficacy of anticancer therapy.
Topics: Humans; Thrombospondin 1; Endothelial Cells; Thrombospondins; Neoplasms; Immunotherapy; Tumor Microenvironment
PubMed: 37414720
DOI: 10.1016/j.semcdb.2023.06.009 -
Seminars in Cell & Developmental Biology Mar 2024Thrombospondin-4 (TSP-4) belongs to the extracellular matrix glycoprotein family of thrombospondins (TSPs). The multidomain, pentameric structure of TSP-4 allows its... (Review)
Review
Thrombospondin-4 (TSP-4) belongs to the extracellular matrix glycoprotein family of thrombospondins (TSPs). The multidomain, pentameric structure of TSP-4 allows its interactions with numerous extracellular matrix components, proteins and signaling molecules that enable its modulation to various physiological and pathological processes. Characterization of TSP-4 expression under development and pathogenesis of disorders has yielded important insights into mechanisms underlying the unique role of TSP-4 in mediating various processes including cell-cell, cell-extracellular matrix interactions, cell migration, proliferation, tissue remodeling, angiogenesis, and synaptogenesis. Maladaptation of these processes in response to pathological insults and stress can accelerate the development of disorders including skeletal dysplasia, osteoporosis, degenerative joint disease, cardiovascular diseases, tumor progression/metastasis and neurological disorders. Overall, the diverse functions of TSP-4 suggest that it may be a potential marker or therapeutic target for prognosis, diagnosis, and treatment of various pathological conditions upon further investigations. This review article highlights recent findings on the role of TSP-4 in both physiological and pathological conditions with a focus on what sets it apart from other TSPs.
Topics: Humans; Thrombospondins; Extracellular Matrix; Cell Movement; Morphogenesis; Cardiovascular Diseases
PubMed: 37391348
DOI: 10.1016/j.semcdb.2023.06.007