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Biochimica Et Biophysica Acta Aug 2014Numerous proteins and small leucine-rich proteoglycans (SLRPs) make up the composition of the extracellular matrix (ECM). Assembly of individual fibrillar components in... (Review)
Review
BACKGROUND
Numerous proteins and small leucine-rich proteoglycans (SLRPs) make up the composition of the extracellular matrix (ECM). Assembly of individual fibrillar components in the ECM, such as collagen, elastin, and fibronectin, is understood at the molecular level. In contrast, the incorporation of non-fibrillar components and their functions in the ECM are not fully understood.
SCOPE OF REVIEW
This review will focus on the role of the matricellular protein thrombospondin (TSP) 2 in ECM assembly. Based on findings in TSP2-null mice and in vitro studies, we describe the participation of TSP2 in ECM assembly, cell-ECM interactions, and modulation of the levels of matrix metalloproteinases (MMPs).
MAJOR CONCLUSIONS
Evidence summarized in this review suggests that TSP2 can influence collagen fibrillogenesis without being an integral component of fibrils. Altered ECM assembly and excessive breakdown of ECM can have both positive and negative consequences including increased angiogenesis during tissue repair and compromised cardiac tissue integrity, respectively.
GENERAL SIGNIFICANCE
Proper ECM assembly is critical for maintaining cell functions and providing structural support. Lack of TSP2 is associated with increased angiogenesis, in part, due to altered endothelial cell-ECM interactions. Therefore, minor changes in ECM composition can have profound effects on cell and tissue function. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.
Topics: Animals; Collagen; Disease Models, Animal; Extracellular Matrix; Humans; Phenotype; Thrombospondins; Tissue Engineering
PubMed: 24440155
DOI: 10.1016/j.bbagen.2014.01.013 -
International Journal of Molecular... May 2020Thrombospondin (TSP)‑1 and TSP‑2 are matricellular proteins in the extracellular matrix (ECM), which serve a significant role in the pathological processes of... (Review)
Review
Thrombospondin (TSP)‑1 and TSP‑2 are matricellular proteins in the extracellular matrix (ECM), which serve a significant role in the pathological processes of various cardiovascular diseases (CVDs). The multiple effects of TSP‑1 and TSP‑2 are due to their ability to interact with various ligands, such as structural components of the ECM, cytokines, cellular receptors, growth factors, proteases and other stromal cell proteins. TSP‑1 and TSP‑2 regulate the structure and activity of the aforementioned ligands by interacting directly or indirectly with them, thereby regulating the activity of different types of cells in response to environmental stimuli. The pathological processes of numerous CVDs are associated with the degradation and remodeling of ECM components, and with cell migration, dysfunction and apoptosis, which may be regulated by TSP‑1 and TSP‑2 through different mechanisms. Therefore, investigating the role of TSP‑1 and TSP‑2 in different CVDs and the potential signaling pathways they are associated with may provide a new perspective on potential therapies for the treatment of CVDs. In the present review, the current understanding of the roles TSP‑1 and TSP‑2 serve in various CVDs were summarized. In addition, the interacting ligands and the potential pathways associated with these thrombospondins in CVDs are also discussed.
Topics: Animals; Apoptosis; Cardiovascular Diseases; Cell Movement; Extracellular Matrix; Humans; Ligands; Signal Transduction; Thrombospondin 1; Thrombospondins
PubMed: 32323748
DOI: 10.3892/ijmm.2020.4507 -
The International Journal of... Jun 2004Angiogenesis is a complex, multifactorial process that involves signals from endothelial cells and from the stoma. Extracellular matrix proteins participate in the... (Review)
Review
Angiogenesis is a complex, multifactorial process that involves signals from endothelial cells and from the stoma. Extracellular matrix proteins participate in the modulation of growth factor response, contribute to the architecture of the vasculature and provide signals for the stabilization of mature capillary beds. The identification of the relevant extracellular matrix molecules and the characterization of their effects has been a central focus of research in vascular biology. Thrombospondin-1 is an extracellular glycoprotein first to be recognized as an inhibitor of angiogenesis more than a decade ago. Since then, much has been learned about its ability to regulate vascular growth in several angiogenesis models, functional domains have been identified, and mechanisms of action determined. This review summarizes current understanding on the effects of thrombospondin-1 and -2 during the process of angiogenesis. We will also extend our comments to ADAMTS1, a member of a relatively novel group of matrix metalloproteinases with thrombospondin repeats and shown to affect endothelial cell function and angiogenesis.
Topics: Animals; Blood Vessels; Cattle; Endothelial Cells; Humans; Metalloproteases; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Thrombospondins
PubMed: 15094121
DOI: 10.1016/j.biocel.2004.01.025 -
Seminars in Cell & Developmental Biology Mar 2024Thrombospondins (TSPs) are multidomain, calcium-binding glycoproteins that have wide-ranging roles in vertebrates in cell interactions, extracellular matrix (ECM)... (Review)
Review
Thrombospondins (TSPs) are multidomain, calcium-binding glycoproteins that have wide-ranging roles in vertebrates in cell interactions, extracellular matrix (ECM) organisation, angiogenesis, tissue remodelling, synaptogenesis, and also in musculoskeletal and cardiovascular functions. Land animals encode five TSPs, which assembly co-translationally either as trimers (subgroup A) or pentamers (subgroup B). The vast majority of research has focused on this canonical TSP family, which evolved through the whole-genome duplications that took place early in the vertebrate lineage. With benefit of the growth in genome- and transcriptome-predicted proteomes of a much wider range of animal species, examination of TSPs throughout metazoan phyla has revealed extensive conservation of subgroup B-type TSPs in invertebrates. In addition, these searches established that canonical TSPs are, in fact, one branch within a TSP superfamily that includes other clades designated mega-TSPs, sushi-TSPs and poriferan-TSPs. Despite the apparent simplicity of poriferans and cnidarians as organisms, these phyla encode a greater diversity of TSP superfamily members than vertebrates. We discuss here the molecular characteristics of the TSP superfamily members, current knowledge of their expression profiles and functions in invertebrates, and models for the evolution of this complex ECM superfamily.
Topics: Animals; Thrombospondins; Invertebrates; Evolution, Molecular
PubMed: 37202276
DOI: 10.1016/j.semcdb.2023.05.004 -
Nephron. Experimental Nephrology 2009Thrombospondins (TSPs) are multifunctional matricellular glycoproteins which are involved in the regulation of angiogenesis, proliferation, apoptosis, the... (Review)
Review
Thrombospondins (TSPs) are multifunctional matricellular glycoproteins which are involved in the regulation of angiogenesis, proliferation, apoptosis, the NO-cGMP-dependent protein kinase pathway and transforming growth factor (TGF) beta activation. The TSP family consists of 5 members, but currently only data on effects of TSP-1 and TSP-2 in renal disease are available. Both TSPs are hardly expressed within the healthy renal cortex and can be upregulated during renal disease. Using different animal models for renal disease, TSP-1 and -2 were found to be important regulators of pathophysiological changes during renal disease with similar and contrary effects. TSP-1 is a major activator for TGF-beta resulting in profibrotic effects in the injured kidney. In contrast, TSP-2 lacks the ability for its activation. Proapoptotic actions of TSP-1 were found during renal ischemia/reperfusion injury. While TSP-1 exerts proinflammatory actions, the currently available data for TSP-2 propose anti-inflammatory effects for this molecule. Both TSPs are known angiogenesis inhibitors, which could be proved for TSP-2, but antiangiogenic effects for TSP-1 were only evident by treatment with TSP-1 peptides in renal disease. In addition, TSP-2 can inhibit cell proliferation and matrix metalloproteinase 2 activity.
Topics: Animals; Humans; Kidney Diseases; Signal Transduction; Thrombospondins
PubMed: 19182492
DOI: 10.1159/000198235 -
Journal of Orthopaedic Research :... Jan 2021Fracture healing is a complex process that relies heavily on the carefully orchestrated expansion and differentiation of periosteal mesenchymal progenitor cells (MSC)....
Fracture healing is a complex process that relies heavily on the carefully orchestrated expansion and differentiation of periosteal mesenchymal progenitor cells (MSC). Identification of new markers for periosteal MSCs is essential for the development of fracture therapeutics. Expression of the matricellular protein thrombospondin-2 (TSP2) increases during early fracture healing; however, it is currently unknown what cell population expresses TSP2. Using a TSP2 GFP reporter mouse and a stabilized murine fracture model, we characterized the expression of TSP2 during the inflammatory, soft callus formation, and hard callus formation phases of fracture healing. In addition, using TSP2 GFP positive cells harvested from reporter mouse cells, we characterized the cell population using flow cytometry and colony formation assays. In uninjured diaphyseal bone, we observed TSP2 expression in the cells located along the inner periosteum. We also observed a population of TSP2 expressing cells in undifferentiated regions of early fracture callus and along the periphery of the callus. Later in callus development, TSP2 cells were broadly distributed in the undifferentiated callus, but GFP was not expressed by chondrocytes. Flow cytometry confirmed that the majority of TSP2 expressing cells were positive for traditional murine MSC markers. Our in vitro assays further supported these findings by demonstrating all adherent and colony-forming cells expressed TSP2. Taken together, our results suggest that TSP2 is expressed by undifferentiated MSCs, but downregulated in chondrocytes. Clinical significance: expression of the matricellular protein TSP2 is a promising new marker to identify MSCs in early fracture healing.
Topics: Animals; Bony Callus; Cell Proliferation; Chondrocytes; Chondrogenesis; Fractures, Bone; Genes, Reporter; Mice; Thrombospondins
PubMed: 32437051
DOI: 10.1002/jor.24749 -
Cancer Biology & Therapy Apr 2004
Topics: Angiogenesis Inhibitors; Cell Survival; Endothelial Cells; Humans; Neoplasms; Neovascularization, Pathologic; Receptor, TIE-2; Thrombospondins
PubMed: 15107618
DOI: 10.4161/cbt.3.4.737 -
The Journal of Investigative... Dec 2000Thrombospondin 2 (TSP2)-null mice, generated by targeted disruption of the Thbs2 gene, display a complex phenotype that is characterized, in part, by a variety of... (Review)
Review
Thrombospondin 2 (TSP2)-null mice, generated by targeted disruption of the Thbs2 gene, display a complex phenotype that is characterized, in part, by a variety of connective tissue abnormalities and increased vascular density in skin and subcutaneous tissues. In this paper we summarize the evidence that TSP2 functions as a matricellular protein to influence cell function by modulating cell-matrix interactions, rather than acting as an integral component of the matrix. Thus, the structurally abnormal collagen fibrils detected in skin appear to be the consequence of the defective adhesion demonstrated by dermal fibroblasts in culture that, in turn, result from increased matrix metalloproteinase 2 (MMP2, gelatinase A) production by these cells. Corroborating evidence for such a mode of action comes from transmission electron microscopic images of developing flexor muscle tendons that show distinct abnormalities in fibroblast-collagen fibril interactions in TSP2-null tissue. The increased vascular density seen in skin of TSP2-null mice can be reproduced in a number of models of injury, including subcutaneous implantation of polyvinyl alcohol sponges and silicone rubber discs, and excisional skin wounds. Experiments are proposed to distinguish between a primarily endothelial cell versus an extracellular matrix origin for the increased angiogenesis in TSP2-null mice.
Topics: Animals; Collagen; Humans; Mice; Mice, Knockout; Neovascularization, Physiologic; Skin; Thrombospondins
PubMed: 11147677
DOI: 10.1046/j.1087-0024.2000.00005.x -
Journal of Hepatology Dec 2021The microenvironment of intrahepatic cholangiocarcinoma (iCCA) is hypovascularized, with an extensive lymphatic network. This leads to rapid cancer spread into regional...
BACKGROUND & AIMS
The microenvironment of intrahepatic cholangiocarcinoma (iCCA) is hypovascularized, with an extensive lymphatic network. This leads to rapid cancer spread into regional lymph nodes and the liver parenchyma, precluding curative treatments. Herein, we investigated which factors released in the iCCA stroma drive the inhibition of angiogenesis and promote lymphangiogenesis.
METHODS
Quantitative proteomics was performed on extracellular fluid (ECF) proteins extracted both from cancerous and non-cancerous tissues (NCT) of patients with iCCA. Computational biology was applied on a proteomic dataset to identify proteins involved in the regulation of vessel formation. Endothelial cells incubated with ECF from either iCCA or NCT specimens were used to assess the role of candidate proteins in 3D vascular assembly, cell migration, proliferation and viability. Angiogenesis and lymphangiogenesis were further investigated in vivo by a heterotopic transplantation of bone marrow stromal cells, along with endothelial cells in SCID/beige mice.
RESULTS
Functional analysis of upregulated proteins in iCCA unveils a soluble angio-inhibitory milieu made up of thrombospondin (THBS)1, THBS2 and pigment epithelium-derived factor (PEDF). iCCA ECF was able to inhibit in vitro vessel morphogenesis and viability. Antibodies blocking THBS1, THBS2 and PEDF restored tube formation and endothelial cell viability to levels observed in NCT ECF. Moreover, in transplanted mice, the inhibition of blood vessel formation, the de novo generation of the lymphatic network and the dissemination of iCCA cells in lymph nodes were shown to depend on THBS1, THBS2 and PEDF expression.
CONCLUSIONS
THBS1, THBS2 and PEDF reduce blood vessel formation and promote tumor-associated lymphangiogenesis in iCCA. Our results identify new potential targets for interventions to counteract the dissemination process in iCCA.
LAY SUMMARY
Intrahepatic cholangiocarcinoma is a highly aggressive cancer arising from epithelial cells lining the biliary tree, characterized by dissemination into the liver parenchyma via lymphatic vessels. Herein, we show that the proteins THBS1, THBS2 and PEDF, once released in the tumor microenvironment, inhibit vascular growth, while promoting cancer-associated lymphangiogenesis. Therefore, targeting THBS1, THBS2 and PEDF may be a promising strategy to reduce cancer-associated lymphangiogenesis and counteract the invasiveness of intrahepatic cholangiocarcinoma.
Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Animals; Cholangiocarcinoma; Disease Models, Animal; Lymphangiogenesis; Mice; Proteomics; Thrombospondin 1; Thrombospondins; Tumor Microenvironment
PubMed: 34329660
DOI: 10.1016/j.jhep.2021.07.016 -
International Journal of Molecular... Jun 2013Angiogenesis is an important process for tumor growth and progression of various solid tumors including urological cancers. Thrombospondins (TSPs), especially TSP-1, are... (Review)
Review
Angiogenesis is an important process for tumor growth and progression of various solid tumors including urological cancers. Thrombospondins (TSPs), especially TSP-1, are representative "anti"-angiogenic molecules and many studies have clarified their pathological role and clinical significance in vivo and in vitro. In fact, TSP-1 expression is associated with clinicopathological features and prognosis in many types of cancers. However, TSP-1 is a multi-functional protein and its biological activities vary according to the specific tumor environments. Consequently, there is no general agreement on its cancer-related function in urological cancers, and detailed information regarding regulative mechanisms is essential for a better understanding of its therapeutic effects and prognostic values. Various "suppressor genes" and "oncogenes" are known to be regulators and TSP-1-related factors under physiological and pathological conditions. In addition, various types of fragments derived from TSP-1 exist in a given tissue microenvironment and TSP-1 derived-peptides have specific activities. However, a detailed pathological function in human cancer tissues is not still understood. This review will focus on the pathological roles and clinical significance of TSP-1 in urological cancers, including prostate cancer, renal cell carcinoma, and urothelial cancer. In addition, special attention is paid to TSP-1-derived peptide and TSP-1-based therapy for malignancies.
Topics: Animals; Antineoplastic Agents; Humans; Peptide Fragments; Thrombospondin 1; Urologic Neoplasms
PubMed: 23749112
DOI: 10.3390/ijms140612249