-
Annals of Medicine Dec 2012Cardiac remodelling is defined as changes in the size, shape, and function of the heart, which are most commonly caused by hypertension-induced left ventricular... (Review)
Review
Thrombospondin-4, tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14: novel extracellular matrix modulating factors in cardiac remodelling.
Cardiac remodelling is defined as changes in the size, shape, and function of the heart, which are most commonly caused by hypertension-induced left ventricular hypertrophy and myocardial infarction. Both neurohumoral and inflammatory factors have critical roles in the regulation of cardiac remodelling. A characteristic feature of cardiac remodelling is modification of the extracellular matrix (ECM), often manifested by fibrosis, a process that has vital consequences for the structure and function of the myocardium. In addition to established modulators of the ECM, the matricellular protein thrombospondin-4 (TSP-4) as well as the tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 has been recently shown to modulate cardiac ECM. TSP-4 null mice develop pronounced cardiac hypertrophy and fibrosis with defects in collagen maturation in response to pressure overload. TWEAK and Fn14 belong to the tumour necrosis factor superfamily of proinflammatory cytokines. Recently it was shown that elevated levels of circulating TWEAK via Fn14 critically affect the cardiac ECM, characterized by increasing fibrosis and cardiomyocyte hypertrophy in mice. Here we review the literature concerning the role of matricellular proteins and inflammation in cardiac ECM remodelling, with a special focus on TSP-4, TWEAK, and its receptor Fn14.
Topics: Animals; Cytokine TWEAK; Extracellular Matrix; Fibrosis; Humans; Myocardium; Receptors, Tumor Necrosis Factor; TWEAK Receptor; Thrombospondins; Tumor Necrosis Factors; Ventricular Remodeling
PubMed: 22380695
DOI: 10.3109/07853890.2011.614635 -
The Journal of Biological Chemistry Jan 2009Thrombospondin-1 regulates nitric oxide (NO) signaling in vascular cells via CD47. Because CD47 binding motifs are conserved in the C-terminal signature domains of all...
Thrombospondin-1 regulates nitric oxide (NO) signaling in vascular cells via CD47. Because CD47 binding motifs are conserved in the C-terminal signature domains of all five thrombospondins and indirect evidence has implied CD47 interactions with other family members, we compared activities of recombinant signature domains of thrombospondin-1, -2, and -4 to interact with CD47 and modulate cGMP signaling. Signature domains of thrombospondin-2 and -4 were less active than that of thrombospondin-1 for inhibiting binding of radiolabeled signature domain of thrombospondin-1 or SIRPalpha (signal-regulatory protein) to cells expressing CD47. Consistent with this binding selectivity, the signature domain of thrombospondin-1 was more potent than those of thrombospondin-2 or -4 for inhibiting NO-stimulated cGMP synthesis in vascular smooth muscle cells and downstream effects on cell adhesion. In contrast to thrombospondin-1- and CD47-null cells, primary vascular cells from thrombospondin-2-null mice lack enhanced basal and NO-stimulated cGMP signaling. Effects of endogenous thrombospondin-2 on NO/cGMP signaling could be detected only in thrombospondin-1-null cells. Furthermore, tissue survival of ischemic injury and acute recovery of blood flow in thrombospondin-2-nulls resembles that of wild type mice. Therefore, thrombospondin-1 is the dominant regulator of NO/cGMP signaling via CD47, and its limiting role in acute ischemic injury responses is not shared by thrombospondin-2.
Topics: Animals; CD47 Antigen; Cells, Cultured; Cyclic GMP; Humans; Ischemia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide; Protein Binding; Receptors, Immunologic; Signal Transduction; Thrombospondins
PubMed: 19004835
DOI: 10.1074/jbc.M804860200 -
Methods in Cell Biology 2018Thrombospondins are a family of five secreted proteins that have diverse roles in modulating cellular function. Thrombospondins-1 and 2 were identified as matricellular...
Thrombospondins are a family of five secreted proteins that have diverse roles in modulating cellular function. Thrombospondins-1 and 2 were identified as matricellular proteins based on their functional roles combined with their transient appearance or accumulation in extracellular matrix at specific times during development and in response to injury or stress in mature tissues. Thrombospondin-1 is a major component of platelet α-granules, which provides a convenient source for purification of the protein. Methods are described to prepare thrombospondin-1 from human platelets in a biologically active form with minimal degradation or contamination with other platelet proteins. A nondenaturing method is described for removing bound transforming growth factor-β1.
Topics: Blood Platelets; Chromatography, Affinity; Extracellular Matrix; Fibronectins; Heparin; Humans; Thrombospondin 1; Transforming Growth Factor beta1
PubMed: 29310787
DOI: 10.1016/bs.mcb.2017.08.021 -
Cell Feb 2005Though all communication between neurons occurs through synapses, we know surprisingly little about the mechanisms inducing their formation. In this issue of Cell,... (Review)
Review
Though all communication between neurons occurs through synapses, we know surprisingly little about the mechanisms inducing their formation. In this issue of Cell, Barres and colleagues (Christopherson et al., 2005) demonstrate that glial-derived thrombospondins and additional soluble glial-secreted factors regulate synapse assembly and functional maturation.
Topics: Animals; Cell Communication; Cell Differentiation; Central Nervous System; Growth Cones; Humans; Neuroglia; Neuronal Plasticity; Synapses; Thrombospondins
PubMed: 15707887
DOI: 10.1016/j.cell.2005.01.021 -
Biochemical and Biophysical Research... Sep 2015The thrombospondins (TSPs) are matricellular proteins that exert multifunctional effects by binding cytokines, cell-surface receptors and other proteins. TSPs play...
INTRODUCTION
The thrombospondins (TSPs) are matricellular proteins that exert multifunctional effects by binding cytokines, cell-surface receptors and other proteins. TSPs play important roles in vascular pathobiology and are all expressed in arterial lesions. The differential effects of TSP-1, -2, and -5 represent a gap in knowledge in vascular smooth muscle cell (VSMC) physiology. Our objective is to determine if structural differences of the TSPs imparted different effects on VSMC functions critical to the formation of neointimal hyperplasia. We hypothesize that TSP-1 and -2 induce similar patterns of migration, proliferation and gene expression, while the effects of TSP-5 are different.
METHODS
Human aortic VSMC chemotaxis was tested for TSP-2 and TSP-5 (1-40 μg/mL), and compared to TSP-1 and serum-free media (SFM) using a modified Boyden chamber. Next, VSMCs were exposed to TSP-1, TSP-2 or TSP-5 (0.2-40 μg/mL). Proliferation was assessed by MTS assay. Finally, VSMCs were exposed to TSP-1, TSP-2, TSP-5 or SFM for 3, 6 or 24 h. Quantitative real-time PCR was performed on 96 genes using a microfluidic card. Statistical analysis was performed by ANOVA or t-test, with p < 0.05 being significant.
RESULTS
TSP-1, TSP-2 and TSP-5 at 20 μg/mL all induce chemotaxis 3.1 fold compared to serum-free media. TSP-1 and TSP-2 induced proliferation 53% and 54% respectively, whereas TSP-5 did not. In the gene analysis, overall, cardiovascular system development and function is the canonical pathway most influenced by TSP treatment, and includes multiple growth factors, cytokines and proteases implicated in cellular migration, proliferation, vasculogenesis, apoptosis and inflammation pathways.
CONCLUSIONS AND RELEVANCE
The results of this study indicate TSP-1, -2, and -5 play active roles in VSMC physiology and gene expression. Similarly to TSP-1, VSMC chemotaxis to TSP-2 and -5 is dose-dependent. TSP-1 and -2 induces VSMC proliferation, but TSP-5 does not, likely due conservation of N-terminal domains in TSP-1 and -2. In addition, TSP-1, -2 and -5 significantly affect VSMC gene expression; however, little overlap exists in the specific genes altered. This study further delineates TSP-1, -2 and -5's contributions to processes related to VSMC physiology.
Topics: Cartilage Oligomeric Matrix Protein; Cell Movement; Cell Proliferation; Cells, Cultured; Chemotaxis; Gene Expression; Humans; Myocytes, Smooth Muscle; Neointima; Thrombospondin 1; Thrombospondins
PubMed: 26168731
DOI: 10.1016/j.bbrc.2015.07.044 -
British Journal of Cancer Oct 2022RSPO fusions that lead to WNT pathway activation are potential therapeutic targets in colorectal cancer (CRC), but their clinicopathological significance remains unclear.
BACKGROUND
RSPO fusions that lead to WNT pathway activation are potential therapeutic targets in colorectal cancer (CRC), but their clinicopathological significance remains unclear.
METHODS
We screened 1019 CRCs for RSPO fusions using multiplex reverse transcription-PCR. The RSPO fusion-positive tumours were subjected to whole-exome sequencing (WES).
RESULTS
Our analysis identified 29 CRCs with RSPO fusions (2.8%), consisting of five with an EIF3E-RSPO2 fusion and 24 with PTPRK-RSPO3 fusions. The patients were 17 women and 12 men. Thirteen tumours (45%) were right-sided. Histologically, approximately half of the tumours (13/29, 45%) had a focal or extensive mucinous component that was significantly more frequent than the RSPO fusion-negative tumours (13%; P = 8.1 × 10). Four tumours (14%) were mismatch repair-deficient. WES identified KRAS, BRAF, and NRAS mutations in a total of 27 tumours (93%). In contrast, pathogenic mutations in major WNT pathway genes, such as APC, CTNNB1 and RNF43, were absent. RSPO fusion status did not have a statistically significant influence on the overall or recurrence-free survival. These clinicopathological and genetic features were also confirmed in a pooled analysis of previous studies.
CONCLUSION
RSPO fusion-positive CRCs constitute a rare subgroup of CRCs with several characteristic clinicopathological and genetic features.
Topics: Female; Humans; Male; Colorectal Neoplasms; Gene Fusion; Mutation; Thrombospondins; Wnt Signaling Pathway
PubMed: 35715628
DOI: 10.1038/s41416-022-01880-w -
Cellular and Molecular Life Sciences :... Oct 2011Tissue microfibrils contain fibrillin-1 as a major constituent. Microfibrils regulate bioavailability of TGFβ superfamily growth factors and are structurally crucial in... (Review)
Review
Tissue microfibrils contain fibrillin-1 as a major constituent. Microfibrils regulate bioavailability of TGFβ superfamily growth factors and are structurally crucial in the ocular zonule. FBN1 mutations typically cause the Marfan syndrome, an autosomal dominant disorder manifesting with skeletal overgrowth, aortic aneurysm, and lens dislocation (ectopia lentis). Infrequently, FBN1 mutations cause dominantly inherited Weill-Marchesani syndrome (WMS), isolated ectopia lentis (IEL), or the fibrotic condition, geleophysic dysplasia (GD). Intriguingly, mutations in ADAMTS [a disintegrin-like and metalloprotease (reprolysin-type) with thrombospondin type 1 motif] family members phenocopy these disorders, leading to recessive WMS (ADAMTS10), WMS-like syndrome (ADAMTS17), IEL (ADAMTSL4 and ADAMTS17) and GD (ADAMTSL2). An ADAMTSL2 founder mutation causes Musladin-Lueke syndrome, a fibrotic disorder in beagle dogs. The overlapping disease spectra resulting from fibrillin-1 and ADAMTS mutations, interaction of ADAMTS10 and ADAMTSL2 with fibrillin-1, and evidence that these ADAMTS proteins accelerate microfibril biogenesis, constitutes a consilience suggesting that some ADAMTS proteins evolved to provide a novel mechanism regulating microfibril formation and consequently cell behavior.
Topics: ADAM Proteins; Amino Acid Motifs; Animals; Binding Sites; Dogs; Extracellular Matrix; Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Metalloendopeptidases; Mice; Microfibrils; Microfilament Proteins; Multigene Family; Mutation; Thrombospondins; Transforming Growth Factor beta
PubMed: 21858451
DOI: 10.1007/s00018-011-0780-9 -
Journal of Experimental & Clinical... Jan 2021Cancer-associated fibroblasts (CAFs), the primary component of tumor stroma in tumor microenvironments, are well-known contributors to the malignant progression of...
Thrombospondin 4/integrin α2/HSF1 axis promotes proliferation and cancer stem-like traits of gallbladder cancer by enhancing reciprocal crosstalk between cancer-associated fibroblasts and tumor cells.
BACKGROUND
Cancer-associated fibroblasts (CAFs), the primary component of tumor stroma in tumor microenvironments, are well-known contributors to the malignant progression of gallbladder cancer (GBC). Thrombospondins (THBSs or TSPs) comprise a family of five adhesive glycoproteins that are overexpressed in many types of cancers. However, the expression and potential roles of TSPs in the crosstalk between CAFs and GBC cells has remained unclear.
METHODS
Peritumoral fibroblasts (PTFs) and CAFs were extracted from GBC tissues. Thrombospondin expression in GBC was screened by RT-qPCR. MTT viability assay, colony formation, EdU incorporation assay, flow cytometry analysis, Transwell assay, tumorsphere formation and western blot assays were performed to investigate the effects of CAF-derived TSP-4 on GBC cell proliferation, EMT and cancer stem-like features. Subcutaneous tumor formation models were established by co-implanting CAFs and GBC cells or GBC cells overexpressing heat shock factor 1 (HSF1) to evaluate the roles of TSP-4 and HSF1 in vivo. To characterize the mechanism by which TSP-4 is involved in the crosstalk between CAFs and GBC cells, the levels of a variety of signaling molecules were detected by coimmunoprecipitation, immunofluorescence staining, and ELISA assays.
RESULTS
In the present study, we showed that TSP-4, as the stromal glycoprotein, is highly expressed in CAFs from GBC and that CAF-derived TSP-4 induces the proliferation, EMT and cancer stem-like features of GBC cells. Mechanistically, CAF-secreted TSP-4 binds to the transmembrane receptor integrin α2 on GBC cells to induce the phosphorylation of HSF1 at S326 and maintain the malignant phenotypes of GBC cells. Moreover, the TSP-4/integrin α2 axis-induced phosphorylation of HSF1 at S326 is mediated by Akt activation (p-Akt at S473) in GBC cells. In addition, activated HSF1 signaling increased the expression and paracrine signaling of TGF-β1 to induce the transdifferentiation of PTFs into CAFs, leading to their recruitment into GBC and increased TSP-4 expression in CAFs, thereby forming a positive feedback loop to drive the malignant progression of GBC.
CONCLUSIONS
Our data indicate that a complex TSP-4/integrin α2/HSF1/TGF-β cascade mediates reciprocal interactions between GBC cells and CAFs, providing a promising therapeutic target for gallbladder cancer patients.
Topics: Animals; Cancer-Associated Fibroblasts; Cell Proliferation; Female; Gallbladder Neoplasms; Humans; Integrin alpha2; Male; Mice; Mice, Nude; Thrombospondins; Transfection; Tumor Microenvironment
PubMed: 33407730
DOI: 10.1186/s13046-020-01812-7 -
The Journal of Biological Chemistry Jul 1981A hydrodynamic model of the high molecular weight platelet glycoprotein thrombospondin is formulated from physical solution measurements of molecular weight, partial...
A hydrodynamic model of the high molecular weight platelet glycoprotein thrombospondin is formulated from physical solution measurements of molecular weight, partial specific volume, sedimentation coefficient, and intrinsic viscosity. Simultaneous sedimentation equilibrium analysis of thrombospondin in buffered saline prepared in H2O and D2O yielded values of 420,000 and 0.714 ml/g for the molecular weight and partial specific volume, respectively. A sedimentation coefficient of 8.6 S was found to be independent of the protein concentration over the range 0-6 mg/ml. The intrinsic viscosity was determined to be 40 ml/g at 20 degrees C for native thrombospondin and 52 ml/g for thrombospondin in the presence of 6 M guanidine-HCl. Based on these values thrombospondin is best described as a prolate ellipsoid with an axial ratio of 9.3. This model agrees well with the electron microscopic image of thrombospondin as a nodular rod (7 X 65 nm)-shaped molecule with an axial ratio of 10. Sedimentation equilibrium analysis and sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated that thrombospondin is comprised of three 140,000-dalton polypeptide chains. The percentage of residues in alpha-helix was calculated to be only 3% from the circular dichroism spectrum.
Topics: Blood Platelets; Circular Dichroism; Glycoproteins; Humans; Microscopy, Electron; Molecular Weight; Peptide Fragments; Protein Conformation; Thrombospondins; Trypsin; Viscosity
PubMed: 7251605
DOI: No ID Found -
Neuro-oncology Apr 2005Angiogenesis is necessary for tumor growth beyond a volume of approximately 2 mm(3). This observation, along with the accessibility of tumor vessels to therapeutic... (Review)
Review
Angiogenesis is necessary for tumor growth beyond a volume of approximately 2 mm(3). This observation, along with the accessibility of tumor vessels to therapeutic targeting, has resulted in a research focus on inhibitors of angiogenesis. A number of endogenous inhibitors of angiogenesis are found in the body. Some of these are synthesized by specific cells in different organs, and others are created by extracellular proteolytic cleavage of plasma-derived or extracellular matrix-localized proteins. In this review, we focus on angiostatin, endostatin, PEX, pigment epithelial-derived factor, and thrombospondin (TSP)-1 and -2, either because these molecules are expressed in malignant glioma biopsies or because animal studies in malignant glioma models have suggested that their therapeutic administration could be efficacious. We review the known mechanisms of action, potential receptors, expression in glioma biopsy samples, and studies testing their potential therapeutic efficacy in animal models of malignant glioma. Two conclusions can be made regarding the mechanisms of action of these inhibitors: (1) Several of these inhibitors appear to mediate their antiangiogenic effect through multiple protein-protein interactions that inhibit the function of proangiogenic molecules rather than through a specific receptor-mediated signaling event, and (2) TSP-1 and TSP-2 appear to mediate their antiangiogenic effect, at least in part, through a specific receptor, CD36, which initiates the antiangiogenic signal. Although not proven in gliomas, evidence suggests that expression of specific endogenous inhibitors of angiogenesis in certain organs may be part of a host antitumor response. The studies reviewed here suggest that new antiangiogenic therapies for malignant gliomas offer exciting promise as nontoxic, growth-inhibitory agents.
Topics: Angiogenesis Inhibitors; Angiostatins; Animals; Brain Neoplasms; Endostatins; Eye Proteins; Glioma; Humans; Neovascularization, Pathologic; Nerve Growth Factors; Peptide Fragments; Serpins; Signal Transduction; Thrombospondin 1; Thrombospondins
PubMed: 15831230
DOI: 10.1215/S115285170400119X