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Archives of Biochemistry and Biophysics Jul 2023Intercellular communication is pivotal in various stages of cancer progression. For smart and effective communication, cancer cells employ diverse modes of messaging...
Intercellular communication is pivotal in various stages of cancer progression. For smart and effective communication, cancer cells employ diverse modes of messaging that may be further fine-tuned by the microenvironmental changes. Extracellular matrix (ECM) stiffening due to excess deposition and crosslinking of collagen is one of the crucial tumor-microenvironmental changes that influence a plethora of cellular processes, including cell-cell communication. We herein studied the crosstalk between exosomes and tunneling nanotubes (TNT), the two distinct means of cell-cell communication under varying ECM-stiffness conditions. We show that exosomes promote the formation of tunneling nanotubes in breast cancer cells, which results in cellular internet. Interestingly, exosomes drastically increased the fraction of cells connected by TNT; however, they elicited no effect on the number of TNTs per pair of connected cells or the length of TNT. The observed pro-TNT effects of exosomes were found to be ECM-stiffness dependent. ECM-stiffness tuned exosomes were found to promote TNT formation predominantly via the 'cell dislodgment model'. At the molecular level, exosomal thrombospondin-1 was identified as a critical pro-TNT factor. These findings underline the influence of ECM stiffening on two diverse modes of cell communication and their interdependence, which may have significant implications in cancer biomedical research.
Topics: Humans; Female; Breast Neoplasms; Nanotubes; Cell Communication; Extracellular Matrix; Thrombospondins
PubMed: 37146866
DOI: 10.1016/j.abb.2023.109624 -
Internal Medicine (Tokyo, Japan) 2016A 30-year-old woman with proteinuria first noted at 26 weeks of gestation was admitted to undergo further evaluation. A renal biopsy revealed membranous nephropathy... (Review)
Review
A 30-year-old woman with proteinuria first noted at 26 weeks of gestation was admitted to undergo further evaluation. A renal biopsy revealed membranous nephropathy (MN). There was no evidence of any secondary MN. Prednisolone was initiated 6 months after delivery. Four months later, her urine protein became negative. Enhanced granular staining for thrombospondin type-1 domain-containing 7A (THSD7A) in the glomeruli was retrospectively detected in a biopsy specimen. A literature review revealed that 60% of cases of THSD7A-related MN occurred in women of childbearing age. Therefore, THSD7A-related MN should be considered in female patients presenting with idiopathic MN in childbearing age.
Topics: Adult; Anti-Inflammatory Agents; Cytoplasmic Granules; Female; Glomerulonephritis, Membranous; Humans; Immunohistochemistry; Kidney Glomerulus; Prednisolone; Pregnancy; Pregnancy Complications; Proteinuria; Thrombospondins; Treatment Outcome
PubMed: 27629964
DOI: 10.2169/internalmedicine.55.6726 -
Pediatric Research Mar 2017We have previously identified TAX2 peptide as an orthosteric antagonist for thrombospondin-1 (TSP-1) interaction with the cell-surface receptor CD47. TAX2 displays...
BACKGROUND
We have previously identified TAX2 peptide as an orthosteric antagonist for thrombospondin-1 (TSP-1) interaction with the cell-surface receptor CD47. TAX2 displays exciting antiangiogenic, antitumor, and antimetastatic properties in both allograft and xenograft models of melanoma as well as pancreatic carcinoma. Here, TAX2 therapeutic potential was investigated in two distinct preclinical mouse models of neuroblastoma.
METHODS
SK-N-BE(2) (MYCN-amplified) and SK-N-SH (MYCN-negative) human neuroblastoma cells have been implanted in outbred NMRI nude mice prior to systemic administrations of TAX2, and then tumor growth as well as intratumoral blood flow were longitudinally monitored. At study termination, subcutaneous xenografts were macroscopically and histopathologically examined.
RESULTS
In both models, TAX2 induced a significant inhibition of tumor burden in mice engrafted with large pre-established neuroblastoma tumors. Indeed, TAX2 administered at biologically relevant doses sharply alters xenograft vascularization as well as multiple features of tumor progression.
CONCLUSION
Altogether, our results present TAX2 peptide specifically targeting TSP-1:CD47 interaction as a new putative therapeutic approach for treating neuroblastoma, whether utilized alone or in combination with existing chemotherapy drugs.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; CD47 Antigen; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Neovascularization, Pathologic; Neuroblastoma; Peptides; Peptides, Cyclic; Thrombospondins; Treatment Outcome; Tumor Burden
PubMed: 27842053
DOI: 10.1038/pr.2016.242 -
Virchows Archiv : An International... Jun 2019Thrombospondin type 1 domain-containing 7A (THSD7A) is a recently identified target antigen of idiopathic membranous nephropathy (iMN). The clinicopathological...
Thrombospondin type 1 domain-containing 7A (THSD7A) is a recently identified target antigen of idiopathic membranous nephropathy (iMN). The clinicopathological characteristics of THSD7A-associated MN are poorly characterised due to low prevalence among MN patients. Among 469 consecutive cases of pathologically confirmed MN diagnosed at four centres in Japan, 14 cases were confirmed positive for THSD7A by immunohistochemistry (3.0%). The prevalence of THSD7A-associated MN tended to be higher in northern Japan. Most cases demonstrated nephrotic-range proteinuria (12/14 cases, 86%). In two patients, cancer was detected at the time of renal biopsy (small-cell carcinoma of the lung and prostatic adenocarcinoma with neuroendocrine differentiation). Both tumours were negative for THSD7A. Four patients had concurrent or previous incidence of allergic diseases, including one patient with Kimura's disease. Pathological analysis of kidney biopsy tissue revealed slight mesangial cell proliferation in three cases and spike formation in one case. Immunofluorescence studies demonstrated that IgG subclass was mainly IgG4-dominant/codominant (12/13, 92% cases), while the case with prostatic cancer had an IgG2-dominant distribution. The immunostaining profile for components of the lectin complement pathways was not significant in three cases including two patients with malignancy. One case was dual positive for THSD7A and PLA2R. Of 10 cases with known clinical follow-up data, 6 demonstrated reduced serum creatinine and 8 presented reduced proteinuria. In summary, although the major IgG phenotype was usually IgG4-dominant/codominant, clinical background was otherwise heterogeneous. Further investigation of regional differences in THSD7A-associated MN prevalence may reveal genetic and environmental risk factor and associated pathogenic mechanisms.
Topics: Autoantibodies; Female; Fluorescent Antibody Technique; Glomerulonephritis, Membranous; Humans; Immunohistochemistry; Incidence; Middle Aged; Prevalence; Risk Factors; Thrombospondins
PubMed: 30868298
DOI: 10.1007/s00428-019-02558-0 -
Circulation Research Sep 2004
Topics: Animals; Cardiac Output, Low; Extracellular Matrix; Humans; Hypertrophy, Left Ventricular; Mice; Models, Cardiovascular; Myocardium; Rats; Signal Transduction; Thrombospondins
PubMed: 15345666
DOI: 10.1161/01.RES.0000142315.88477.42 -
Matrix Biology : Journal of the... May 2023Limited proteolysis of thrombospondins is a powerful mechanism to ensure dynamic tuning of their activities in the extracellular space. Thrombospondins are... (Review)
Review
Limited proteolysis of thrombospondins is a powerful mechanism to ensure dynamic tuning of their activities in the extracellular space. Thrombospondins are multifunctional matricellular proteins composed of multiple domains, each with a specific pattern of interactions with cell receptors, matrix components and soluble factors (growth factors, cytokines and proteases), thus with different effects on cell behavior and responses to changes in the microenvironment. Therefore, the proteolytic degradation of thrombospondins has multiple functional consequences, reflecting the local release of active fragments and isolated domains, exposure or disruption of active sequences, altered protein location, and changes in the composition and function of TSP-based pericellular interaction networks. In this review current data from the literature and databases is employed to provide an overview of cleavage of mammalian thrombospondins by different proteases. The roles of the fragments generated in specific pathological settings, with particular focus on cancer and the tumor microenvironment, are discussed.
Topics: Animals; Humans; Thrombospondins; Proteolysis; Neoplasms; Peptide Hydrolases; Tumor Microenvironment; Extracellular Matrix; Mammals
PubMed: 37003348
DOI: 10.1016/j.matbio.2023.03.011 -
Bone Sep 2021During skeletal development most bones are first formed as cartilage templates, which are gradually replaced by bone. If later in life those bones break, temporary...
During skeletal development most bones are first formed as cartilage templates, which are gradually replaced by bone. If later in life those bones break, temporary cartilage structures emerge to bridge the fractured ends, guiding the regenerative process. This bone formation process, known as endochondral ossification (EO), has been widely studied for its potential to reveal factors that might be used to treat patients with large bone defects. The extracellular matrix of cartilage consists of different types of collagens, proteoglycans and a variety of non-collagenous proteins that organise the collagen fibers in complex networks. Thrombospondin-5, also known as cartilage oligomeric matrix protein (TSP-5/COMP) is abundant in cartilage, where it has been described to enhance collagen fibrillogenesis and to interact with a variety of growth factors, matrix proteins and cellular receptors. However, very little is known about the skeletal distribution of its homologue thrombospondin-4 (TSP-4). In our study, we compared the spatiotemporal expression of TSP-5 and TSP-4 during postnatal bone formation and fracture healing. Our results indicate that in both these settings, TSP-5 distributes across all layers of the transient cartilage, while the localisation of TSP-4 is restricted to the population of hypertrophic chondrocytes. Furthermore, in fractured bones we observed TSP-4 sparsely distributed in the periosteum, while TSP-5 was absent. Last, we analysed the chemoattractant effects of the two proteins on endothelial cells and bone marrow stem cells and hypothesised that, of the two thrombospondins, only TSP-4 might promote blood vessel invasion during ossification. We conclude that TSP-4 is a novel factor involved in bone formation. These findings reveal TSP-4 as an attractive candidate to be evaluated for bone tissue engineering purposes.
Topics: Cartilage; Cartilage Oligomeric Matrix Protein; Chondrocytes; Endothelial Cells; Humans; Osteogenesis; Thrombospondins
PubMed: 33971315
DOI: 10.1016/j.bone.2021.115999 -
Turkish Neurosurgery 2021To measure the serum levels of strong angiostatic and synaptogenetic molecules thrombospondin-1 (TSP-1) and thrombospondin-2 (TSP-2) in patients with temporal lobe...
AIM
To measure the serum levels of strong angiostatic and synaptogenetic molecules thrombospondin-1 (TSP-1) and thrombospondin-2 (TSP-2) in patients with temporal lobe epilepsy (TLE) before and after surgery.
MATERIAL AND METHODS
In this prospective study, 20 patients operated for TLE and 20 healthy subjects were included. Serum levels of TSP-1 and TSP-2 were measured using enzyme-linked immunosorbent assay (ELISA).
RESULTS
Our findings showed that both groups had higher serum levels of both molecules "before" surgery than 10 days ?after?
SURGERY
However, a significant difference was noted between ?before? and "after" surgery regarding TSP-1 (p=0.00001). Although a marked decrease was found "after" surgery with respect to TSP-2, the difference did not reach statistical significance (p=0.22). In patients with TLE, serum levels of both molecules ?before? surgery were found to be significantly higher than in healthy controls (TSP-1, p=0.00001; TSP-2, p=0.007).
CONCLUSION
Serum levels of TSP-1 and TSP-2 are determined to be higher in patients with TLE than in healthy subjects, and the resection of epileptogenic tissues decreases the serum levels of these molecules. Future studies should involve a higher number of patients with serial serum levels of TSP-1 and TSP-2 at the long-term follow-up to correlate with seizure outcome.
Topics: Adult; Anterior Temporal Lobectomy; Biomarkers; Epilepsy, Temporal Lobe; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prospective Studies; Thrombospondin 1; Thrombospondins; Young Adult
PubMed: 33372257
DOI: 10.5137/1019-5149.JTN.29081-20.4 -
Biochemical Pharmacology Sep 2018Thrombospondin (TSP)-2, a matricellular glycoprotein of the TSP family, regulates multiple biological functions, including proliferation, angiogenesis, cell adhesion,...
Thrombospondin (TSP)-2, a matricellular glycoprotein of the TSP family, regulates multiple biological functions, including proliferation, angiogenesis, cell adhesion, and extracellular matrix (ECM) modeling. The clinical relevance of TSP-2 has been explored in many different cancers. TSP-2 expression levels vary between different cancer types, and their role in tumor progression remains controversial. Although previous studies have reported higher serum TSP-2 levels in patients with non-small cell lung cancer, the role of TSP-2 in lung cancer progression remains to be addressed. A total of 585 lung adenocarcinoma datasets, including mRNA sequencing and clinical data, were retrieved from The Cancer Genome Atlas (TCGA). Forty paired adjacent normal tissues and lung tumor tissue datasets were used to examine TSP-2 expression levels. Tumor microarray were performed with immunohistochemical staining to examine TSP-2 expression in lung cancer patients. Transwell migration assay, quantitative real-time PCR and Western blot were used to investigate molecular mechanism of TSP-2 in lung cancer cell. TSP-2 promotes matrix metalloproteinase-13 (MMP-13) expression, cell migration, and cell invasion by mediating integrin αvβ3/FAK/Akt/NF-κB signal transduction. Using TSP-2 knockdown stable cell lines, we found that TSP-2 knockdown reduces MMP-13 expression and cell mobility. When we manipulated the tumor tissue microarray and TCGA datasets to investigate the clinical relevance of TSP-2, we found high TSP-2 expression levels in lung cancer specimens. The present study demonstrates that TSP-2 regulates cell mobility through MMP-13 expression in lung cancer cells. In addition, TSP-2 expression was associated with MMP-13 expression and poor prognosis in lung cancer. TSP-2 may therefore be a promising novel target for lung cancer treatment.
Topics: A549 Cells; Cell Movement; Enzyme Induction; Humans; Lung Neoplasms; Matrix Metalloproteinase 13; Neoplasm Invasiveness; Thrombospondins
PubMed: 30031810
DOI: 10.1016/j.bcp.2018.07.024 -
Indian Journal of Ophthalmology Apr 2020To evaluate the frequency and the association of Thrombospondin 1 (THBS1) gene single nucleotide polymorphisms (SNPs) in Asian Indian patients with optical full...
PURPOSE
To evaluate the frequency and the association of Thrombospondin 1 (THBS1) gene single nucleotide polymorphisms (SNPs) in Asian Indian patients with optical full thickness corneal grafting surgery.
METHODS
Prospective case-control analysis of optical penetrating keratoplasty patients with and without immune rejection and controls for genotyping of 3 THBS1 gene SNPs (rs1478604 A>G; rs2228261 C>T; rs2228262 A>G) by Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS PCR).
RESULTS
Among 58 patients [45 with immune allograft rejection (DNA isolation was possible in 38 samples) and 13 without immune corneal allograft rejection] and 65 controls, allele frequencies observed for rs1478604 (A>G) are A: 69.7% and 72.6%, G: 30.2% and 27.3%; for rs2228261 (C>T) are T: 70.2% and 62.3%, C: 29.7% and 37.6%; and for rs2228262 (A>G) A: 97.4% and 98.4%; G 2.5% and 1.5% respectively. Genotype frequencies were rs1478604 (A>G) AA: 57.8% and 59.3%, AG 23.6% and 26.5%; GG 18.4% and 14%; for rs2228261 (C>T) TT: 40.5% and 33.8%, TC: 59% and 56.9%, CC: 0% and 9.2%; for rs2228262 (A>G) AA: 94.8% and 96.8%, AG: 5.1% and 3.1% in rejection and controls respectively. The allele and genotype frequency for the 3 described THSB1 SNPs did not show any difference between the corneal graft immune rejection patients and controls.
CONCLUSION
Asian Indian population evaluated for THBS1 gene SNPs by ARMS PCR genotyping in Asian Indian population did not show any genetic association to immune rejection occurrence in our study.
Topics: Allografts; Asian People; Case-Control Studies; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Polymorphism, Single Nucleotide; Prospective Studies; Thrombospondin 1; Thrombospondins
PubMed: 32174570
DOI: 10.4103/ijo.IJO_552_19