Disease relevance of SPARC

• Osteonectin/SPARC induction by ectopic beta(3) integrin in human radial growth phase primary melanoma cells [1].
• Stromal SPARC was linked with tumor necrosis (P = 0.01) and, marginally, with node metastasis (P = 0.07), as well as with high levels of carbonic anhydrase 9 and LDH in cancer cells (P = 0.0001 and P = 0.01, respectively) [2].
• SPARC produced by melanoma cells modulates polymorphonuclear leukocytes recruitment and anti-tumor cytotoxic activity, indicating a possible role of SPARC in tumor evasion from immune surveillance [3]
• Using a novel monoclonal antibody (10-255), we examined immunohistochemically the patterns of SPARC expression in non-small cell lung cancer (NSCLC) [2].
• Immunohistochemical staining for SPARC showed cytoplasmic immunoreactivity of neoplastic cells in all diffuse astrocytomas analyzed [4].
• SPARC was also coincident with enhanced levels of cancer cell differentiated embryo-chondrocyte expressed gene 1, hypoxia inducible factor 2alpha, and thymidine phosphorylase (P = 0.01, P = 0.05, and P = 0.03, respectively) [2].

High impact information on SPARC

• The osteonectin-collagen complexes also nucleate mineral phase deposition from metastable balanced salt solutions, Antibodies to osteonectin cross-react with bone and, to a lesser extent, dentin, but not with other tissues [5].
• Osteonectin is a 32,000 dalton bone-specific protein that binds selectively to both hydroxyapatite and collagen [5].
• The present study reports that the suppression of SPARC expression by human melanoma cells using a SPARC antisense expression vector results in a significant decrease in the in vitro adhesive and invasive capacities of tumor cells, completely abolishing their in vivo tumorigenicity [6].
• The cDNA encodes a secreted acidic calcium-binding glycoprotein of 664 aa residues, designated hevin, exhibiting 62% identity with the antiadhesive extracellular matrix protein SPARC, over a region of 232 aa spanning more than four fifths of the SPARC coding sequence [7].
• Excess VEGF-A increased CNV before injury because VEGFR-1 activation was silenced by secreted protein, acidic and rich in cysteine (SPARC) [8].

Chemical compound and disease context of SPARC

• Moreover, when compared with control specimens, significantly increased levels of SPARC mRNA were found in fibrotic livers from two animal models of liver disease: murine schistosomiasis and carbon tetrachloride-induced fibrosis in rats [9].
• In the current study, we have examined the expression of secreted protein, acidic and rich in cysteine (SPARC) in adipose tissue and its significance in obesity and coronary artery disease (CAD) [10].
• In summary, SPARC was transiently expressed by interstitial fibroblasts at sites of tubulointerstitial injury and fibrosis, and by smooth muscle cells and cells in the adventitia of injured arteries in the Ang II-model [11].
• The analysis of SPARC would help evaluate the effect of the unique matricellular glycoprotein on renal disease progression in ADPKD [12].
• Effect of resveratrol on matrix metalloproteinase-2 (MMP-2) and Secreted Protein Acidic and Rich in Cysteine (SPARC) on human cultured glioblastoma cells [13].

Biological context of SPARC

• FISH to metaphase chromosomes and interphase nuclei established that IG90 lies centromeric to SPARC [14].
• Cosmids IG90 and SPARC, which map to distal 5q, encompass two and one hypervariable microsatellite markers, respectively [14].
• This information combined with the data generated by genetic linkage analysis demonstrated that the TCOF1 locus is closely flanked proximally by IG90 and distally by SPARC [14].
• SPARC has been found in association with tissues undergoing cell proliferation, migration, and extracellular matrix remodeling [9].
• SPARC (secreted protein, acidic and rich in cysteine) is a matricellular protein that modulates cell adhesion and proliferation and is thought to function in tissue remodeling and angiogenesis [15].

Anatomical context of SPARC

• SPARC inhibited the binding of PDGF-BB and PDGF-AB, but not PDGF-AA, to human dermal fibroblasts in a dose-dependent manner [16].
• Extracts from a Kupffer-endothelial cell fraction exhibited traces of SPARC transcript, but expression of SPARC mRNA was absent in extracts from freshly isolated hepatocytes [9].
• Peptides derived from SPARC domain IV, which contains a disulfide-bonded EF-hand sequence and binds to endothelial cells, mimicked the effect of native SPARC [15].
• These results suggest that the osteonectin/SPARC gene appears activated in certain human tissues characterized by de novo formation of basement membrane [17].
• SPARC synthesis by cultured chondrocytes was measured by Northern blot analysis, immunoblotting, and sandwich enzyme-linked immunosorbent assay [18].

Associations of SPARC with chemical compounds

• 125I-PDGF-BB and -AB also bound specifically to SPARC that was immobilized on microtiter wells or bound to nitrocellulose after transfer from SDS/polyacrylamide gels [16].
• We also detected an increased production of SPARC protein in the liver of animals treated with carbon tetrachloride [9].
• Moreover, an additional diminution of VEGF activity by SPARC is accomplished through a reduction in the tyrosine phosphorylation of mitogen-activated protein kinases [15].
• The common region of loss in these three 5q- syndrome patients includes the macrophage colony-stimulating factor-1 receptor (CSF1R), secreted protein, acidic, cysteine-rich (SPARC), and glutamate receptor (GR1A1) genes [19].
• We have previously shown that angiogenesis, as reflected by fibrovascular invasion into subcutaneously implanted polyvinyl alcohol (PVA) sponges, is increased in SPARC-null mice (6-9 months of age) relative to their wild-type (WT) counterparts [20].

Physical interactions of SPARC

• Using ELISA, purified osteonectin binds to solid-phase-adsorbed thrombospondin with a dissociation constant (Kd) of 0.7 nM [21].
• Bone osteonectin-dependent binding of plasminogen to collagen matrix is reversed by the addition of epsilon-aminocaproic acid [22].
• Crystal structure of a pair of follistatin-like and EF-hand calcium-binding domains in BM-40 [23].
• In vitro, the heparin-binding multimeric isoform of vitronectin bound to immobilized osteonectin in a saturable manner with half-maximal binding at 30-40 nM [24].
• By phage display and in vitro-binding assays, we now show that SPARC interacts with stabilin-1, a scavenger receptor expressed by tissue macrophages and sinusoidal endothelial cells [25].

Regulatory relationships of SPARC

• Western and Northern blots showed that TGF-beta enhanced SPARC synthesis at the protein and mRNA levels [26].
• In addition, SPARC synthesis was enhanced in synovial cells of RA and OA joints [18].
• Epidermal growth factor (EGF) up-regulated the synthesis of DNA and fibronectin and inhibited SPARC and ALPase levels [27].
• CONCLUSION: SPARC may play a role in remodelling and repair of periodontal tissue by promoting proliferation and MMP-2 production [28].
• A consequence of SPARC recognition by alphaVbeta5 is enhanced VEGF production [29].
• Downregulation of either FAK or ILK expression inhibited SPARC-mediated AKT phosphorylation, and targeting both FAK and ILK attenuated AKT activation more potently than targeting either FAK or ILK alone [30].
• Immunoblotting of the secreted fraction of RNAi-transfected melanoma cells confirmed that downregulation of SPARC expression promoted decreased levels of N-CAD and CLU and increased secretion of HSP27 [31].

Other interactions of SPARC

• Previous studies have localized the TCOF1 locus between D5S519 (proximal) and SPARC (distal), a region of 22 centirays as estimated by radiation hybrid mapping [32].
• Expression of osteonectin was also associated with reduced adhesion to vitronectin, but not to fibronectin [1].
• METHODS: Fibroblasts from skin biopsy specimens of 2 normal individuals were transfected with siRNA of SPARC and siRNA of CTGF [33].
• CONCLUSIONS: SPARC or its combination with GPC3 is thus considered a potentially useful tumor marker, especially for melanoma at an early stage [34].
• Adding transforming growth factor-beta (TGF-beta) decreased laminin and ALPase levels, whereas it increased SPARC and fibronectin levels 3- to 10-fold [26].

Analytical, diagnostic and therapeutic context of SPARC

• Sequence analysis disclosed a striking homology to SPARC, known to be involved in tumorigenesis [35].
• Immunohistochemistry was used to localize SPARC, TN, and thrombospondin 1 in biopsies of organizing pneumonia, idiopathic pulmonary fibrosis (nine cases of usual interstitial pneumonia, one of desquamative interstitial pneumonia), and control lungs [36].
• Real-time quantitative reverse transcriptase-polymerase chain reaction and Western blotting were used to measure transcription and protein levels of SPARC and type I collagen, respectively [37].
• EXPERIMENTAL DESIGN: Secreted SPARC protein was quantified using ELISA in the sera from 109 melanoma patients, five patients with large congenital melanocytic nevus, 61 age-matched healthy donors, and 13 disease-free patients after undergoing a surgical removal [34].
• The levels of SPARC, ALPase and calcium deposits in the three pulp cell cultures were 10-250 times those of human foreskin fibroblasts [38].

References