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SPARC peptides FSEN and FSEC inhibit endothelial cell migration. HUVEC cells were treated with serial dilutions of SPARC peptides with or without 10 ng/ml bFGF in a modified Boyden chamber. Relative stimulation was calculated as percentage of bFGF-induced migration. (A) Peptide FSEN inhibited bFGF-stimulated endothelial migration with an EC50 of ~2 nM. (B) Peptide FSEC displayed a strong dose-dependent inhibition of bFGF-stimulated endothelial migration with an EC50 ~1 pM. Dark circles represent bFGF-stimulated migration; light circles represent basal migration in the absence of an activator.
Source publication
New, more effective strategies are needed to treat highly aggressive neuroblastoma. Our laboratory has previously shown that full-length Secreted Protein Acidic and Rich in Cysteine (SPARC) and a SPARC peptide corresponding to the follistatin domain of the protein (FS-E) potently block angiogenesis and inhibit the growth of neuroblastoma tumors in...
Context in source publication
Context 1
... assays were performed with human umbilical vein endothelial cells (HUVEC) and each of the synthetic SPARC peptides to characterize their anti-angiogenic properties in vitro and to compare their potencies with the original peptide FS-E. As shown in Figure 2, the C- terminal loop peptide FSEC inhibited bFGF-stimulated endothelial cell migration with an EC 50 of ~1 pM, which was even lower than EC 50 of ~10 pM of the original FS-E peptide. Higher concentrations of peptide FSEC did not inhibit endothelial cell migration, which is also a property of peptide FS-E [26] and the full-length SPARC [10]. ...Similar publications
Controlled and site-specific regulation of growth factor signaling remains a major challenge for current antiangiogenic therapies, as these antiangiogenic agents target normal vasculature as well tumor vasculature. In this article, we identified the prion-like protein doppel as a potential therapeutic target for tumor angiogenesis. We investigated...
Citations
... However, the multifunctional nature of SPARC means that its role can differ depending on the microenvironment [22]. Therefore, SPARC also has a tumour-suppressing effect in various cancer tissues, including colorectal [23], pancreatic [24], prostate [25], and breast cancer [26], as well as neuroblastoma [27]. Consistent with our findings, prior research has shown that high SPARC expression inhibits LC progression [28]. ...
SPARC is an acidic, cysteine-rich, calcium-binding member of the non-collagen glycoproteins originating in bone. Although implicated in the development of several cancers, the functions and mechanisms of SPARC remain unclear. The aim of this study was to investigate whether smooth muscle cell (SMC)-associated SPARC acts an important tumour suppressor in lung adenocarcinoma (LUAD). SPARC inhibits immune evasion in LUAD by suppressing CD276 functionality. We downloaded RNA-sequencing data from patients with LUAD in The Cancer Genome Atlas and identified a set of genes showing SMC-specific expression in these samples. We then screened for differentially expressed genes (DEGs). Enrichment analysis using the Gene Expression Omnibus identified key genes, while immune pathway analysis explored the expression of immune checkpoints involved in LUAD immune regulation. We further validated the differential expression of SPARC and CD276 using immunohistochemistry. Among the upregulated DEGs, SPARC exhibited high enrichment in SMCs, whereas 13 immune checkpoints, such as LAIR1 and CTLA4, were excluded. The infiltration level of the CD276 immune checkpoint was lower in the high-risk group than in the low-risk group. While our results suggest a correlation between SPARC, CD276 and LUAD, additional studies are needed to validate these findings and elucidate the underlying mechanisms before definitive conclusions can be drawn regarding their utility in clinical practice.
... Interestingly, Stab1 KO only present with a mild perisinusoidal fibrosis and no glomerulofibrotic nephropathy, which suggests a functional compensation of the loss of Stab1 by Stab2. Last, ligands of Stab1 also influence cancer progression as SPARC inhibits metastasis of breast cancer cells [13] or reduces the growth of neuroblastoma [14], Lewis lung carcinoma, or EL4 cells [15]. ...
Simple Summary
Deficiency and targeting of Stabilin-1, which is expressed by liver sinusoidal endothelial cells and subsets of macrophages, has been shown to improve anti-tumor immune responses in preclinical and early clinical studies. This study investigated whether targeting of Stab1 might also influence melanoma liver colonization, as hepatic metastasis of melanoma is a poor prognostic factor. In two models of hepatic melanoma metastasis, no direct influence of anti-Stab1 treatment was found. However, effects on the local microenvironment were observed. We suggest that the organ- and tumor-specific effects of anti-Stab1 therapies should be further considered and analyzed in future human studies.
Abstract
Background: This study analyzed the role of Stabilin-1 on hepatic melanoma metastasis in preclinical mouse models. Methods: In Stabilin-1−/− mice (Stab1 KO), liver colonization of B16F10 luc2 and Wt31 melanoma was investigated. The numbers, morphology, and vascularization of hepatic metastases and the hepatic microenvironment were analyzed by immunofluorescence. Results: While hepatic metastasis of B16F10 luc2 or Wt31 melanoma was unaltered between Stab1 KO and wildtype (Ctrl) mice, metastases of B16F10 luc2 tended to be smaller in Stab1 KO. The endothelial differentiation of both types of liver metastases was similar in Stab1 KO and Ctrl. No differences in initial tumor cell adhesion and retention to the liver vasculature were detected in the B16F10 luc2 model. Analysis of the immune microenvironment revealed a trend towards higher levels of CD45⁺Gr-1⁺ cells in Stab1 KO as compared to Ctrl in the B16F10 luc2 model. Interestingly, significantly higher levels of POSTN were found in the matrix of hepatic metastases of Wt31, while liver metastases of B16F10 luc2 showed a trend towards increased deposition of RELN. Conclusions: Hepatic melanoma metastases show resistance to Stabilin-1 targeting approaches. This suggests that anti-Stab1 therapies should be considered with respect to the tumor entity or target organs.
... However, SPARC may act as a tumor suppressor for some cancer types, such as ovarian 27 and neuroblastomas. 28 Thus, it can be seen that the regulatory effect of SPARC is related to the immune status of the organism. ...
Purpose
Airway remodeling is a critical feature of asthma. Secreted protein acidic and rich in cysteine (SPARC), which plays a cardinal role in regulating cell-matrix interactions, has been implicated in various fibrotic diseases. However, the effect of SPARC in asthma remains unknown.
Methods
We studied the expression of SPARC in human bronchial epithelial cells and serum of asthmatics as well as in the lung tissues of chronic asthma mice. The role of SPARC was examined by using a Lentivirus-mediated SPARC knockdown method in the ovalbumin (OVA)-induced asthma mice. The biological processes regulated by SPARC were identified using RNA sequencing. The function of SPARC in the remodeling process induced by transforming growth factor β1 (TGFβ1) was conducted by using SPARC small interfering RNA (siRNA) or recombinant human SPARC protein in 16HBE cells.
Results
We observed that SPARC was up-regulated in human bronchial epithelia of asthmatics and the asthmatic mice. The levels of serum SPARC in asthmatics were also elevated and negatively correlated with the forced expiratory volume in one second (FEV1) to forced vital capacity ratio (FVC) (r = −0.485, P < 0.01) and FEV1 (%predicted) (r = −0.425, P = 0.001). In the chronic asthmatic mice, Lentivirus-mediated SPARC knockdown significantly decreased airway remodeling and airway hyper-responsiveness. According to gene set enrichment analysis, negatively enriched pathways found in the OVA + short hairpin-SPARC group included ECM organization and collagen formation. In the lung function studies, knockdown of SPARC by siRNA reduced the expression of remodeling-associated biomarkers, cell migration, and contraction by blocking the TGFβ1/Smad2 pathway. Addition of human recombinant SPARC protein promoted the TGFβ1-induced remodeling process, cell migration, and contraction in 16HBE cells via the TGFβ1/Smad2 pathway.
Conclusions
Our studies provided evidence for the involvement of SPARC in the airway remodeling of asthma via the TGFβ1/Smad2 pathway.
... The in vitro study demonstrated that SPARC could increase basic fibroblast growth factor-induced fibroblast migration, thus leading to accumulation of fibroblast in tumor stroma [76]. Chlenski et al. demonstrated that SPARC peptides had potent anti-angiogenic and anti-tumorigenic effects in neuroblastoma [77]. ...
The SPARC gene plays multiple roles in extracellular matrix synthesis and cell shaping, associated with tumor cell migration, invasion, and metastasis. The SPARC gene is also involved in the epithelial-mesenchymal transition (EMT) process, which is a critical phenomenon leading to a more aggressive cancer cell phenotype. SPARC gene overexpression has shown to be associated with poor survival in the mesothelioma (MESO) cohort from the TCGA database, indicating that this gene may be a powerful prognostic factor in MESO. Its overexpression is correlated with the immunosuppressive tumor microenvironment. Here, we summarize the omics advances of the SPARC gene, including the summary of SPARC gene expression associated with prognosis in pancancer and MESO, the immunosuppressive microenvironment, and cancer cell stemness. In addition, SPARC might be targeted by microRNAs. Notably, despite the controversial functions on angiogenesis, SPARC may directly or indirectly contribute to tumor angiogenesis in MESO. In conclusion, SPARC is involved in tumor invasion, metastasis, immunosuppression, cancer cell stemness, and tumor angiogenesis, eventually impacting patient survival. Strategies targeting this gene may provide novel therapeutic approaches to the treatment of MESO.
... For example, endostatin, an internal antiangiogenic protein, has two disulfide bonds. It has been shown that secreted protein, which is acidic and rich in cysteine (SPARK), is able to inhibit both ovarian metastasis and the progression of breast cancer [196]. FSEC, as a positive control with the consensus sequence "CELDENNTPMC", is shown to be antiangiogenic using the TargetAntiAngio program. ...
... FSEC, as a positive control with the consensus sequence "CELDENNTPMC", is shown to be antiangiogenic using the TargetAntiAngio program. FSEC is a member of the SPARK family with a disulfide bond that inhibits angiogenesis and tumor growth experimentally [196]. Interestingly, the most potent antiangiogenic peptides, such as CPP10-1344 (SKWCRDHSRC) from Conus kinoshitai conotoxin and CPP10-1743, harbor at least one disulfide bond with high stability. ...
Complex pathological diseases, such as cancer, infection, and Alzheimer’s, need to be targeted by multipronged curative. Various omics technologies, with a high rate of data generation, demand artificial intelligence to translate these data into druggable targets. In this study, 82 marine venomous animal species were retrieved, and 3505 cryptic cell-penetrating peptides (CPPs) were identified in their toxins. A total of 279 safe peptides were further analyzed for antimicrobial, anticancer, and immunomodulatory characteristics. Protease-resistant CPPs with endosomal-escape ability in Hydrophis hardwickii, nuclear-localizing peptides in Scorpaena plumieri, and mitochondrial-targeting peptides from Synanceia horrida were suitable for compartmental drug delivery. A broad-spectrum S. horrida-derived antimicrobial peptide with a high binding-affinity to bacterial membranes was an antigen-presenting cell (APC) stimulator that primes cytokine release and naïve T-cell maturation simultaneously. While antibiofilm and wound-healing peptides were detected in Synanceia verrucosa, APC epitopes as universal adjuvants for antiviral vaccination were in Pterois volitans and Conus monile. Conus pennaceus-derived anticancer peptides showed antiangiogenic and IL-2-inducing properties with moderate BBB-permeation and were defined to be a tumor-homing peptide (THP) with the ability to inhibit programmed death ligand-1 (PDL-1). Isoforms of RGD-containing peptides with innate antiangiogenic characteristics were in Conus tessulatus for tumor targeting. Inhibitors of neuropilin-1 in C. pennaceus are proposed for imaging probes or therapeutic delivery. A Conus betulinus cryptic peptide, with BBB-permeation, mitochondrial-targeting, and antioxidant capacity, was a stimulator of anti-inflammatory cytokines and non-inducer of proinflammation proposed for Alzheimer’s. Conclusively, we have considered the dynamic interaction of cells, their microenvironment, and proportional-orchestrating-host- immune pathways by multi-target-directed CPPs resembling single-molecule polypharmacology. This strategy might fill the therapeutic gap in complex resistant disorders and increase the candidates’ clinical-translation chance.
... SPARC can be produced by both cancer cells and cells that form the TME [118] (Figure 2b). The clearest data about the role of SPARC in tumor angiogenesis are coming from investigations of gastric cancer, bladder cancer, pancreatic carcinoma, and neuro-and glioblastoma [61,62,[119][120][121][122][123][124][125]. SPARC has both direct and indirect anti-angiogenic activity. ...
... Synthetic SPARC peptide inhibited bFGF-stimulated endothelial cell migration in vitro and angiogenesis in vivo. Decrease in the number of CD31+ endothelial cells and SMA+ pericytes was found in SPARC peptide-treated Matrigel plugs compared to the positive controls with bFGF alone [120]. In SPARC peptide-treated neuroblastoma xenografts, a reduction of the quantity of ECs as well as normalization of blood vessel architecture were detected compared to control [120]. ...
... Decrease in the number of CD31+ endothelial cells and SMA+ pericytes was found in SPARC peptide-treated Matrigel plugs compared to the positive controls with bFGF alone [120]. In SPARC peptide-treated neuroblastoma xenografts, a reduction of the quantity of ECs as well as normalization of blood vessel architecture were detected compared to control [120]. ...
Angiogenesis is crucial to the supply of a growing tumor with nutrition and oxygen. Inhibition of angiogenesis is one of the main treatment strategies for colorectal, lung, breast, renal, and other solid cancers. However, currently applied drugs that target VEGF or receptor tyrosine kinases have limited efficiency, which raises a question concerning the mechanism of patient resistance to the already developed drugs. Tumor-associated macrophages (TAMs) were identified in the animal tumor models as a key inducer of the angiogenic switch. TAMs represent a potent source not only for VEGF, but also for a number of other pro-angiogenic factors. Our review provides information about the activity of secreted regulators of angiogenesis produced by TAMs. They include members of SEMA and S100A families, chitinase-like proteins, osteopontin, and SPARC. The COX-2, Tie2, and other factors that control the pro-angiogenic activity of TAMs are also discussed. We highlight how these recent findings explain the limitations in the efficiency of current anti-angiogenic therapy. Additionally, we describe genetic and posttranscriptional mechanisms that control the expression of factors regulating angiogenesis. Finally, we present prospects for the complex targeting of the pro-angiogenic activity of TAMs.
... SPARC peptide FSEC corresponds to the conserved C terminal loop of antiangiogenic FS-E peptide and exhibited effective vessel normalizing and antitumor properties in the neuroblastoma xenograft models. [24,25] FSEC with less structural complexity than FS-E peptide has a conformation-dependent antiangiogenic function with an essential disulfide bond in its structure. On the other hand, D PPA is a proteolysis resistance peptide antagonist with a high affinity to the PD-L1 and has a blocking effect on the PD-1/PD-L1 interaction. ...
The effectiveness of cancer immunotherapy is impaired by the dysfunctional vasculature of tumors. Created hypoxia zones and limited delivery of cytotoxic immune cells help to have immune resistance in tumor tissue. Structural and functional normalization of abnormal tumor vasculature provide vessels for more perfusion efficiency and drug delivery that result in alleviating the hypoxia in the tumor site and increasing infiltration of antitumor T cells. Taking advantage of peptide amphiphiles, herein, a novel peptide amphiphile nanoparticle composed of an antiangiogenic peptide (FSEC) and an immune checkpoint blocking peptide (DPPA) is designed and characterized. FSEC peptide is known to be involved in vessel normalization of tumors in vivo. DPPA is an inhibitory peptide of the PD‐1/PD‐L1 immune checkpoint pathway. The peptide amphiphile nanoparticle sets out to test whether simultaneous modulation of tumor vasculature and immune systems in the tumor microenvironment has a synergistic effect on tumor suppression. Increased intratumoral infiltration of immune cells following vascular normalization, and simultaneously blocking the immune checkpoint function of PD‐L1 reactivates effective immune responses to the tumors. In summary, the current study provides a new perspective on the regulation of tumor vessel normalization and immunotherapy based on functional peptide nanoparticles as nanomedicine for improved therapeutic purposes.
... 11 The endocytic ligands of STAB1 include SPARC, a protein that modulates progression of various cancers. 12,13 Meanwhile, the cancer-promoting role of STAB1 has been demonstrated in B16 melanoma and EL-4 lymphoma mouse models. 14 Until now, the potential impact of STAB1 expression on the prognosis of CN-AML has not been examined. ...
Cytogenetically normal acute myeloid leukemia (CN-AML) presents with diverse outcomes in different patients and is categorized as an intermediate prognosis group. It is important to identify prognostic factors for CN-AML risk stratification. In this study, using the TCGA CN-AML dataset, we found that the scavenger receptor stabilin-1 (STAB1) is a prognostic factor for poor outcomes and validated it in three other independent CN-AML datasets. The high STAB1 expression (STAB1high) group had shorter event-free survival compared with the low STAB1 expression (STAB1low) group in both the TCGA dataset (n = 79; p = 0.0478) and GEO: GSE6891 dataset (n = 187; p = 0.0354). Differential expression analysis between the STAB1high and STAB1low groups revealed that upregulated genes in the STAB1high group were enriched in pathways related to cell adhesion and migration and immune responses. We confirmed that STAB1 suppression inhibits cell growth in KG1a and NB4 leukemia cells. Expression correlation analyses between STAB1 and cancer drug targets suggested that patients in the STAB1low group are more sensitive to the BCL2 inhibitor venetoclax, and we confirmed it in cell lines. In conclusion, we identified STAB1 as a prognostic factor for CN-AML in multiple datasets, explored its underlying mechanism, and provided potential therapeutic indications.
... In addition, the ∆ (Cys83 Cys99) rhChM-1 mutant lacking the 17 amino acid residues from Cys 83 -Cys 99 and but retained three disulfide bonds, still appeared to exhibit its inhibitory effect [37]. Similarly, Chlenski et al. [20] designed and synthesized two peptides consisting of FSEC (CELDENNTPMC) and FSEN (CQNHAKHGKVC) from FS-E (CQNHCKHGKVCELDENNTPMC) by linking Cys 1 to Cys 3 and Cys 2 to Cys 4, owing to the need to construct simpler peptides with less complex structures. FS-E is classified in the group of secreted protein acidic and rich in cysteine (SPARC). ...
... FS-E is classified in the group of secreted protein acidic and rich in cysteine (SPARC). In this study [20], the authors divided the experimental processes into three parts including: (i) endothelial cell migration assay (ii) inhibition of neuroblastoma tumor growth and (iii) inhibition of tumor induced angiogenesis. Firstly, in order to evaluate the capability of the two simple peptides to inhibit endothelial cell migration, HUVEC were treated with serial dilution of FSEC and FSEN by monitoring the percentage of stimulation compared with beta-fibroblast growth factor (bFGF) as a positive control. ...
... Meanwhile, K5mut2 lacking one Cys, lost all its inhibitory effects. In summary, anti-angiogenic peptides containing Cys residues that formed disulfide bonds play an important role in (i) inhibiting blood vessel proliferation through the activation of angiostatin contributes to a lack of nutrients and blood supply to tumor cells [20,42], (ii) increasing anti-angiogenesis via reduction of specific receptors for pro-angiogenic molecules, (iii) inducing cell apoptosis [35,43], and (iv) balancing opposing signals in the tumor microenvironment [44]. Although our prediction model showed that Cys is the most important amino acid for the inhibition of blood vessel proliferation and tumor growth, other peptides which does not contain Cys have also demonstrated anti-angiogenic activity. ...
Cancer remains one of the major causes of death worldwide. Angiogenesis is crucial for the pathogenesis of various human diseases, especially solid tumors. The discovery of anti-angiogenic peptides is a promising therapeutic route for cancer treatment. Thus, reliably identifying anti-angiogenic peptides is extremely important for understanding their biophysical and biochemical properties that serve as the basis for the discovery of new anti-cancer drugs. This study aims to develop an efficient and interpretable computational model called TargetAntiAngio for predicting and characterizing anti-angiogenic peptides. TargetAntiAngio was developed using the random forest classifier in conjunction with various classes of peptide features. It was observed via an independent validation test that TargetAntiAngio can identify anti-angiogenic peptides with an average accuracy of 77.50% on an objective benchmark dataset. Comparisons demonstrated that TargetAntiAngio is superior to other existing methods. In addition, results revealed the following important characteristics of anti-angiogenic peptides: (i) disulfide bond forming Cys residues play an important role for inhibiting blood vessel proliferation; (ii) Cys located at the C-terminal domain can decrease endothelial formatting activity and suppress tumor growth; and (iii) Cyclic disulfide-rich peptides contribute to the inhibition of angiogenesis and cell migration, selectivity and stability. Finally, for the convenience of experimental scientists, the TargetAntiAngio web server was established and made freely available online.
... It has been reported that the deletion of the SPARC N terminal acidic domain decreased the migration of glioma cells [49]. The follistatin-like domain blocked angiogenesis and plays a remarkable role in growth inhibition of neuroblastoma tumors [50]. The C-terminal domain of SPARC inhibited the spreading of human urothelial cells [51]. ...
Migration and metastasis of tumor cells greatly contributes to the failure of cancer treatment. Recently, the extracellular protein secreted protein acidic and rich in cysteine (SPARC) has been reported closely related to tumorigenesis. Some articles have suggested that SPARC promoted metastasis in several highly metastatic tumors. However, there are also some studies shown that SPARC acted as an antitumor factor. SPARC‐induced epithelial‐to‐mesenchymal transition (EMT) in melanoma cells and promoted EMT in hepatocellular carcinoma. Therefore, the role of SPARC in tumorigenesis and its relationship with EMT is still unclear. In this study, we investigated the expression change of SPARC in A549 and H1299 lung cancer cells undergoing EMT process. Our study indicated that SPARC was upregulated in A549 and H1299 cells EMT process. We further investigated the function of SPARC on proliferation, migration, and EMT process of A549 and H1299 cells. Overexpression of SPARC promoted the migration and EMT of A549 and H1299 cells. Knockdown SPARC inhibited the EMT of A549 cells. Overexpression of SPARC induced the increased expression of p‐Akt and P‐ERK. Furthermore, exogenous SPARC peptide promoted transforming growth factor (TGF)‐β1‐induced EMT of A549 and H1299 cells. SPARC knockdown partially eliminated TGF‐β1 function in inducing EMT of A549 cells. SPARC follistatin‐like functional domain reduced the expression of E‐cadherin, but had no effect on the expression of p‐Akt and p‐ERK. In conclusion, we elucidated that SPARC contributes to tumorigenesis by promoting migration and EMT of A549 and H1299 lung cancer cells. These results will provide some new suggestion for lung cancer treatment.
