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Cancer Research May 2023Glioblastomas (GBM) are aggressive brain tumors with extensive intratumoral heterogeneity that contributes to treatment resistance. Spatial characterization of GBMs...
UNLABELLED
Glioblastomas (GBM) are aggressive brain tumors with extensive intratumoral heterogeneity that contributes to treatment resistance. Spatial characterization of GBMs could provide insights into the role of the brain tumor microenvironment in regulating intratumoral heterogeneity. Here, we performed spatial transcriptomic and single-cell analyses of the mouse and human GBM microenvironment to dissect the impact of distinct anatomical regions of brains on GBM. In a syngeneic GBM mouse model, spatial transcriptomics revealed that numerous extracellular matrix (ECM) molecules, including biglycan, were elevated in areas infiltrated with brain tumor-initiating cells (BTIC). Single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin using sequencing showed that ECM molecules were differentially expressed by GBM cells based on their differentiation and cellular programming phenotypes. Exogeneous biglycan or overexpression of biglycan resulted in a higher proliferation rate of BTICs, which was associated mechanistically with low-density lipoprotein receptor-related protein 6 (LRP6) binding and activation of the Wnt/β-catenin pathway. Biglycan-overexpressing BTICs developed into larger tumors and displayed mesenchymal phenotypes when implanted intracranially in mice. This study points to the spatial heterogeneity of ECM molecules in GBM and suggests that the biglycan-LRP6 axis could be a therapeutic target to curb tumor growth.
SIGNIFICANCE
Characterization of the spatial heterogeneity of glioblastoma identifies regulators of brain tumor-initiating cells and tumor growth that could serve as candidates for therapeutic interventions to improve the prognosis of patients.
Topics: Humans; Animals; Mice; Biglycan; Glioblastoma; Brain Neoplasms; Brain; Spatial Analysis; Cell Proliferation; Tumor Microenvironment
PubMed: 37067922
DOI: 10.1158/0008-5472.CAN-22-3004 -
Osteoarthritis and Cartilage Aug 2021To delineate the activities of decorin and biglycan in the progression of post-traumatic osteoarthritis (PTOA).
OBJECTIVE
To delineate the activities of decorin and biglycan in the progression of post-traumatic osteoarthritis (PTOA).
DESIGN
Three-month-old inducible biglycan (Bgn) and decorin/biglycan compound (Dcn/Bgn) knockout mice were subjected to the destabilization of the medial meniscus (DMM) surgery to induce PTOA. The OA phenotype was evaluated by assessing joint structure and sulfated glycosaminoglycan (sGAG) staining via histology, surface collagen fibril nanostructure and calcium content via scanning electron microscopy, tissue modulus via atomic force microscopy-nanoindentation, as well as subchondral bone structure and meniscus ossification via micro-computed tomography. Outcomes were compared with previous findings in the inducible decorin (Dcn) knockout mice.
RESULTS
In the DMM model, Bgn mice developed similar degree of OA as the control (0.44 [-0.18 1.05] difference in modified Mankin score), different from the more severe OA phenotype observed in Dcn mice (1.38 [0.91 1.85] difference). Dcn/Bgn mice exhibited similar histological OA phenotype as Dcn mice (1.51 [0.97 2.04] difference vs control), including aggravated loss of sGAGs, salient surface fibrillation and formation of osteophyte. Meanwhile, Dcn/Bgn mice showed further cartilage thinning than Dcn mice, resulting in the exposure of underlying calcified tissues and aberrantly high surface modulus. Bgn and Dcn/Bgn mice developed altered subchondral trabecular bone structure in both Sham and DMM groups, while Dcn and control mice did not.
CONCLUSION
In PTOA, decorin plays a more crucial role than biglycan in regulating cartilage degeneration, while biglycan is more important in regulating subchondral bone structure. The two have distinct activities and modest synergy in the pathogenesis of PTOA.
Topics: Animals; Biglycan; Cancellous Bone; Cartilage, Articular; Decorin; Disease Models, Animal; Disease Progression; Menisci, Tibial; Mice, Knockout; Ossification, Heterotopic; Osteoarthritis; Osteophyte; Tibial Meniscus Injuries; Mice
PubMed: 33915295
DOI: 10.1016/j.joca.2021.03.019 -
Breast Cancer Research : BCR May 2021Biglycan is a proteoglycan found in the extracellular matrix. We have previously shown that biglycan is secreted from tumor endothelial cells and induces tumor...
BACKGROUND
Biglycan is a proteoglycan found in the extracellular matrix. We have previously shown that biglycan is secreted from tumor endothelial cells and induces tumor angiogenesis and metastasis. However, the function of stroma biglycan in breast cancer is still unclear.
METHODS
Biglycan gene analysis and its prognostic values in human breast cancers were based on TCGA data. E0771 breast cancer cells were injected into WT and Bgn KO mice, respectively.
RESULTS
Breast cancer patients with high biglycan expression had worse distant metastasis-free survival. Furthermore, biglycan expression was higher in the tumor stromal compartment compared to the epithelial compartment. Knockout of biglycan in the stroma (Bgn KO) in E0771 tumor-bearing mice inhibited metastasis to the lung. Bgn KO also impaired tumor angiogenesis and normalized tumor vasculature by repressing tumor necrosis factor-ɑ/angiopoietin 2 signaling. Moreover, fibrosis was suppressed and CD8+ T cell infiltration was increased in tumor-bearing Bgn KO mice. Furthermore, chemotherapy drug delivery and efficacy were improved in vivo in Bgn KO mice.
CONCLUSION
Our results suggest that targeting stromal biglycan may yield a potent and superior anticancer effect in breast cancer.
Topics: Angiopoietin-2; Animals; Biglycan; Breast Neoplasms; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Female; Fibrosis; Humans; Mice; Mice, Knockout; Neoplasm Metastasis; Neovascularization, Pathologic; Paclitaxel; Prognosis; Signal Transduction; Stromal Cells; Treatment Outcome; Tumor Microenvironment; Tumor Necrosis Factor-alpha
PubMed: 33966638
DOI: 10.1186/s13058-021-01423-w -
International Journal of Molecular... Mar 2017In its soluble form, the extracellular matrix proteoglycan biglycan triggers the synthesis of the macrophage chemoattractants, chemokine (C-C motif) ligand CCL2 and CCL5...
In its soluble form, the extracellular matrix proteoglycan biglycan triggers the synthesis of the macrophage chemoattractants, chemokine (C-C motif) ligand CCL2 and CCL5 through selective utilization of Toll-like receptors (TLRs) and their adaptor molecules. However, the respective downstream signaling events resulting in biglycan-induced CCL2 and CCL5 production have not yet been defined. Here, we show that biglycan stimulates the production and activation of sphingosine kinase 1 (SphK1) in a TLR4- and Toll/interleukin (IL)-1R domain-containing adaptor inducing interferon (IFN)-β (TRIF)-dependent manner in murine primary macrophages. We provide genetic and pharmacological proof that SphK1 is a crucial downstream mediator of biglycan-triggered CCL2 and CCL5 mRNA and protein expression. This is selectively driven by biglycan/SphK1-dependent phosphorylation of the nuclear factor NF-κB p65 subunit, extracellular signal-regulated kinase (Erk)1/2 and p38 mitogen-activated protein kinases. Importantly, in vivo overexpression of soluble biglycan causes Sphk1-dependent enhancement of renal CCL2 and CCL5 and macrophage recruitment into the kidney. Our findings describe the crosstalk between biglycan- and SphK1-driven extracellular matrix- and lipid-signaling. Thus, SphK1 may represent a new target for therapeutic intervention in biglycan-evoked inflammatory conditions.
Topics: Adaptor Proteins, Vesicular Transport; Animals; Biglycan; Cells, Cultured; Chemokine CCL2; Chemokine CCL5; Extracellular Matrix; HEK293 Cells; Humans; MAP Kinase Signaling System; Macrophages; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphotransferases (Alcohol Group Acceptor); Toll-Like Receptor 4; Transcription Factor RelA; p38 Mitogen-Activated Protein Kinases
PubMed: 28282921
DOI: 10.3390/ijms18030595 -
International Journal of Molecular... Jan 2021Proteoglycan (PG) is a glycosaminoglycan (GAG)-conjugated protein essential for maintaining tissue strength and elasticity. The most abundant skin PGs, biglycan and...
Proteoglycan (PG) is a glycosaminoglycan (GAG)-conjugated protein essential for maintaining tissue strength and elasticity. The most abundant skin PGs, biglycan and decorin, have been reported to decrease as skin ages. Insulin-like growth factor-1 (IGF-1) is important in various physiological functions such as cell survival, growth, and apoptosis. It is well known that the serum level of IGF-1 decreases with age. Therefore, we investigated whether and how IGF-1 affects biglycan and decorin. When primary cultured normal human dermal fibroblasts (NHDFs) were treated with IGF-1, protein levels of biglycan and decorin increased, despite no difference in mRNA expression. This increase was not inhibited by transcription blockade using actinomycin D, suggesting that it is mediated by IGF-1-induced enhanced translation. Additionally, both mRNA and protein expression of ADAMTS5, a PG-degrading enzyme, were decreased in IGF-1-treated NHDFs. Knockdown of ADAMTS5 via RNA interference increased protein expression of biglycan and decorin. Moreover, mRNA and protein expression of ADAMTS5 increased in aged human skin tissues compared to young tissue. Overall, IGF-1 increases biglycan and decorin, which is achieved by improving protein translation to increase synthesis and preventing ADAMTS5-mediated degradation. This suggests a new role of IGF-1 as a regulator for biglycan and decorin in skin aging process.
Topics: ADAMTS5 Protein; Adolescent; Adult; Aged; Aged, 80 and over; Biglycan; Cells, Cultured; Child; Decorin; Down-Regulation; Female; Fibroblasts; Gene Expression Profiling; Gene Knockdown Techniques; Healthy Volunteers; Humans; Insulin-Like Growth Factor I; Male; Primary Cell Culture; Protein Biosynthesis; Proteolysis; Skin; Skin Aging; Up-Regulation; Young Adult
PubMed: 33573338
DOI: 10.3390/ijms22031403 -
Clinical Laboratory Mar 2021Non-alcoholic steatohepatitis (NASH) has risen in prevalence substantially through the years. Although course and progression of the disease are variable, fibrosis is...
BACKGROUND
Non-alcoholic steatohepatitis (NASH) has risen in prevalence substantially through the years. Although course and progression of the disease are variable, fibrosis is the most important factor. We intended to explore utility of serum biglycan (BGN) in NASH and its capacity in anticipating liver fibrosis.
METHODS
Serum tests of consecutive patients with biopsy-confirmed NASH and age, gender-matched healthy volunteers were utilized to evaluate serum BGN levels using ELISA kits. The correlation between BGN and histopathological highlights of NASH was examined. While patients with fibrosis scores < 2 were assembled in mild and scores of (≥ 2) were in significant fibrosis groups. Univariate/multivariate regression analyses were performed to assess the independent predictive variables of liver fibrosis. Receiver operating characteristics (ROC) were applied to locate the best cutoff values of BGN for NASH and fibrosis.
RESULTS
Seventy patients with NASH and 70 controls were recruited in the study. BGN levels were lower in NASH patients contrasted with controls 137.70 ± 33.12 pg/mL vs. 259.61 ± 187.34 pg/mL, respectively, and p < 0.001. In correlation, serum BGN was related to liver fibrosis and inflammation. The comparison between mild and significant fibrosis groups regarding BGN was as follows 155.92 ± 49.97 pg/mL vs. 390.07 ± 214.746 pg/mL, respectively, (p < 0.001). In multivariate analyses, BGN was an independent predictive factor of significant fibrosis (OR, 1.030; 95% CI: 1.011 - 1.048; p < 0.001). ROC analysis revealed that BGN was statistically significant in determination of significant fibrosis (AUROC, 0.955; 95% CI, 0.877 - 0.990; p < 0.001). Best cutoff value was 189.58 pg/mL with the best sensitivity (93.55%) and specificity (87.18%).
CONCLUSIONS
Serum BGN may be a new non-invasive indicative marker for the presence of NASH, significant fibrosis, and a treatment goal in the disease process.
Topics: Biglycan; Biomarkers; Biopsy; Humans; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; ROC Curve
PubMed: 33739030
DOI: 10.7754/Clin.Lab.2020.200709 -
FASEB Journal : Official Publication of... Aug 2021While biglycan (BGN) is suggested to direct diverse signaling cascades, the effects of soluble BGN as a ligand on metabolic traits have not been studied. Herein, we...
While biglycan (BGN) is suggested to direct diverse signaling cascades, the effects of soluble BGN as a ligand on metabolic traits have not been studied. Herein, we tested the effects of BGN on obesity in high-fat diet (HFD)-induced obese animals and glucose metabolism, with the underlying mechanism responsible for observed effects in vitro. Our results showed that BGN administration (1 mg/kg body weight, intraperitoneally) significantly prevented HFD-induced obesity, and this was mainly attributed to reduced food intake. Also, intracerebroventricular injection of BGN reduced food intake and body weight. The underlying mechanism includes modulation of neuropeptides gene expression involved in appetite in the hypothalamus in vitro and in vivo. In addition, BGN regulates glucose metabolism as shown by improved glucose tolerance in mice as well as AMPK/AKT dual pathway-driven enhanced glucose uptake and GLUT4 translocation in L6 myoblast cells. In conclusion, our results suggest BGN as a potential therapeutic target to treat risk factors for metabolic diseases.
Topics: AMP-Activated Protein Kinases; Animals; Biglycan; Cell Line; Feeding Behavior; Glucose; Mice; Mice, Inbred ICR; Muscle, Skeletal; Obesity; Proto-Oncogene Proteins c-akt; Rats
PubMed: 34314059
DOI: 10.1096/fj.202002039RR -
Biochimica Et Biophysica Acta.... Dec 2018Dietary fructose is a major contributor to the epidemic of diabetes and obesity, and it is an excellent model to study metabolic syndrome. Based on previous studies that...
Dietary fructose is a major contributor to the epidemic of diabetes and obesity, and it is an excellent model to study metabolic syndrome. Based on previous studies that Bgn gene occupies a central position in a network of genes in the brain in response to fructose consumption, we assessed the capacity of Bgn to modulate the action of fructose on brain and body. We exposed male biglycan knockout mice (Bgn) to fructose for 7 weeks, and results showed that Bgn mice compensated for a decrement in learning and memory performance when exposed to fructose. These results were consistent with an attenuation of the action of fructose on hippocampal CREB levels. Fructose also reduced the levels of CREB and BDNF in primary hippocampal neuronal cultures. Bgn siRNA treatment abolished these effects of fructose on CREB and BDNF levels, in conjunction with a reduction in a fructose-related increase in Bgn protein. In addition, fructose consumption perturbed the systemic metabolism of glucose and lipids, that were also altered in the Bgn mice. Transcriptomic profiling of hypothalamus, hippocampus, and liver supported the regulatory action of Bgn on key molecular pathways involved in metabolism, immune response, and neuronal plasticity. Overall results underscore the tissue-specific role of the extracellular matrix in the regulation of metabolism and brain function, and support Bgn as a key modulator for the impact of fructose across body and brain.
Topics: Animals; Biglycan; Body Composition; Brain Diseases; Cells, Cultured; Cyclic AMP Response Element-Binding Protein; Fructose; Gene Expression Profiling; Glucose; Glucose Intolerance; Lipid Metabolism; Liver; Male; Maze Learning; Metabolic Networks and Pathways; Mice, Knockout
PubMed: 30291886
DOI: 10.1016/j.bbadis.2018.10.002 -
Journal of Orthopaedic Research :... Oct 2023Biglycan, a small leucine-rich proteoglycan (SLRP), is involved in collagen fibrillogenesis and also acts as a signaling molecule. Although decorin has been considered...
Biglycan, a small leucine-rich proteoglycan (SLRP), is involved in collagen fibrillogenesis and also acts as a signaling molecule. Although decorin has been considered as the primary SLRP in developing and maintaining tendon structure and mechanics, more recent work using inducible knockdown models suggests that biglycan is involved in tendon homeostasis. The purpose of the study was to determine the role of biglycan in tendon homeostasis to maintain mechanical and structural integrity in aged mice. Aged (485 days old) female Bgn control (wild type [WT], n = 16) and 16 bitransgenic conditional Bgn mice (I-Bgn , n = 16) with a tamoxifen-inducible Cre (driven by ROSA) were utilized. After biglycan knockdown, the transgenic model demonstrated effective knockdown of the target gene without any compensation from other SLRPs or type I collagen. Patellar tendon cellularity was not modified after biglycan knockdown. However, biglycan knockdown had an impact on collagen fibrillogenesis with a higher percentage of small diameter fibrils (25-45 nm) and a lower percentage of medium size fibrils (150-165 nm) in I-Bgn tendons. Biglycan knockdown also induced a reduction in the midsubstance modulus and maximum stress compared to WT. Stress relaxation was reduced at 4% strain in I-Bgn tendons but no changes were observed in dynamic modulus and tan delta. As in mature tendons (120 days old), this study showed significant effects of biglycan knockdown on mechanical and structural properties of aged tendons only 30 days after knockdown. These data suggest that biglycan has a major role in maintaining homeostasis in aged tendon.
Topics: Female; Mice; Animals; Biglycan; Decorin; Biomechanical Phenomena; Tendons; Collagen; Aging; Extracellular Matrix Proteins
PubMed: 36822659
DOI: 10.1002/jor.25536 -
Experimental Dermatology Jan 2024Alopecia is a prevalent problem of cutaneous appendages and lacks effective therapy. Recently, researchers have been focusing on mesenchymal components of the hair...
Alopecia is a prevalent problem of cutaneous appendages and lacks effective therapy. Recently, researchers have been focusing on mesenchymal components of the hair follicle, i.e. dermal papilla cells, and we previously identified biglycan secreted by dermal papilla cells as the key factor responsible for hair follicle-inducing ability. In this research, we hypothesized biglycan played an important role in hair follicle cycle and regeneration through regulating the Wnt signalling pathway. To characterize the hair follicle cycle and the expression pattern of biglycan, we observed hair follicle morphology in C57BL/6 mice on Days 0, 3, 5, 12 and 18 post-depilation and found that biglycan is highly expressed at both mRNA and protein levels throughout anagen in HFs. To explore the role of biglycan during the phase transit process and regeneration, local injections were administered in C57BL/6 and nude mice. Results showed that local injection of biglycan in anagen HFs delayed catagen progression and involve activating the Wnt/β-catenin signalling pathway. Furthermore, local injection of biglycan induced HF regeneration and up-regulated expression of key Wnt factors in nude mice. In addition, cell analyses exhibited biglycan knockdown inactivated the Wnt signalling pathway in early-passage dermal papilla cell, whereas biglycan overexpression or incubation activated the Wnt signalling pathway in late-passage dermal papilla cells. These results indicate that biglycan plays a critical role in regulating HF cycle transit and regeneration in a paracrine and autocrine fashion by activating the Wnt/β-catenin signalling pathway and could be a potential treatment target for hair loss diseases.
Topics: Mice; Animals; Hair Follicle; beta Catenin; Mice, Nude; Biglycan; Mice, Inbred C57BL; Wnt Signaling Pathway; Alopecia; Regeneration; Cell Proliferation
PubMed: 37967213
DOI: 10.1111/exd.14969