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Cancer Cell Dec 2020To what extent stromal cells in the tumor microenvironment (TME) are transformed by colorectal cancer (CRC) cells is unexplored. To dissect alterations in these...
To what extent stromal cells in the tumor microenvironment (TME) are transformed by colorectal cancer (CRC) cells is unexplored. To dissect alterations in these non-malignant cells, we performed single-cell multiomics sequencing of 21 patients with microsatellite-stable CRCs and 6 cancer-free, elderly individuals. Surprisingly, somatic copy number alterations (SCNAs) are prevalent in immune cells, fibroblasts, and endothelial cells in both the TME and the normal tissues of each individual. Moreover, the proportions of fibroblasts with SCNAs in tumors (11.1%-47.7%) are much higher than those in adjacent normal tissues (1.1%-10.6%), with gain of chromosome 7 strongly enriched in the TME, clearly indicating clonal expansion. Furthermore, five genes (BGN, RCN3, TAGLN, MYL9, and TPM2) are identified as fibroblast-specific biomarkers of poorer prognosis of CRC. Our study provides evidence and functional relevance of pervasive genomic alterations in the stromal cells of TME in CRC.
Topics: Biglycan; Biomarkers, Tumor; Calcium-Binding Proteins; Case-Control Studies; Chromosomes, Human, Pair 7; Colorectal Neoplasms; DNA Copy Number Variations; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; Microfilament Proteins; Muscle Proteins; Myosin Light Chains; Prognosis; Sequence Analysis, RNA; Single-Cell Analysis; Stromal Cells; Tropomyosin; Tumor Microenvironment
PubMed: 33096021
DOI: 10.1016/j.ccell.2020.09.015 -
The Journal of Histochemistry and... Nov 2020Small leucine rich proteoglycans (SLRPs), including Biglycan, have key roles in many organ and tissue systems. The goal of this article is to review the function of... (Review)
Review
Small leucine rich proteoglycans (SLRPs), including Biglycan, have key roles in many organ and tissue systems. The goal of this article is to review the function of Biglycan and other related SLRPs in mineralizing tissues of the skeleton. The review is divided into sections that include Biglycan's role in structural biology, signaling, craniofacial and long bone homeostasis, remodeled skeletal tissues, and in human genetics. While many cell types in the skeleton are now known to be affected by Biglycan, there are still unanswered questions about its mechanism of action(s).
Topics: Animals; Biglycan; Humans; Muscle, Skeletal
PubMed: 32623936
DOI: 10.1369/0022155420937371 -
Oncoimmunology 2022Cancer-associated fibroblasts (CAFs) are essential for tumor microenvironment remodeling and correlate with tumor progression. However, interactions between CAFs and...
Cancer-associated fibroblasts (CAFs) are essential for tumor microenvironment remodeling and correlate with tumor progression. However, interactions between CAFs and tumor cells and immune cells in triple-negative breast cancer (TNBC) are still poorly explored. Here, we investigate the role of CAFs in TNBC and potential novel mediators of their functions. The clustering of classic markers was applied to estimate the relative abundance of CAFs in TNBC cohorts. Primary fibroblasts were isolated from normal and tumor samples. The RNA and culture medium of fibroblasts were subjected to RNA sequencing and mass spectrometry to explore the upregulated signatures in CAFs. Microdissection and single-cell RNA sequencing datasets were used to examine the expression profiles. CAFs were associated with hallmark signalings and immune components in TNBC. Clustering based on CAF markers in the literature revealed different CAF infiltration groups in TNBC: low, medium and high. Most of the cancer hallmark signaling pathways were enriched in the high CAF infiltration group. Furthermore, RNA sequencing and mass spectrometry identified biglycan (BGN), a soluble secreted protein, as upregulated in CAFs compared to normal cancer-adjacent fibroblasts (NAFs). The expression of biglycan was negatively correlated with CD8 + T cells. Biglycan indicated poor prognostic outcomes and might be correlated with the immunosuppressive tumor microenvironment (TME). In conclusion, CAFs play an essential role in tumor progression and the TME. We identified an extracellular protein, biglycan, as a prognostic marker and potential therapeutic target in TNBC.
Topics: Biglycan; Cancer-Associated Fibroblasts; Fibroblasts; Humans; Triple Negative Breast Neoplasms; Tumor Microenvironment
PubMed: 35003899
DOI: 10.1080/2162402X.2021.2020984 -
International Journal of Biological... 2023Peritoneal metastasis (PM) is most frequent in gastric cancer (GC) and cancer-associated fibroblasts (CAFs) play a critical role in this process. However, the concrete...
Peritoneal metastasis (PM) is most frequent in gastric cancer (GC) and cancer-associated fibroblasts (CAFs) play a critical role in this process. However, the concrete mechanism of crosstalk between CAFs and cancer cells in PM of GC remains unclear. Microarray sequencing of GC focus and PM lesions was performed, and biglycan (BGN) was screened for further study. Clinically, BGN expression was higher in GC tissues than adjacent normal tissues, and high expression correlated with poor prognosis. experiments demonstrated that BGN promoted tumor progression and the transformation of mesothelial cells (MCs) into cancer-associated fibroblasts like cells (CAFLCs). In turn, CAFLCs-derived fibroblast activation protein (FAP) facilitated the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of GC cells. GC-derived BGN combined with toll like receptor 2 (TLR2)/TLR4 on MCs to activate the NF-κB pathway and promote the transformation of MCs into CAFLCs by the recovery experiment, coimmunoprecipitation assay, nuclear and cytoplasmic protein extraction assay. CAFLCs-derived FAP could activate the JAK2/STAT3 signaling pathway in GC. Finally, activated STAT3 promoted BGN transcription in GC, resulting in a BGN/FAP-STAT3 positive feedback loop. Taken together, mutual interaction between tumor cells and activated MCs mediated by a BGN/FAP-STAT3 positive feedback loop facilitates PM of GC and provides a potential biomarker and therapeutic target for GC metastasis.
Topics: Humans; Biglycan; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Peritoneal Neoplasms; Signal Transduction; STAT3 Transcription Factor; Stomach Neoplasms; Feedback, Physiological
PubMed: 36632455
DOI: 10.7150/ijbs.72218 -
Frontiers in Oncology 2021The complex and adaptive nature of malignant neoplasm constitute a major challenge for the development of effective anti-oncogenic therapies. Emerging evidence has... (Review)
Review
The complex and adaptive nature of malignant neoplasm constitute a major challenge for the development of effective anti-oncogenic therapies. Emerging evidence has uncovered the pivotal functions exerted by the small leucine-rich proteoglycans, decorin and biglycan, in affecting tumor growth and progression. In their soluble forms, decorin and biglycan act as powerful signaling molecules. By receptor-mediated signal transduction, both proteoglycans modulate key processes vital for tumor initiation and progression, such as autophagy, inflammation, cell-cycle, apoptosis, and angiogenesis. Despite of their structural homology, these two proteoglycans interact with distinct cell surface receptors and thus modulate distinct signaling pathways that ultimately affect cancer development. In this review, we summarize growing evidence for the complex roles of decorin and biglycan signaling in tumor biology and address potential novel therapeutic implications.
PubMed: 34917515
DOI: 10.3389/fonc.2021.801801 -
American Journal of Physiology. Cell... Jun 2022The class I small leucine-rich proteoglycan biglycan is a crucial structural extracellular matrix component that interacts with a wide range of extracellular matrix... (Review)
Review
The class I small leucine-rich proteoglycan biglycan is a crucial structural extracellular matrix component that interacts with a wide range of extracellular matrix molecules. In addition, biglycan is involved in sequestering growth factors such as transforming growth factor-β and bone morphogenetic proteins and thereby regulating pathway activity. Biglycan consists of a 42-kDa core protein linked to two glycosaminoglycan side chains and both are involved in protein interactions. Biglycan is encoded by the gene located on the X-chromosome and is expressed in various tissues, including vascular tissue, skin, brain, kidney, lung, the immune system, and the musculoskeletal system. Although an increasing amount of data on the biological function of biglycan in the vasculature has been produced, its role in thoracic aortic aneurysms is still not fully elucidated. This review focuses on the role of biglycan in the healthy thoracic aorta and the development of thoracic aortic aneurysm and dissections in both mice and humans.
Topics: Animals; Aorta, Thoracic; Biglycan; Bone Morphogenetic Proteins; Extracellular Matrix Proteins; Mice; Signal Transduction; Transforming Growth Factor beta
PubMed: 35476501
DOI: 10.1152/ajpcell.00036.2022 -
Frontiers in Physiology 2023Endochondral bone development and regeneration relies on activation and proliferation of periosteum derived-cells (PDCs). Biglycan (Bgn), a small proteoglycan found in...
Endochondral bone development and regeneration relies on activation and proliferation of periosteum derived-cells (PDCs). Biglycan (Bgn), a small proteoglycan found in extracellular matrix, is known to be expressed in bone and cartilage, however little is known about its influence during bone development. Here we link biglycan with osteoblast maturation starting during embryonic development that later affects bone integrity and strength. Biglycan gene deletion reduced the inflammatory response after fracture, leading to impaired periosteal expansion and callus formation. Using a novel 3D scaffold with PDCs, we found that biglycan could be important for the cartilage phase preceding bone formation. The absence of biglycan led to accelerated bone development with high levels of osteopontin, which appeared to be detrimental to the structural integrity of the bone. Collectively, our study identifies biglycan as an influencing factor in PDCs activation during bone development and bone regeneration after fracture.
PubMed: 36875017
DOI: 10.3389/fphys.2023.1119368 -
Oncoimmunology 2023Myelodysplastic syndromes (MDS) and their progression to secondary acute myeloid leukemia (sAML) are associated with an altered protein expression including...
Myelodysplastic syndromes (MDS) and their progression to secondary acute myeloid leukemia (sAML) are associated with an altered protein expression including extracellular matrix (ECM) components thereby promoting an inflammatory environment. Since the role of the proteoglycan biglycan (BGN) as an inflammatory mediator has not yet been investigated in both diseases and might play a role in disease progression, its expression and/or function was determined in cell lines and bone marrow biopsies (BMBs) of MDS and sAML patients and subpopulations of MDS stem cells by Western blot and immunohistochemistry. The bone marrow (BM) microenvironment was analyzed by multispectral imaging, patients' survival by Cox regression. ROC curves were assessed for diagnostic value of BGN. All cell lines showed a strong BGN surface expression in contrast to only marginal expression levels in mononuclear cells and CD34 cells from healthy donors. In the MDS-L cell line, CD34CD33 and CD34CD33 blast subpopulations exhibited a differential BGN surface detection. Increased BGN mediated inflammasome activity of CD34CD33TLR4 cells was observed, which was inhibited by direct targeting of BGN or NLRP3. BGN was heterogeneously expressed in BMBs of MDS and sAML, but was not detected in control biopsies. BGN expression in BMBs positively correlated with MUM1 and CD8, but negatively with CD33TLR4 cell infiltration and was accompanied by a decreased progression-free survival of MDS patients. BGN-mediated inflammasome activation appears to be a crucial mechanism in MDS pathogenesis implicating its use as suitable biomarker and potential therapeutic target. Ab, antibody; alloSCT, allogenic stem cell transplant; AML, acute myeloid leukemia; BGN, biglycan; BM, bone marrow; BMB, bone marrow biopsy; casp1, caspase 1; CTLA-4, cytotoxic T lymphocyte-associated protein 4; DAMP, danger-associated molecular pattern; ECM, extracellular matrix; FCS, fetal calf serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HD, healthy donor; HSPC, hematopoietic stem and progenitor cell; HSC, hematopoietic stem cell; IFN, interferon; IHC, immunohistochemistry; IL, interleukin; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; MSI, multispectral imaging; NGS, next-generation sequencing; NLRP3, NLR family pyrin domain containing 3; OS, overall survival; PBMC, peripheral blood mononuclear cell; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1, PFS, progression-free survival; PRR, pattern recognition receptor; SC, stem cell; SLRP, small leucine-rich proteoglycan; TGF, transforming growth factor; TIRAP, toll/interleukin 1 receptor domain-containing adapter protein; TLR, toll-like receptor; Treg, regulatory T cell.
Topics: Humans; Leukocytes, Mononuclear; Biglycan; Toll-Like Receptor 4; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammasomes; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Antigens, CD34; Neoplasms, Second Primary; Caspase 1; Tumor Microenvironment
PubMed: 36531688
DOI: 10.1080/2162402X.2022.2152998 -
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 -
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