scholarly journals Glioma Cells Acquire Stem-like Characters by Extrinsic Ribosome Stimuli

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2970
Author(s):  
Yuki Shirakawa ◽  
Kunimasa Ohta ◽  
Shunsuke Miyake ◽  
Ayumi Kanemaru ◽  
Akari Kuwano ◽  
...  
Keyword(s):  
Stem Cell ◽  
Ribosomal Protein ◽  
Ribosomal Proteins ◽  
Molecular Mechanisms ◽  
High Grade Glioma ◽  
Stem Cell Markers ◽  
Perivascular Niche ◽  
Cell Spheroid ◽  
Stat3 Phosphorylation ◽  
Rps6 Phosphorylation

Although glioblastoma (GBM) stem-like cells (GSCs), which retain chemo-radio resistance and recurrence, are key prognostic factors in GBM patients, the molecular mechanisms of GSC development are largely unknown. Recently, several studies revealed that extrinsic ribosome incorporation into somatic cells resulted in stem cell properties and served as a key trigger and factor for the cell reprogramming process. In this study, we aimed to investigate the mechanisms underlying GSCs development by focusing on extrinsic ribosome incorporation into GBM cells. Ribosome-induced cancer cell spheroid (RICCS) formation was significantly upregulated by ribosome incorporation. RICCS showed the stem-like cell characters (number of cell spheroid, stem cell markers, and ability for trans differentiation towards adipocytes and osteocytes). In RICCS, the phosphorylation and protein expression of ribosomal protein S6 (RPS6), an intrinsic ribosomal protein, and STAT3 phosphorylation were upregulated, and involved in the regulation of cell spheroid formation. Consistent with those results, glioma-derived extrinsic ribosome also promoted GBM-RICCS formation through intrinsic RPS6 phosphorylation. Moreover, in glioma patients, RPS6 phosphorylation was dominantly observed in high-grade glioma tissues, and predominantly upregulated in GSCs niches, such as the perinecrosis niche and perivascular niche. Those results indicate the potential biological and clinical significance of extrinsic ribosomal proteins in GSC development.

scholarly journals PCGF1 promotes epigenetic activation of stemness markers and colorectal cancer stem cell enrichment

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Guangyu Ji ◽  
Wenjuan Zhou ◽  
Jingyi Du ◽  
Juan Zhou ◽  
Dong Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cell ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Tumour Progression ◽  
Stem Cell Markers ◽  
Epigenetic Regulator ◽  
Cell Enrichment ◽  
Histone Trimethylation

AbstractColorectal cancer (CRC) stem cells are resistant to cancer therapy and are therefore responsible for tumour progression after conventional therapy fails. However, the molecular mechanisms underlying the maintenance of stemness are poorly understood. In this study, we identified PCGF1 as a crucial epigenetic regulator that sustains the stem cell-like phenotype of CRC. PCGF1 expression was increased in CRC and was significantly correlated with cancer progression and poor prognosis in CRC patients. PCGF1 knockdown inhibited CRC stem cell proliferation and CRC stem cell enrichment. Importantly, PCGF1 silencing impaired tumour growth in vivo. Mechanistically, PCGF1 bound to the promoters of CRC stem cell markers and activated their transcription by increasing the H3K4 histone trimethylation (H3K4me3) marks and decreasing the H3K27 histone trimethylation (H3K27me3) marks on their promoters by increasing expression of the H3K4me3 methyltransferase KMT2A and the H3K27me3 demethylase KDM6A. Our findings suggest that PCGF1 is a potential therapeutic target for CRC treatment.

scholarly journals TMIC-57. PRO-TUMORAL EFFECTS OF INTRA-TUMORAL NEUTROPHILS IN THE GLIOBLASTOMA MICROENVIRONMENT

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi260-vi260
Author(s):  
Sumedh Shah ◽  
Garima Yagnik ◽  
Alan Nguyen ◽  
Harsh Wadhwa ◽  
Jordan Spatz ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Flow Cytometric Analysis ◽  
Leukotriene B4 ◽  
Low Grade ◽  
Stem Cell Markers ◽  
Perivascular Niche ◽  
Migration Assay

Abstract While macrophage enrichment and lymphocyte depletion have been described in glioblastoma, intratumoral neutrophils and their effect on glioblastoma have been under-characterized. While tumor-associated neutrophils (TANs) were initially regarded as passive bystanders due to their short-lived nature, investigation of TANs in other cancer types revealed pro-tumoral roles. Therefore, we sought to characterize TANs in the glioblastoma microenvironment using transcriptomic analysis and define their oncologic effects. Flow cytometric analysis of patient samples for neutrophils (CD11b+/CD15+/CD66b+) revealed higher percentages of TANs in glioblastoma compared to low-grade gliomas (1.76% [n=13] vs. 0.33% [n=6], p=0.03). Using the Transwell migration assay with glioblastoma tumor conditioned-media (CM), we found that recruitment of circulating neutrophils to tumor sites is mediated by leukotriene-B4 chemoattraction and that this interaction can be blocked with the addition of LtB4 receptor antagonist, LY293111. TANs were morphologically activated, unlike circulating neutrophils from GBM patients (P< 0.05) and, while not intravascular, were close to blood vessels. We performed single-cell RNA sequencing of isolated TANs and found a distinct transcriptomic profile relative to circulating neutrophils from these patients, particularly upregulated osteopontin. Osteopontin concentration was significantly higher in TAN CM than in patient-matched peripheral blood neutrophil CM (3.2ng/mL [n=3] vs. 0.02ng/mL [n=3], p< 0.05). Because osteopontin is linked to GBM stem cell-like phenotype maintenance and TANs localized to the perivascular niche where GBM stem cells reside, we investigated TAN-GBM stem cell interactions and osteopontin as a potential mediator. We found TAN CM increased proliferation and stem cell markers (Nanog, Oct4, Sox2) of stem cell-containing GBM neurospheres (p< 0.01). These effects were blocked by osteopontin-neutralizing antibodies (p< 0.01). Our work defines neutrophil-mediated pro-tumoral effects and their mechanisms and identifies a novel approach to target GBM stem cells—by disrupting the immune cell mediators that create their supportive microenvironment in the perivascular niche.

scholarly journals Identification of Novel Cancer Stem Cell Markers in Glioblastoma by Comparing Tumor Cells with Stem-cell-like Cell Lines

2021 ◽  
Vol 11 (2) ◽  
pp. 1567-1583
Author(s):  
Divya G.
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Tumor Cells ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Cell Attachment ◽  
Microarray Dataset ◽  
Gene Expression Omnibus ◽  
Stem Cell Markers ◽  
Cancer Stem Cell Markers

Aim. The aim of this study is to identify differential gene expression for glioblastoma tumor cells, normoxic and hypoxic glioblastoma stem-like cell lines. Finding the upregulated and downregulated gene and pathway interactions. Analysis to find the differential expression genes and pathway interactions. Materials and methods. The gene expression profiling data from the microarray dataset GSE45117 from the Gene Expression Omnibus (GEO) database, as well as differentially expressed genes (DEGs) between the 2 categories, are used in this analysis. 4 Samples of Glioblastoma tumors were considered as group 1 and 4 samples of normoxic and Hypoxic glioblastoma stem-like cell lines were considered as group 2 in the GEO2R web tool that has been used to screen them. Results. The gene-gene interactions among the DEGs and the GGI network with 37 nodes and 13 edges. The stem-cell-like cell lines showed lower expression of endothelin-related genes such as EDN3 and EDNRA along with dysregulation of enzymes such as PDK1, PGK1 which points to dysregulation of cellular respiratory pathways. This effect in consensus with under expression of cell attachment genes such as COL2A1, COL5A2, COL15A1 denotes a strong shift toward metastasis. Conclusion. Thus, a computational pipeline for identifying the significant genes and pathways involved in the glioblastoma tumors and glioblastoma stem-like cell lines. This study provides a path towards discovering potential leads for the treatment of glioblastoma and aids in comprehending the underlying novel molecular mechanisms.

scholarly journals Stem cell characteristics promote aggressiveness of diffuse large B-cell lymphoma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kung-Chao Chang ◽  
Ruo-Yu Chen ◽  
Yu-Chu Wang ◽  
Liang-Yi Hung ◽  
L. Jeffrey Medeiros ◽  
...  
Keyword(s):  
Stem Cell ◽  
B Cell ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Tumor Formation ◽  
Stem Cell Markers ◽  
Large B Cell Lymphoma ◽  
Large B Cell

AbstractDiffuse large B-cell lymphoma (DLBCL) may present initially in bone marrow, liver and spleen without any lymphadenopathy (referred to as BLS-type DLBCL), which is aggressive and frequently associated with hemophagocytic syndrome. Its tumorigenesis and molecular mechanisms warrant clarification. By gene microarray profiling with bioinformatics analysis, we found higher expression of the stem cell markers HOXA9 and NANOG, as well as BMP8B, CCR6 and S100A8 in BLS-type than conventional DLBCL. We further validated expression of these markers in a large cohort of DLBCL including BLS-type cases and found that expression of HOXA9 and NANOG correlated with inferior outcome and poor prognostic parameters. Functional studies with gene-overexpressed and gene-silenced DLBCL cell lines showed that expression of NANOG and HOXA9 promoted cell viability and inhibited apoptosis through suppression of G2 arrest in vitro and enhanced tumor formation and hepatosplenic infiltration in a tail-vein-injected mouse model. Additionally, HOXA9-transfected tumor cells showed significantly increased soft-agar clonogenic ability and tumor sphere formation. Interestingly, B cells with higher CCR6 expression revealed a higher chemotactic migration for CCL20. Taken together, our findings support the concept that tumor or precursor cells of BLS-type DLBCL are attracted by chemotaxis and home to the bone marrow, where the microenvironment promotes the expression of stem cell characteristics and aggressiveness of tumor cells.

scholarly journals Gastric Stem Cell and Cellular Origin of Cancer

Biomedicines ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 100 ◽  
Author(s):  
Masahiro Hata ◽  
Yoku Hayakawa ◽  
Kazuhiko Koike
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Stem Cell Markers ◽  
Cell Markers ◽  
Cellular Origin ◽  
Cell Niche ◽  
Stem Cell Populations ◽  
G Protein Coupled

Several stem cell markers within the gastrointestinal epithelium have been identified in mice. One of the best characterized is Lgr5 (leucine-rich repeat-containing G-protein coupled receptor 5) and evidence suggests that Lgr5+ cells in the gut are the origin of gastrointestinal cancers. Reserve or facultative stem or progenitor cells with the ability to convert to Lgr5+ cells following injury have also been identified. Unlike the intestine, where Lgr5+ cells at the crypt base act as active stem cells, the stomach may contain unique stem cell populations, since gastric Lgr5+ cells seem to behave as a reserve rather than active stem cells, both in the corpus and in the antral glands. Gastrointestinal stem cells are supported by a specific microenvironment, the stem cell niche, which also promotes tumorigenesis. This review focuses on stem cell markers in the gut and their supporting niche factors. It also discusses the molecular mechanisms that regulate stem cell function and tumorigenesis.

scholarly journals Albino seedling lethality 4; Chloroplast 30S Ribosomal Protein S1 is Required for Chloroplast Ribosome Biogenesis and Early Chloroplast Development in Rice

Rice ◽  
2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kunneng Zhou ◽  
Caijuan Zhang ◽  
Jiafa Xia ◽  
Peng Yun ◽  
Yuanlei Wang ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Ribosomal Protein ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Molecular Mechanisms ◽  
Chloroplast Development ◽  
Phage Type ◽  
Chloroplast Biogenesis ◽  
Ribosomal Protein S1 ◽  
Seedling Lethality

Abstract Background Ribosomes responsible for transcription and translation of plastid-encoded proteins in chloroplasts are essential for chloroplast development and plant growth. Although most ribosomal proteins in plastids have been identified, the molecular mechanisms regulating chloroplast biogenesis remain to be investigated. Results Here, we identified albinic seedling mutant albino seedling lethality 4 (asl4) caused by disruption of 30S ribosomal protein S1 that is targeted to the chloroplast. The mutant was defective in early chloroplast development and chlorophyll (Chl) biosynthesis. A 2855-bp deletion in the ASL4 allele was verified as responsible for the mutant phenotype by complementation tests. Expression analysis revealed that the ASL4 allele was highly expressed in leaf 4 sections and newly expanded leaves during early leaf development. Expression levels were increased by exposure to light following darkness. Some genes involved in chloroplast biogenesis were up-regulated and others down-regulated in asl4 mutant tissues compared to wild type. Plastid-encoded plastid RNA polymerase (PEP)-dependent photosynthesis genes and nuclear-encoded phage-type RNA polymerase (NEP)-dependent housekeeping genes were separately down-regulated and up-regulated, suggesting that plastid transcription was impaired in the mutant. Transcriptome and western blot analyses showed that levels of most plastid-encoded genes and proteins were reduced in the mutant. The decreased contents of chloroplast rRNAs and ribosomal proteins indicated that chloroplast ribosome biogenesis was impaired in the asl4 mutant. Conclusions Rice ASL4 encodes 30S ribosomal protein S1, which is targeted to the chloroplast. ASL4 is essential for chloroplast ribosome biogenesis and early chloroplast development. These data will facilitate efforts to further elucidate the molecular mechanism of chloroplast biogenesis.

scholarly journals CBMS-09 Intercellular communication at glioblastoma stem cell niches

2020 ◽  
Vol 2 (Supplement_3) ◽  
pp. ii4-ii4
Author(s):  
Takuichiro Hide ◽  
Yuki Shirakawa ◽  
Hirofumi Jono ◽  
Ichiyo Shibahara ◽  
Madoka Inukai ◽  
...  
Keyword(s):  
Growth Factors ◽  
Ribosomal Proteins ◽  
High Grade Glioma ◽  
Small Population ◽  
Perivascular Niche ◽  
Sox2 Expression ◽  
Glioblastoma Stem Cell ◽  
Heterogenous Population ◽  
New Treatment ◽  
Intercellular Communications

Abstract Glioblastoma multiforme (GBM) contains heterogenous population of cells including a small population of GBM stem cells (GSCs), which potentially cause therapeutic resistance and tumor recurrence. GSCs harbored in special microenvironments, such as perinecrotic niche, perivascular niche, border niche. However, the mechanisms underlying the pathogenesis and maintenance of GSCs remain largely unknown. Stemness and chemo-radioresistance was promoted by not only additional mutation, but also microenvironment of GBM cells. Previously, we had reported that growth factors and cytokines secreted by oligodendrocyte lineage cells and macrophages/microglia induce stemness and chemo-radioresistance into GBM cells. Recently, Ito et al. reported that incorporation of ribosomes and ribosomal proteins into somatic cells promoted lineage trans-differentiation toward multipotency. Ribosomal proteins exist intra- and extracellularly. There is a possibility that ribosomal proteins promote stemness into cancer cells, we focused on 40S ribosomal protein S6 (RPS6), which is related to cell proliferation in lung and pancreatic cancer, but not reported in GBM. RPS6 was significantly upregulated in high-grade glioma. SiRNA-mediated RPS6 knock-down significantly suppressed the characteristics of GSCs, including their tumorsphere potential and stemness marker expression, such as Nestin and Sox2. RPS6 overexpression enhanced the tumorsphere potential of GSCs. Moreover, RPS6 expression was significantly correlated with SOX2 expression in different glioma grades. Immunohistochemistry data indicated that RPS6 was predominant detected at GSC niches, concurrently with the data from IVY GAP databases. Furthermore, RPS6 and other ribosomal proteins were upregulated in GSC-predominant areas in this database. The present results indicate that, in GSC niches, ribosomal proteins play crucial roles in the development and maintenance of GSCs and are clinically associated with chemo-radioresistance and GBM recurrence. These results suggested that intercellular communications through growth factors, cytokines, and ribosomes are regarded as new treatment targets of GBM.

scholarly journals Andrographolide Promotes Neural Differentiation of Rat Adipose Tissue-Derived Stromal Cells through Wnt/β-Catenin Signaling Pathway

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Yan Liang ◽  
Miao Li ◽  
Tao Lu ◽  
Wang Peng ◽  
Jian-Huang Wu
Keyword(s):  
Adipose Tissue ◽  
Stem Cell ◽  
Stromal Cells ◽  
Neural Differentiation ◽  
Molecular Mechanisms ◽  
Adult Stem Cell ◽  
High Yield ◽  
Control Group ◽  
Stem Cell Markers ◽  
Neural Lineage

Adipose tissue-derived stromal cells (ADSCs) are a high-yield source of pluripotent stem cells for use in cell-based therapies. We explored the effect of andrographolide (ANDRO, one of the ingredients of the medicinal herb extract) on the neural differentiation of rat ADSCs and associated molecular mechanisms. We observed that rat ADSCs were small and spindle-shaped and expressed multiple stem cell markers including nestin. They were multipotent as evidenced by adipogenic, osteogenic, chondrogenic, and neural differentiation under appropriate conditions. The proportion of cells exhibiting neural-like morphology was higher, and neurites developed faster in the ANDRO group than in the control group in the same neural differentiation medium. Expression levels of the neural lineage markers MAP2, tau, GFAP, and β-tubulin III were higher in the ANDRO group. ANDRO induced a concentration-dependent increase in Wnt/β-catenin signaling as evidenced by the enhanced expression of nuclear β-catenin and the inhibited form of GSK-3β (pSer9). Thus, this study shows for the first time how by enhancing the neural differentiation of ADSCs we expect that ANDRO pretreatment may increase the efficacy of adult stem cell transplantation in nervous system diseases, but more exploration is needed.

scholarly journals Use of constitutive and inducible oncogene-containing iPSCs as surrogates for transgenic mice to study breast oncogenesis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Christine Nguyen ◽  
Julie P. T. Nguyen ◽  
Arnav P. Modi ◽  
Ihsaan Ahmad ◽  
Sarah C. Petrova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Transgenic Mice ◽  
Target Cell ◽  
Molecular Mechanisms ◽  
Stem Cell Markers ◽  
In Vivo Models ◽  
Essentially Normal

Abstract Background Powerful constitutive and inducible transgenic / bitransgenic / tritransgenic murine models of breast cancer have been used over the past two decades to shed light on the molecular mechanisms by which the given transgenic oncogenes have interacted with other cellular genes and set in motion breast cancer initiation and progression. However, these transgenic models, as in vivo models only, are expensive and restrictive in the opportunities they provide to manipulate the experimental variables that would enable a better understanding of the molecular events related to initial transformation and the target cell being transformed. Methods To overcome some of these limitations, we derived oncogene-containing induced pluripotent stem cell (iPSC) clones from tail vein fibroblasts of these transgenic mice and manipulated them both in vitro and in vivo in non-transgenic background mice. We created the iPSC clones with a relatively low M.O.I, producing retroviral integrations which averaged only 1 to 2 sites per retroviral plasmid construct used. Results Most iPSC clones derived from each group displayed an essentially normal murine karyotype, strong expression of the exogenous reprogrammable genes and significant expression of characteristic endogenous murine surface stem cell markers including SSEA-1 (CD15), PECAM-1 (CD31), Ep-Cam (CD326), and Nectin (CD112), but no expression of their transgene. A majority (75%) of iPSC clones displayed a normal murine karyotype but 25% exhibited a genomically unstable karyotype. However, even these later clones exhibited stable and characteristic iPSC properties. When injected orthotopically, select iPSC clones, either constitutive or inducible, no longer expressed their exogenous pluripotency reprogramming factors but expressed their oncogenic transgene (PyVT or ErbB2) and participated in both breast ontogenesis and subsequent oncogenesis. When injected non-orthotopically or when differentiated in vitro along several different non-mammary lineages of differentiation, the iPSC clones failed to do so. Although many clones developed anticipated teratomas, select iPSC clones under the appropriate constitutive or inducible conditions exhibited both breast ontogenesis and oncogenesis through the same stages as exhibited by their transgenic murine parents and, as such, represent transgenic surrogates. Conclusions The iPSC clones offer a number of advantages over transgenic mice including cost, the ability to manipulate and tag in vitro, and create an in vitro model of breast ontogeny and oncogenesis that can be used to gain additional insights into the differentiated status of the target cell which is susceptible to transformation. In addition, the use of these oncogene-containing iPSC clones can be used in chemopreventive studies of breast cancer.

Albino seedling lethality 4 ; chloroplast 30S ribosomal protein S1 required for chloroplast ribosome biogenesis and early chloroplast development in rice

2021 ◽  
Author(s):  
Kunneng Zhou ◽  
Caijuan Zhang ◽  
Jiafa Xia ◽  
Peng Yun ◽  
Yuanlei Wang ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Molecular Mechanisms ◽  
Chloroplast Development ◽  
Chlorophyll Biosynthesis ◽  
Housekeeping Genes ◽  
Chloroplast Biogenesis ◽  
Ribosomal Protein S1 ◽  
Photosynthesis Genes

Abstract Background : Ribosomes responsible for transcription and translation of plastid-encoded proteins in chloroplasts are essential for chloroplast development and plant growth. Although most ribosomal proteins in plastids have been identified, the molecular mechanisms regulating chloroplast biogenesis remain to be investigated. Results: Here, we identified albinic seedling mutant asl4 caused by disruption of 30S ribosomal protein S1 that is targeted to the chloroplast . The mutant was defective in early chloroplast development and chlorophyll biosynthesis . A 2,855-bp deletion in the ASL4 allele was verified as responsible for the mutant phenotype by complementation tests. Expression analysis revealed that the ASL4 allele was highly expressed in leaf 4 sections and newly expanded leaves during early leaf development. Expression levels were increased by exposure to light following darkness. Some genes involved in chloroplast biogenesis were up-regulated and others down-regulated in asl4 mutant tissues compared to wild type. PEP-dependent photosynthesis genes and NEP-dependent housekeeping genes were separately down-regulated and up-regulated, suggesting that plastid transcription was impaired in the mutant. Transcriptome and western blot analyses showed that levels of most plastid-encoded genes and proteins were reduced in the mutant. The decreased contents of chloroplast rRNAs and ribosomal proteins indicated that chloroplast ribosome biogenesis was impaired in the asl4 mutant. Conclusion: Rice ASL4 encodes 30S ribosomal protein S1, which is targeted to the chloroplast. ASL4 is essential for chloroplast ribosome biogenesis and early chloroplast development. These data will facilitate efforts to further elucidate the molecular mechanism of chloroplast biogenesis.

Sign in / Sign up

Export Citation Format

Share Document