scholarly journals TRIM28 Selective Nanobody Reduces Glioblastoma Stem Cell Invasion

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5141
Author(s):  
Andrej Porčnik ◽  
Metka Novak ◽  
Barbara Breznik ◽  
Bernarda Majc ◽  
Barbara Hrastar ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Invasion ◽  
Therapy Response ◽  
Low Grade ◽  
Therapeutic Tool ◽  
Tumour Heterogeneity ◽  
Primary Brain Tumour ◽  
Glioblastoma Stem Cell

Glioblastoma (GB), is the most common and aggressive malignant primary brain tumour in adults. Intra- and inter-tumour heterogeneity, infiltrative GB cell invasion and presence of therapy-resistant GB stem cells (GSCs) represent major obstacles to favourable prognosis and poor therapy response. Identifying the biomarkers of the most aggressive tumour cells and their more efficient targeting strategies are; therefore, crucial. Recently, transcription factor TRIM28 has been identified as a GB biomarker and, in this study, we have shown high expression of TRIM28 in GB and in low grade gliomas as well as higher expression in GSCs vs. differentiated GB cells, although in both cases not significant. We demonstrated significant in vitro inhibition of GB cells and GSCs invasiveness and spread in zebrafish brains in vivo by anti-TRIM28 selective nanobody NB237. TRIM28 was also enriched in GB (tumour) core and associated with the expression of stem cell genes, but was not prognostic for overall survival. However, based on the above results, we conclude that TRIM28 nanobody NB237 offers a new opportunity as a GB therapeutic tool.

Morusin inhibits glioblastoma stem cell growth in vitro and in vivo through stemness attenuation, adipocyte transdifferentiation, and apoptosis induction

2014 ◽  
Vol 55 (1) ◽  
pp. 77-89 ◽  
Author(s):  
Huijie Guo ◽  
Chuanlan Liu ◽  
Liuqi Yang ◽  
Lihua Dong ◽  
Li Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Growth ◽  
Apoptosis Induction ◽  
Glioblastoma Stem Cell

scholarly journals EXTH-75. IN VITRO AND IN VIVO EFFICACY OF COMBINATORIAL INHIBITION OF LSD1 AND HDACS IN PATIENT DERIVED GLIOBLASTOMA STEM CELL MODELS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii103-ii104
Author(s):  
Achintyan Gangadharan ◽  
Leslie Grasse ◽  
Alexsandra Espejo ◽  
Ravesanker Ezhilarasan ◽  
Tiara Collier ◽  
...  
Keyword(s):  
Stem Cell ◽  
Combination Treatment ◽  
Molecular Mechanisms ◽  
Single Agent ◽  
Survival Rates ◽  
Combination Strategy ◽  
In Vivo Efficacy ◽  
Glioblastoma Stem Cell

Abstract Inhibitors of histone deacetylases (HDACi) have been tested in glioblastoma (GBM), however, single agent clinical efficacy has not been proven, prompting study of combinatorial approaches. A rational HDACi combination strategy is with inhibition of LSD1, lysine specific demethylase 1, a histone demethylase known to exist in complex with HDAC1/2. We previously showed in vivo efficacy of combining a brain permeant LSD1 inhibitor, tranylcypromine (TCP) together with vorinostat. More selective inhibitors of LSD1 have been developed and were tested in the current study together with the HDACi, vorinostat or panobinostat in a panel of patient derived glioblastoma stem cell (GSC) lines that have been characterized as radio-resistant or radiosensitive. To test in vitro sensitivity, dose response experiments were conducted in nine GSC cell lines using three LSD1 inhibitors or two HDACi as single agents or in combination. Two non-tumor lines were also tested to assess selective cytotoxicity for brain tumor lines. Cell viability and clonogenicity assays were performed. Several radio-resistant GSC lines showed sensitivity to single agent LSD1 inhibitors, whereas some radio-sensitive GSCs did not, indicating distinct molecular mechanisms of response. Intracranial orthotopic xenograft models were used to test in vivo efficacy using the radioresistant GSC20 line. Interestingly, LSD1 inhibition alone promoted tumor burden reduction and better survival rates than combination treatment. RNA-Seq guided biomarkers of sensitivity to the LSD1/HDAC inhibitor combination were assessed in vitro and in vivo. Both in vivo and in vitro data show that GSC20 treated with GSK LSD1 inhibitor had higher levels of HKDC1 gene with in vivo data also showing elevated levels of FTH1. In vivo mouse data for vorinostat and combination treatment groups showed that only the FTH1 gene level was elevated, providing a potential explanation for low in vivo efficacy. Collectively, our data suggests that LSD1 inhibition represents a viable strategy in GBM.

scholarly journals Metformin and Vitamin D Modulate Inflammation and Autophagy during Adipose-Derived Stem Cell Differentiation

2021 ◽  
Vol 22 (13) ◽  
pp. 6686
Author(s):  
Sara Cruciani ◽  
Giuseppe Garroni ◽  
Renzo Pala ◽  
Maria Laura Cossu ◽  
Giorgio Carlo Ginesu ◽  
...  
Keyword(s):  
Vitamin D ◽  
Stem Cell ◽  
Adipogenic Differentiation ◽  
Stem Cell Differentiation ◽  
Low Grade ◽  
Mrna Levels ◽  
Tnf Α ◽  
Shock Proteins

Adipose-derived stem cells (ADSCs) came out from the regenerative medicine landscape for their ability to differentiate into several phenotypes, contributing to tissue regeneration both in vitro and in vivo. Dysregulation in stem cell recruitment and differentiation during adipogenesis is linked to a chronic low-grade inflammation and macrophage infiltration inside the adipose tissue, insulin resistance, cardiovascular disease and obesity. In the present paper we aimed to evaluate the role of metformin and vitamin D, alone or in combination, in modulating inflammation and autophagy in ADSCs during adipogenic commitment. ADSCs were cultured for 21 days in the presence of a specific adipogenic differentiation medium, together with metformin, or vitamin D, or both. We then analyzed the expression of FoxO1 and Heat Shock Proteins (HSP) and the secretion of proinflammatory cytokines IL-6 and TNF-α by ELISA. Autophagy was also assessed by specific Western blot analysis of ATG12, LC3B I, and LC3B II expression. Our results showed the ability of the conditioned media to modulate adipogenic differentiation, finely tuning the inflammatory response and autophagy. We observed a modulation in HSP mRNA levels, and a significant downregulation in cytokine secretion. Taken together, our findings suggest the possible application of these molecules in clinical practice to counteract uncontrolled lipogenesis and prevent obesity and obesity-related metabolic disorders.

scholarly journals Alpha-secretase inhibition reduces human glioblastoma stem cell growth in vitro and in vivo by inhibiting Notch

2012 ◽  
Vol 14 (10) ◽  
pp. 1215-1226 ◽  
Author(s):  
Desiree H. Floyd ◽  
Benjamin Kefas ◽  
Oleksandr Seleverstov ◽  
Olga Mykhaylyk ◽  
Charli Dominguez ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Growth ◽  
Human Glioblastoma ◽  
Glioblastoma Stem Cell

MESENCHYMAL TNFR1 EXPRESSION PRESERVES THE COLONIC EPITHELIAL STEM CELL NICHE

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S7-S8
Author(s):  
Safina Gadeock ◽  
Cambrian Liu ◽  
Brent Polk
Keyword(s):  
Stem Cell ◽  
Stem Cell Niche ◽  
Mesenchymal Cells ◽  
Epithelial Stem Cells ◽  
Epithelial Stem Cell ◽  
Long Term Treatment ◽  
Lgr5 Expression ◽  
Cell Niche

Abstract Tumor necrosis factor (TNF) is a highly expressed cytokine in inflammatory bowel disease (IBD). Although TNF can induce colonic epithelial dysfunction and apoptosis, recent studies suggest that TNF signalling promotes epithelial wound repair and stem cell function. Here we investigated the role of TNF receptor 1 (TNFR1) in mediating TNF’s effects on colonic epithelial stem cells, integral to mucosal healing in colitis. We demonstrate that Tnfr1-/- mice exhibit loss in Lgr5 expression (-52%, p<0.02; N=6) compared to wildtype (WT) controls. However, the opposite result was found in vitro, wherein murine Tnfr1-/- colonoids demonstrated a significant increase in Lgr5 expression (66%, p<0.007; N=6) compared to WT colonoids. Similarly, human colonoids treated with an anti-TNFR1 antibody also demonstrated an increase in Lgr5 expression, relative to IgG controls. To resolve the contradiction in the in vivo versus in vitro environment, we hypothesized that mesenchymal TNFR1 expression regulates the epithelial stem cell niche. To determine the relationships between these cell types, we co-cultured WT or Tnfr1-/- colonoids with WT or Tnfr1-/- colonic myofibroblasts (CMFs). We found that epithelial Lgr5 expression was significantly higher (by 52%, p<0.05; N=3) when co-cultured with WT compared to TNFR1-/- myofibroblasts. The loss of TNFR1 expression in vivo increases the number of αSMA+ mesenchymal cells by nearly 56% (N=6) but considerably reduces the pericryptal PDGFRα+ cells, suggesting modifications in mesenchymal populations that contribute to the epithelial stem cell niche. Functionally, primary Tnfr1-/--CMFs displayed PI3k (p<0.001; N=3) and MAPK (p<0.01; N=3)-dependent increases in migration, proliferation, and differentiation, but RNA profiling demonstrated by diminished levels of stem cell niche factors, Rspo3 (-80%, p<0.0001; N=6) and Wnt2b (-63%, p<0.008; N=6) compared to WT-CMFs. Supplementation with 50ng recombinant Rspo3 for 5 d to Lgr5-GFP organoids co-cultured with TNFR1-/--CMFs restored Lgr5 expression to wildtype levels. Therefore, TNFR1-mediated TNF signalling in mesenchymal cells promotes their ability to support an epithelial stem cell niche. These results should motivate future studies of the stem cell niche in the context of long-term treatment with anti-TNF therapies.

scholarly journals Regulation of sarcomagenesis by the empty spiracles homeobox genes EMX1 and EMX2

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Manuel Pedro Jimenez-García ◽  
Antonio Lucena-Cacace ◽  
Daniel Otero-Albiol ◽  
Amancio Carnero
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Transcription Factors ◽  
Neural Crest ◽  
Tumor Suppressors ◽  
Homeobox Genes ◽  
Neuronal Cell ◽  
Cell Gene Expression

AbstractThe EMX (Empty Spiracles Homeobox) genes EMX1 and EMX2 are two homeodomain gene members of the EMX family of transcription factors involved in the regulation of various biological processes, such as cell proliferation, migration, and differentiation, during brain development and neural crest migration. They play a role in the specification of positional identity, the proliferation of neural stem cells, and the differentiation of certain neuronal cell phenotypes. In general, they act as transcription factors in early embryogenesis and neuroembryogenesis from metazoans to higher vertebrates. The EMX1 and EMX2’s potential as tumor suppressor genes has been suggested in some cancers. Our work showed that EMX1/EMX2 act as tumor suppressors in sarcomas by repressing the activity of stem cell regulatory genes (OCT4, SOX2, KLF4, MYC, NANOG, NES, and PROM1). EMX protein downregulation, therefore, induced the malignance and stemness of cells both in vitro and in vivo. In murine knockout (KO) models lacking Emx genes, 3MC-induced sarcomas were more aggressive and infiltrative, had a greater capacity for tumor self-renewal, and had higher stem cell gene expression and nestin expression than those in wild-type models. These results showing that EMX genes acted as stemness regulators were reproduced in different subtypes of sarcoma. Therefore, it is possible that the EMX genes could have a generalized behavior regulating proliferation of neural crest-derived progenitors. Together, these results indicate that the EMX1 and EMX2 genes negatively regulate these tumor-altering populations or cancer stem cells, acting as tumor suppressors in sarcoma.

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