scholarly journals In Vivo Melanoma Cell Morphology Reflects Molecular Signature and Tumor Aggressiveness

2022 ◽  
Author(s):  
Alessandra Marconi ◽  
Marika Quadri ◽  
Francesca Farnetani ◽  
Silvana Ciardo ◽  
Elisabetta Palazzo ◽  
...  
Keyword(s):  
Melanoma Cell ◽  
Cell Morphology ◽  
Molecular Signature ◽  
Tumor Aggressiveness

scholarly journals Regeneration linked miRNA modify tumor phenotype and can enforce multi-lineage growth arrest in vivo

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Siamak Salehi ◽  
Oliver D. Tavabie ◽  
Augusto Villanueva ◽  
Julie Watson ◽  
David Darling ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Growth Inhibition ◽  
Tumor Aggressiveness ◽  
Novel Treatment ◽  
Tumor Phenotype ◽  
Aggressive Tumor ◽  
In Vivo Growth ◽  
Regulation Of Regeneration

AbstractRegulated cell proliferation is an effector mechanism of regeneration, whilst dysregulated cell proliferation is a feature of cancer. We have previously identified microRNA (miRNA) that regulate successful and failed human liver regeneration. We hypothesized that these regulators may directly modify tumor behavior. Here we show that inhibition of miRNAs -503 and -23a, alone or in combination, enhances tumor proliferation in hepatocyte and non-hepatocyte derived cancers in vitro, driving more aggressive tumor behavior in vivo. Inhibition of miRNA-152 caused induction of DNMT1, site-specific methylation with associated changes in gene expression and in vitro and in vivo growth inhibition. Enforced changes in expression of two miRNA recapitulating changes observed in failed regeneration led to complete growth inhibition of multi-lineage cancers in vivo. Our results indicate that regulation of regeneration and tumor aggressiveness are concordant and that miRNA-based inhibitors of regeneration may constitute a novel treatment strategy for human cancers.

scholarly journals O-GlcNAcylation protein disruption by Thiamet G promotes changes on the GBM U87-MG cells secretome molecular signature

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Maria Cecilia Oliveira-Nunes ◽  
Glaucia Julião ◽  
Aline Menezes ◽  
Fernanda Mariath ◽  
John A. Hanover ◽  
...  
Keyword(s):  
Experimental Evidence ◽  
Critical Role ◽  
Molecular Signature ◽  
Label Free ◽  
Intercellular Signaling ◽  
Tumor Aggressiveness ◽  
Signaling Axis ◽  
Literature Evidence ◽  
Therapeutic Tools

AbstractGlioblastoma (GBM) is a grade IV glioma highly aggressive and refractory to the therapeutic approaches currently in use. O-GlcNAcylation plays a key role for tumor aggressiveness and progression in different types of cancer; however, experimental evidence of its involvement in GBM are still lacking. Here, we show that O-GlcNAcylation plays a critical role in maintaining the composition of the GBM secretome, whereas inhibition of OGA activity disrupts the intercellular signaling via microvesicles. Using a label-free quantitative proteomics methodology, we identified 51 proteins in the GBM secretome whose abundance was significantly altered by activity inhibition of O-GlcNAcase (iOGA). Among these proteins, we observed that proteins related to proteasome activity and to regulation of immune response in the tumor microenvironment were consistently downregulated in GBM cells upon iOGA. While the proteins IGFBP3, IL-6 and HSPA5 were downregulated in GBM iOGA cells, the protein SQSTM1/p62 was exclusively found in GBM cells under iOGA. These findings were in line with literature evidence on the role of p62/IL-6 signaling axis in suppressing tumor aggressiveness and our experimental evidence showing a decrease in radioresistance potential of these cells. Taken together, our findings provide evidence that OGA activity may regulate the p62 and IL-6 abundance in the GBM secretome. We propose that the assessment of tumor status from the main proteins present in its secretome may contribute to the advancement of diagnostic, prognostic and even therapeutic tools to approach this relevant malignancy.

scholarly journals Macropinocytosis requires Gal-3 in a subset of patient-derived glioblastoma stem cells

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Laetitia Seguin ◽  
Soline Odouard ◽  
Francesca Corlazzoli ◽  
Sarah Al Haddad ◽  
Laurine Moindrot ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Survival ◽  
Small Gtpases ◽  
Molecular Signature ◽  
Carbohydrate Binding ◽  
Pancreatic Cancers ◽  
Galectin 3 ◽  
Pharmacologic Inhibition

AbstractRecently, we involved the carbohydrate-binding protein Galectin-3 (Gal-3) as a druggable target for KRAS-mutant-addicted lung and pancreatic cancers. Here, using glioblastoma patient-derived stem cells (GSCs), we identify and characterize a subset of Gal-3high glioblastoma (GBM) tumors mainly within the mesenchymal subtype that are addicted to Gal-3-mediated macropinocytosis. Using both genetic and pharmacologic inhibition of Gal-3, we showed a significant decrease of GSC macropinocytosis activity, cell survival and invasion, in vitro and in vivo. Mechanistically, we demonstrate that Gal-3 binds to RAB10, a member of the RAS superfamily of small GTPases, and β1 integrin, which are both required for macropinocytosis activity and cell survival. Finally, by defining a Gal-3/macropinocytosis molecular signature, we could predict sensitivity to this dependency pathway and provide proof-of-principle for innovative therapeutic strategies to exploit this Achilles’ heel for a significant and unique subset of GBM patients.

Increased expression of MAP2 inhibits melanoma cell proliferation, invasion and tumor growth in vitro and in vivo

2010 ◽  
Vol 19 (11) ◽  
pp. 958-964 ◽  
Author(s):  
Zhiqi Song ◽  
Chun-Di He ◽  
Changkai Sun ◽  
Yanni Xu ◽  
Xin Jin ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Melanoma Cell ◽  
Melanoma Cell Proliferation

Abstract 7: LPA/PKD-1-HDAC7-FoxO1 Signaling-mediated Endothelial CD36 Transcriptional Repression and Proarteriogenic Reprogramming

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Bin Ren ◽  
Brad Best ◽  
Devi Ramakrishnan ◽  
Brian Walcott ◽  
Peter Storz ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcriptional Repression ◽  
Gene Array ◽  
Branching Morphogenesis ◽  
Gene Profiling ◽  
Molecular Signature ◽  
Cd36 Deficiency ◽  
Angiogenesis Assay ◽  
Thrombotic Diseases

Background: CD36 is a scavenger and antiangiogenic receptor that plays an important role in athero-thrombotic diseases, diabetes and cancer and contributes to obesity. Lysophosphatidic acid (LPA), a bioactive phospholipid signaling mediator, abolishes endothelial cell responses to antiangiogenic proteins containing thrombospondin type 1 homology domains by down-regulating endothelial CD36 transcription via protein kinase PKD-1 signaling. However, the precise mechanism as to how angiogenic signaling is integrated to regulate endothelial specific CD36 transcription remain unknown. Hypothesis: LPA represses CD36 transcription through PKD-1-mediated formation of a nuclear transcriptional complex in endothelial cells. Methods: Microvascular endothelial cells expressing CD36 were used for studying signaling and CD36 transcription by real time RT-qPCR, Western blotting, co-immunoprecipitation or avidin-biotin-conjugated DNA-binding assay; angiogenesis gene array was used for angiogenic gene profiling in response to LPA exposure. Spheroid-based angiogenesis assay, in vivo Matrigel assay and tumor angiogenesis model in CD36 deficiency and wild type mice were established to elucidate mechanisms of angiogenic signaling. Results: CD36 transcriptional repression involved PKD-1 signaling mediated formation of FoxO1-HDAC7 complex in the nucleus of endothelial cells. Unexpectedly, turning off CD36 transcription initiated reprogramming MVECs to express ephrin B2, a critical “molecular signature” involved in angiogenesis and arteriogenesis, and increased phosphorylation of Erk1/2, the MAP kinase important in arterial differentiation. PKD-1 signaling was also shown in tumor endothelium of Lewis lung carcinomas, along with low CD36 expression or CD36 deficiency. Angiogenic branching morphogenesis and in vivo angiogenesis were dependent on PKD-1 signaling. Conclusion: LPA/PKD1-HDAC7-FoxO1 signaling axis regulates endothelial CD36 transcription and mediates silencing of the antiangiogenic switch, resulting in proarteriogenic reprogramming. Targeting this signaling cascade could be a novel approach for cancer, diabetes, athero-thrombotic diseases and obesity.

scholarly journals Moderate and intensive mechanical loading differentially modulate the phenotype of tendon stem/progenitor cells in vivo

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0242640
Author(s):  
Jianying Zhang ◽  
Daibang Nie ◽  
Kelly Williamson ◽  
Arthur McDowell ◽  
MaCalus V. Hogan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Progenitor Cells ◽  
Cell Morphology ◽  
Fluorescent Protein ◽  
Treadmill Running ◽  
Whole Body ◽  
Tendon Cells ◽  
Elevated Expression ◽  
Green Fluorescent

To examine the differential mechanobiological responses of specific resident tendon cells, we developed an in vivo model of whole-body irradiation followed by injection of either tendon stem/progenitor cells (TSCs) expressing green fluorescent protein (GFP-TSCs) or mature tenocytes expressing GFP (GFP-TNCs) into the patellar tendons of wild type C57 mice. Injected mice were subjected to short term (3 weeks) treadmill running, specifically moderate treadmill running (MTR) and intensive treadmill running (ITR). In MTR mice, both GFP-TSC and GFP-TNC injected tendons maintained normal cell morphology with elevated expression of tendon related markers collagen I and tenomodulin. In ITR mice injected with GFP-TNCs, cells also maintained an elongated shape similar to the shape found in normal/untreated control mice, as well as elevated expression of tendon related markers. However, ITR mice injected with GFP-TSCs showed abnormal changes, such as cell morphology transitioning to a round shape, elevated chondrogenic differentiation, and increased gene expression of non-tenocyte related genes LPL, Runx-2, and SOX-9. Increased gene expression data was supported by immunostaining showing elevated expression of SOX-9, Runx-2, and PPARγ. This study provides evidence that while MTR maintains tendon homeostasis by promoting the differentiation of TSCs into TNCs, ITR causes the onset of tendinopathy development by inducing non-tenocyte differentiation of TSCs, which may eventually lead to the formation of non-tendinous tissues in tendon tissue after long term mechanical overloading conditions on the tendon.

scholarly journals Stem cell signature in glioblastoma: therapeutic development for a moving target

2015 ◽  
Vol 122 (2) ◽  
pp. 324-330 ◽  
Author(s):  
Ichiro Nakano
Keyword(s):  
High Grade Glioma ◽  
Core Gene ◽  
Metabolic Reprogramming ◽  
Molecular Signature ◽  
Transcriptional Analysis ◽  
Clinical Implications ◽  
Pathways Analysis ◽  
Therapeutic Development

Tumor heterogeneity of adult high-grade glioma (HGG) is recognized in 3 major subtypes based on core gene signatures. However, the molecular signatures and clinical implications of glioma stem cells (GSCs) in individual HGG subtypes remain poorly characterized. Recently genome-wide transcriptional analysis identified two mutually exclusive GSC subtypes with distinct dysregulated signaling and metabolic pathways. Analysis of genetic profiles and phenotypic assays distinguished proneural (PN) from mesenchymal (MES) GSCs and revealed a striking correlation with the corresponding PN or MES HGGs. Similar to HGGs with a MES signature, MES GSCs display more aggressive phenotypes both in vitro and in vivo. Furthermore, MES GSCs are markedly resistant to radiation as compared with PN GSCs, consistent with the relative radiation resistance of MES GBM compared with other subtypes. A systems biology approach has identified a set of transcription factors as the master regulators for the MES signature. Metabolic reprogramming in MES GSCs has also been noticed with the prominent activation of the glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes. This review summarizes recent progress in the characterization of the molecular signature in distinct HGG and GSC subtypes and plasticity between different GSC subtypes as well as between GSCs and non-GSCs in HGG tumors. Clinical implications of the translational GSC research are also discussed.

The negatively charged microenvironment of collagen hydrogels regulates the chondrogenic differentiation of bone marrow mesenchymal stem cells in vitro and in vivo

2020 ◽  
Vol 8 (21) ◽  
pp. 4680-4693
Author(s):  
Jirong Yang ◽  
Yumei Xiao ◽  
Zizhao Tang ◽  
Zhaocong Luo ◽  
Dongxiao Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Protein Adsorption ◽  
Cell Morphology ◽  
Chondrogenic Differentiation ◽  
Collagen Hydrogels ◽  
Marrow Mesenchymal Stem Cells

The different negatively charged microenvironments of collagen hydrogels affect the protein adsorption, cell morphology, and chondrogenic differentiation of BMSCs in vitro and in vivo.

scholarly journals Molecular profile and proangiogenic activity of the adipose-derived stromal vascular fraction used as an autologous innovative medicinal product in patients with systemic sclerosis

2019 ◽  
Vol 78 (3) ◽  
pp. 391-398 ◽  
Author(s):  
Jérémy Magalon ◽  
Mélanie Velier ◽  
Stéphanie Simoncini ◽  
Pauline François ◽  
Baptiste Bertrand ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Medicinal Product ◽  
Transitional Cell ◽  
Stromal Vascular Fraction ◽  
Endothelial Activation ◽  
Good Manufacturing Practice ◽  
Molecular Signature ◽  
Molecular Profile ◽  
Repair Capacity

ObjectiveThe autologous stromal vascular fraction (SVF) from adipose tissue is an alternative to cultured adipose-derived stem cells for use in regenerative medicine and represents a promising therapy for vasculopathy and hand disability in systemic sclerosis (SSc). However, the bioactivity of autologous SVF is not documented in this disease context. This study aimed to compare the molecular and functional profiles of the SVF-based medicinal product obtained from SSc and healthy subjects.MethodsGood manufacturing practice (GMP)-grade SVF from 24 patients with SSc and 12 healthy donors (HD) was analysed by flow cytometry to compare the distribution of the CD45− and CD45+ haematopoietic cell subsets. The ability of SVF to form a vascular network was assessed using Matrigel in vivo assay. The transcriptomic and secretory profiles of the SSc-SVF were assessed by RNA sequencing and multiplex analysis, respectively, and were compared with the HD-SVF.ResultsThe distribution of the leucocyte, endothelial, stromal, pericyte and transitional cell subsets was similar for SSc-SVF and HD-SVF. SSc-SVF retained its vasculogenic capacity, but the density of neovessels formed in SVF-loaded Matrigel implanted in nude mice was slightly decreased compared with HD-SVF. SSc-SVF displayed a differential molecular signature reflecting deregulation of angiogenesis, endothelial activation and fibrosis.ConclusionsOur study provides the first evidence that SSc does not compromise the vascular repair capacity of SVF, supporting its use as an innovative autologous biotherapy. The characterisation of the specific SSc-SVF molecular profile provides new perspectives for delineating markers of the potency of SVF and its targets for the treatment of SSc.

scholarly journals IN-SILICO STUDY OF BIOACTIVE COMPOUNDS OF NATURAL MATERIALS AS A JAK- SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION INHIBITOR FOR ANTI-ALOPECIA

2017 ◽  
Vol 10 (11) ◽  
pp. 331
Author(s):  
Resmi Mustarichie ◽  
Sandra Megantara ◽  
Nyi Mekar Saptarini
Keyword(s):  
Bioactive Compounds ◽  
In Silico ◽  
Hair Growth ◽  
Janus Kinase ◽  
Molecular Signature ◽  
Signal Transducer ◽  
Hydrogen Bond Interaction ◽  
Dermal Papilla Cells ◽  
Ligand Scout

  Objective: This study aims to examine the compounds contained in herbs for the treatment of anti-alopecia by in-silico computation.Methods: JAK (Janus Kinase) regulates the activation of key hair follicle populations such as the hair germ and improves the inductivity of cultured human dermal papilla cells by controlling a molecular signature enriched in intact, fully inductive dermal papillae. JAK2 which was a member of Janus family was used in this study as a receptor (PDB code: 4C61) and 15 compounds normally found in five herbals traditionally used as hair growth as ligands. Molecular modeling of bioactive compounds was performed using MarvinSketch and Prediction of physicochemical properties by ligand scout software. Molecular docking was performed using ligand scout, AutoDock Vina, and PyMOL. Binding affinity (Ei), inhibition constant (Ki), hydrogen bond interaction, and hydrophobic interaction were evaluated to find which of herbs potentially for anti-alopecia.Results: Among 15 compounds studied three of them, 6-hydroxy genistein, coreximine, and scoulerine interacted well with JAK2’s active pocket so it can inhibit JAK- signal transducer and activator of transcription. 6-hydroxy genistein interacted with Asp994, Gly993 Met929, Val863, Leu983, Ala880, and Leu855 whereas coreximine and scoulerine interacted with Leu932, Pro933, Tyr931 and Pro933, Tyr931, Ala880, Val863, Leu983, Leu855, respectively.Conclusion: These results predicted that three compounds, namely, 6-hydroxy genistein, coreximine, and scoulerine which come from Dadap leaves (Erythrina variegata var. orientalis (L.) Merr.) were strongly had the link with JAK2 indicating that this plant extract may be used as hair growth agent/ anti-alopecia. As compounds studied was based on the literature survey, our results suggest compounds from six herbals studied should firstly be tested in-vivo for its anti-alopecia activity, fractionated, elucidated, to check as to whether their compounds responsible for anti-alopecia using the method developed in this paper.

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