scholarly journals Specific and Aspecific Molecular Checkpoints as Potential Targets for Dismantling Tumor Hierarchy and Preventing Relapse and Metastasis Through Shielded Cytolytic Treatments

2021 ◽  
Vol 9 ◽  
Author(s):  
Giovanni Manzo
Keyword(s):  
Stem Cell ◽  
Embryonic Stem ◽  
Growth Strategy ◽  
Messenger Rnas ◽  
Differentiated Cells ◽  
Tumor Sphere ◽  
Non Coding Rnas ◽  
Intercellular Communications ◽  
Host Tissues

I have recently theorized that several similarities exist between the tumor process and embryo development. Starting from an initial cancer stem cell (CSC0), similar to an embryonic stem cell (ESC), after implantation in a niche, primary self-renewing CSCs (CSC1s) would arise, which then generate secondary proliferating CSCs (CSC2s). From these epithelial CSCs, tertiary mesenchymal CSCs (CSC3s) would arise, which, under favorable stereotrophic conditions, by asymmetric proliferation, would generate cancer progenitor cells (CPCs) and then cancer differentiated cells (CDCs), thus giving a defined cell heterogeneity and hierarchy. CSC1s–CSC2s–CSC3s–CPCs–CDCs would constitute a defined “tumor growth module,” able to generate new tumor modules, forming a spherical avascular mass, similar to a tumor sphere. Further growth in situ of this initial tumor would require implantation in the host and vascularization through the overexpression of some aspecific checkpoint molecules, such as CD44, ID, LIF, HSP70, and HLA-G. To expand and spread in the host tissues, this vascularized tumor would then carry on a real growth strategy based on other specific checkpoint factors, such as those contained in the extracellular vesicles (EVs), namely, microRNAs, messenger RNAs, long non-coding RNAs, and integrins. These EV components would be crucial in tumor progression because they can mediate intercellular communications in the surrounding microenvironment and systemically, dictating to recipient cells a new tumor-enslaved phenotype, thus determining pre-metastatic conditions. Moreover, by their induction properties, the EV contents could also frustrate in time the effects of cytolytic tumor therapies, where EVs released by killed CSCs might enter other cancer and non-cancer cells, thus giving chemoresistance, non-CSC/CSC transition (recurrence), and metastasis. Thus, antitumor cytotoxic treatments, “shielded” from the EV-specific checkpoints by suitable adjuvant agents, simultaneously targeting the aforesaid aspecific checkpoints should be necessary for dismantling the hierarchic tumor structure, avoiding recurrence and preventing metastasis.

scholarly journals Mammalian genes induce partially reprogrammed pluripotent stem cells in non-mammalian vertebrate and invertebrate species

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Ricardo Antonio Rosselló ◽  
Chun-Chun Chen ◽  
Rui Dai ◽  
Jason T Howard ◽  
Ute Hochgeschwender ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Pluripotent Stem Cells ◽  
Mammalian Species ◽  
Embryonic Stem ◽  
Model Organisms ◽  
Differentiated Cells ◽  
Transcription Factor Genes ◽  
Induced Pluripotent

Cells are fundamental units of life, but little is known about evolution of cell states. Induced pluripotent stem cells (iPSCs) are once differentiated cells that have been re-programmed to an embryonic stem cell-like state, providing a powerful platform for biology and medicine. However, they have been limited to a few mammalian species. Here we found that a set of four mammalian transcription factor genes used to generate iPSCs in mouse and humans can induce a partially reprogrammed pluripotent stem cell (PRPSCs) state in vertebrate and invertebrate model organisms, in mammals, birds, fish, and fly, which span 550 million years from a common ancestor. These findings are one of the first to show cross-lineage stem cell-like induction, and to generate pluripotent-like cells for several of these species with in vivo chimeras. We suggest that the stem-cell state may be highly conserved across a wide phylogenetic range.

scholarly journals Identification of differentially expressed non-coding RNAs in embryonic stem cell neural differentiation

2012 ◽  
Vol 40 (13) ◽  
pp. 6001-6015 ◽  
Author(s):  
Konstantinia Skreka ◽  
Simon Schafferer ◽  
Irina-Roxanna Nat ◽  
Marek Zywicki ◽  
Ahmad Salti ◽  
...  
Keyword(s):  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Neural Differentiation ◽  
Embryonic Stem ◽  
Differentially Expressed ◽  
Non Coding Rnas

Maintenance of Pluripotent Stem Cells is Influenced by Ser/Thr Metabolism

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-43-SCI-43
Author(s):  
Lewis C. Cantley
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Embryonic Stem ◽  
Isocitrate Dehydrogenase 1 ◽  
Advisory Committees ◽  
Metabolic Intermediates ◽  
Stem Cell Maintenance ◽  
Differentiated Cells ◽  
Methylation Of Dna

Abstract Recent studies have suggested not only that stem cells have different metabolic requirements than terminally differentiated cells, but also that metabolic intermediates may play a role in the maintenance of stem cells. It has long been clear that changes in acetylation and methylation of histones, as well as methylation of DNA play critical roles in deciding cell fate. The availability of critical intermediates in metabolism, especially S-adenosylmethionine (SAM), acetyl-CoA, nicotinamide adenine dinucleotide (NAD) and a-ketoglutarate play critical roles in modulating acetylation and methylation of histones and methylation of DNA. In the course of evaluating an unusual requirement of threonine (Thr) for the growth of murine embryonic stem cells, we found that metabolism of Thr to glycine (Gly) and the subsequent use of the methyl group of Gly for converting homocysteine to methionine is critical for maintaining high levels of SAM and low levels of S-adenosyl-homocysteine. Importantly, depletion of Thr from the media resulted in decreased tri-methylation of histone H3 lysine-4 (H3K4me3), leading to slowed growth and increased differentiation. Thus, abundance of SAM appears to influence H3K4me3, providing a possible mechanism by which modulation of a metabolic pathway might influence stem cell fate. Demethylation of histones and DNA can also be controlled by metabolic intermediates. Mutated forms of isocitrate dehydrogenase 1 (IDH1) and IDH2 that drive acute myeloid leukemia (AML) and other cancers, produce an oncometabolite (2-hydrogyglutarate) that can compete with the a-ketoglutarate requirement for enzymes involved in hydroxy-methylation and subsequent demethylation of DNA and histones. Recent studies indicate that 2-hydroxyglutarate plays a role in blocking differentiation of cancer cells. These and other observations linking intermediates in metabolism to stem cell maintenance will be discussed. Disclosures Cantley: Agios Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

scholarly journals Identification of differentially expressed non-coding RNAs in embryonic stem cell neural differentiation

2012 ◽  
Vol 40 (19) ◽  
pp. 9980-9980 ◽  
Author(s):  
K. Skreka ◽  
S. Schafferer ◽  
I.-R. Nat ◽  
M. Zywicki ◽  
A. Salti ◽  
...  
Keyword(s):  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Neural Differentiation ◽  
Embryonic Stem ◽  
Differentially Expressed ◽  
Non Coding Rnas

The chicken stathmin gene and its expression in the embryo

2000 ◽  
Vol 78 (6) ◽  
pp. 703-713 ◽  
Author(s):  
Sharon Soodeen-Karamath ◽  
Ann M Verrinder Gibbins
Keyword(s):  
Es Cells ◽  
Embryonic Stem ◽  
Early Mouse Embryo ◽  
Differentiated Cells ◽  
Selective Ablation ◽  
Potential Indicator ◽  
Early Mouse ◽  
Intron 2

Stathmin, which functions as an intracellular relay in signal transduction pathways, has been suggested as a potential indicator of pluripotent cells in the early mouse embryo. In this study, chicken stathmin cDNA and genomic DNA were analyzed. In mammals stathmin consists of five exons and four introns; exons 3, 4, and 5 in the mammalian stathmin gene are equivalent to one relatively large exon in the chicken stathmin gene. Introns equivalent to introns 3 and 4 in the mammalian stathmin gene are not present in the counterpart gene in chickens and, although intron 2 was shown to be present in both mammals and birds, it is smaller in the chicken stathmin gene. Despite differences in the genomic organization of the gene and its smaller size in chickens compared with that in humans and mice, similarities in the coding sequences and in the expression of the chicken and mouse stathmin genes at certain stages of embryo development, as determined by whole-mount in situ hybridization experiments, suggest that their products are functional homologues. The argument is thus substantiated for further investigations into the use of regulatory regions of the stathmin gene in a system for the establishment of long-term cultures of germline competent chicken embryonic stem (ES) cells by the selective ablation of differentiated cells in culture using drug selection.Key words: stathmin, chicken, ES cells, oct 3/4.

scholarly journals Blockage of neddylation modification stimulates tumor sphere formation in vitro and stem cell differentiation and wound healing in vivo

2016 ◽  
Vol 113 (21) ◽  
pp. E2935-E2944 ◽  
Author(s):  
Xiaochen Zhou ◽  
Mingjia Tan ◽  
Mukesh K. Nyati ◽  
Yongchao Zhao ◽  
Gongxian Wang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Stem Cell ◽  
Human Cancer ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Skin Wound Healing ◽  
Tumor Sphere ◽  
Sphere Formation

MLN4924, also known as pevonedistat, is the first-in-class inhibitor of NEDD8-activating enzyme, which blocks the entire neddylation modification of proteins. Previous preclinical studies and current clinical trials have been exclusively focused on its anticancer property. Unexpectedly, we show here, to our knowledge for the first time, that MLN4924, when applied at nanomolar concentrations, significantly stimulates in vitro tumor sphere formation and in vivo tumorigenesis and differentiation of human cancer cells and mouse embryonic stem cells. These stimulatory effects are attributable to (i) c-MYC accumulation via blocking its degradation and (ii) continued activation of EGFR (epidermal growth factor receptor) and its downstream pathways, including PI3K/AKT/mammalian target of rapamycin and RAS/RAF/MEK/ERK, via inducing EGFR dimerization. Finally, MLN4924 accelerates EGF-mediated skin wound healing in mouse and stimulates cell migration in an in vitro culture setting. Taking these data together, our study reveals that neddylation modification could regulate stem cell proliferation and differentiation and that a low dose of MLN4924 might have a therapeutic value for stem cell therapy and tissue regeneration.

scholarly journals Down-regulation of MicroRNA-21 Is Involved in the Propofol-induced Neurotoxicity Observed in Human Stem Cell–derived Neurons

2014 ◽  
Vol 121 (4) ◽  
pp. 786-800 ◽  
Author(s):  
Danielle M. Twaroski ◽  
Yasheng Yan ◽  
Jessica M. Olson ◽  
Zeljko J. Bosnjak ◽  
Xiaowen Bai
Keyword(s):  
Cell Death ◽  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Human Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Signal Transducer ◽  
Deoxyuridine Triphosphate ◽  
Transcription 3

Abstract Background: Recent studies in various animal models have suggested that anesthetics such as propofol, when administered early in life, can lead to neurotoxicity. These studies have raised significant safety concerns regarding the use of anesthetics in the pediatric population and highlight the need for a better model to study anesthetic-induced neurotoxicity in humans. Human embryonic stem cells are capable of differentiating into any cell type and represent a promising model to study mechanisms governing anesthetic-induced neurotoxicity. Methods: Cell death in human embryonic stem cell–derived neurons was assessed using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling staining, and microRNA expression was assessed using quantitative reverse transcription polymerase chain reaction. miR-21 was overexpressed and knocked down using an miR-21 mimic and antagomir, respectively. Sprouty 2 was knocked down using a small interfering RNA, and the expression of the miR-21 targets of interest was assessed by Western blot. Results: Propofol dose and exposure time dependently induced significant cell death (n = 3) in the neurons and down-regulated several microRNAs, including miR-21. Overexpression of miR-21 and knockdown of Sprouty 2 attenuated the increase in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling–positive cells following propofol exposure. In addition, miR-21 knockdown increased the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling–positive cells by 30% (n = 5). Finally, activated signal transducer and activator of transcription 3 and protein kinase B (Akt) were down-regulated, and Sprouty 2 was up-regulated following propofol exposure (n = 3). Conclusions: These data suggest that (1) human embryonic stem cell–derived neurons represent a promising in vitro human model for studying anesthetic-induced neurotoxicity, (2) propofol induces cell death in human embryonic stem cell–derived neurons, and (3) the propofol-induced cell death may occur via a signal transducer and activator of transcription 3/miR-21/Sprouty 2–dependent mechanism.

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