Neural stemness contributes to cell tumorigenicity

Abstract Background Previous studies demonstrated the dependence of cancer on nerve. Recently, a growing number of studies reveal that cancer cells share the property and regulatory network with neural stem/progenitor cells. However, relationship between the property of neural stemness and cell tumorigenicity is unknown. Results We show that neural stem/progenitor cells, but not non-neural embryonic or somatic stem/progenitor cell types, exhibit tumorigenicity and the potential for differentiation into tissue types of all germ layers when they are placed in non-native environment by transplantation into immunodeficient nude mice. Likewise, cancer cells capable of tumor initiation have the property of neural stemness because of their abilities in neurosphere formation in neural stem cell-specific serum-free medium and in differentiation potential, in addition to their neuronal differentiation potential that was characterized previously. Moreover, loss of a pro-differentiation factor in myoblasts, which have no tumorigenicity, lead to the loss of myoblast identity, and gain of the property of neural stemness, tumorigenicity and potential for re-differentiation. By contrast, loss of neural stemness via differentiation results in the loss of tumorigenicity. These suggest that the property of neural stemness contributes to cell tumorigenicity, and tumor phenotypic heterogeneity might be an effect of differentiation potential of neural stemness. Bioinformatic analysis reveals that neural genes in general are correlated with embryonic development and cancer, in addition to their role in neural development; whereas non-neural genes are not. Most of neural specific genes emerged in typical species representing transition from unicellularity to multicellularity during evolution. Genes in Monosiga brevicollis, a unicellular species that is a closest known relative of metazoans, are biased toward neural cells. Conclusions We suggest that the property of neural stemness is the source of cell tumorigenicity. This is due to that neural biased unicellular state is the ground state for multicellularity and hence cell type diversification or differentiation during evolution, and tumorigenesis is a process of restoration of neural ground state in somatic cells along a default route that is pre-determined by an evolutionary advantage of neural state.

Download Full-text

Neural stemness contributes to cell tumorigenicity

10.21203/rs.3.rs-49965/v2 ◽

2020 ◽

Author(s):

Liyang Xu ◽

Min Zhang ◽

Lihua Shi ◽

Xiaoli Yang ◽

Lu Chen ◽

...

Keyword(s):

Cancer Cells ◽

Progenitor Cells ◽

Neural Development ◽

Ground State ◽

Cell Types ◽

Bioinformatic Analysis ◽

Neural Cells ◽

Differentiation Potential ◽

Neural Genes ◽

Neural Stem Progenitor Cells

Abstract Background: Previous studies demonstrated the dependence of cancer on nerve. Recently, a growing number of studies reveal that cancer cells share the property and regulatory network with neural stem/progenitor cells. However, relationship between the property of neural stemness and cell tumorigenicity is unknown.Results: We show that neural stem/progenitor cells, but not non-neural embryonic or somatic stem/progenitor cell types, exhibit tumorigenicity and the potential for differentiation into tissue types of all germ layers when they are placed in non-native environment by transplantation into immunodeficient nude mice. Likewise, cancer cells capable of tumor initiation have the property of neural stemness because of their abilities in neurosphere formation in neural stem cell-specific serum-free medium and in differentiation potential, in addition to their neuronal differentiation potential that was characterized previously. Moreover, loss of a pro-differentiation factor in myoblasts, which have no tumorigenicity, lead to the loss of myoblast identity, and gain of the property of neural stemness, tumorigenicity and potential for re-differentiation. By contrast, loss of neural stemness via differentiation results in the loss of tumorigenicity. These suggest that the property of neural stemness contributes to cell tumorigenicity, and tumor phenotypic heterogeneity might be an effect of differentiation potential of neural stemness. Bioinformatic analysis reveals that neural genes in general are correlated with embryonic development and cancer, in addition to their role in neural development; whereas non-neural genes are not. Most of neural specific genes emerged in typical species representing transition from unicellularity to multicellularity during evolution. Genes in Monosiga brevicollis, a unicellular species that is a closest known relative of metazoans, are biased toward neural cells.Conclusions: We suggest that the property of neural stemness is the source of cell tumorigenicity. This is due to that neural biased unicellular state is the ground state for multicellularity and hence cell type diversification or differentiation during evolution, and tumorigenesis is a process of restoration of neural ground state in somatic cells along a default route that is pre-determined by an evolutionary advantage of neural state.

Download Full-text

Neural stemness contributes to cell tumorigenicity

10.21203/rs.3.rs-49965/v1 ◽

2020 ◽

Author(s):

Liyang Xu ◽

Min Zhang ◽

Lihua Shi ◽

Xiaoli Yang ◽

Lu Chen ◽

...

Keyword(s):

Cancer Cells ◽

Progenitor Cells ◽

Neural Development ◽

Ground State ◽

Cell Types ◽

Bioinformatic Analysis ◽

Neural Cells ◽

Differentiation Potential ◽

Neural Genes ◽

Neural Stem Progenitor Cells

Abstract Background Previous studies demonstrated the dependence of cancer on nerve. Recently, a growing number of studies reveal that cancer cells share the property and regulatory network with neural stem/progenitor cells. However, relationship between the property of neural stemness and cell tumorigenicity is unknown. Results We show that neural stem/progenitor cells, but not non-neural embryonic or somatic stem/progenitor cell types, exhibit tumorigenicity and the potential for differentiation into tissue types of all germ layers when they are placed in non-native environment by transplantation into immunodeficient nude mice. Likewise, cancer cells capable of tumor initiation have the property of neural stemness because of their abilities in neurosphere formation in neural stem cell-specific serum-free medium and in differentiation potential, in addition to their neuronal differentiation potential that was characterized previously. Moreover, loss of a pro-differentiation factor in myoblasts, which have no tumorigenicity, lead to the loss of myoblast identity, and gain of the property of neural stemness, tumorigenicity and potential for re-differentiation. These suggest that the property of neural stemness contributes to cell tumorigenicity, and tumor phenotypic heterogeneity might be an effect of differentiation potential of neural stemness. Bioinformatic analysis reveals that neural genes in general are correlated with embryonic development and cancer, in addition to their role in neural development; whereas non-neural genes are not. Most of neural specific genes emerged in typical species representing transition from unicellularity to multicellularity during evolution. Genes in Monosiga brevicollis, a unicellular species that is a closest known relative of metazoans, are biased toward neural cells. Conclusions We suggest that the property of neural stemness is the source of cell tumorigenicity. This is due to that neural biased unicellular state is the ground state for multicellularity and hence cell type diversification or differentiation during evolution, and tumorigenesis is a process of restoration of neural ground state in somatic cells along a default route that is pre-determined by an evolutionary advantage of neural state.

Download Full-text

Zika Virus Infection Leads to Demyelination and Axonal Injury in Mature CNS Cultures

Viruses ◽

10.3390/v13010091 ◽

2021 ◽

Vol 13 (1) ◽

pp. 91

Author(s):

Verena Schultz ◽

Stephanie L. Cumberworth ◽

Quan Gu ◽

Natasha Johnson ◽

Claire L. Donald ◽

...

Keyword(s):

Nervous System ◽

Neural Development ◽

Zika Virus ◽

Developmental Stages ◽

Cell Types ◽

Neural Cells ◽

Zikv Infection ◽

Axonal Pathology ◽

Time Frames

Understanding how Zika virus (Flaviviridae; ZIKV) affects neural cells is paramount in comprehending pathologies associated with infection. Whilst the effects of ZIKV in neural development are well documented, impact on the adult nervous system remains obscure. Here, we investigated the effects of ZIKV infection in established mature myelinated central nervous system (CNS) cultures. Infection incurred damage to myelinated fibers, with ZIKV-positive cells appearing when myelin damage was first detected as well as axonal pathology, suggesting the latter was a consequence of oligodendroglia infection. Transcriptome analysis revealed host factors that were upregulated during ZIKV infection. One such factor, CCL5, was validated in vitro as inhibiting myelination. Transferred UV-inactivated media from infected cultures did not damage myelin and axons, suggesting that viral replication is necessary to induce the observed effects. These data show that ZIKV infection affects CNS cells even after myelination—which is critical for saltatory conduction and neuronal function—has taken place. Understanding the targets of this virus across developmental stages including the mature CNS, and the subsequent effects of infection of cell types, is necessary to understand effective time frames for therapeutic intervention.

Download Full-text

Control of dorsoventral pattern in vertebrate neural development: induction and polarizing properties of the floor plate

Development ◽

10.1242/dev.113.supplement_2.105 ◽

1991 ◽

Vol 113 (Supplement_2) ◽

pp. 105-122 ◽

Cited By ~ 18

Author(s):

Marysia Placzek ◽

Toshiya Yamada ◽

Marc Tessier-Lavigne ◽

Thomas Jessell ◽

Jane Dodd

Keyword(s):

Neural Tube ◽

Neural Development ◽

Cell Types ◽

Floor Plate ◽

Neural Cells ◽

Dorsoventral Patterning ◽

Cellular Mechanisms ◽

Cell Position

Distinct classes of neural cells differentiate at specific locations within the embryonic vertebrate nervous system. To define the cellular mechanisms that control the identity and pattern of neural cells we have used a combination of functional assays and antigenic markers to examine the differentiation of cells in the developing spinal cord and hindbrain in vivo and in vitro. Our results suggest that a critical step in the dorsoventral patterning of the embryonic CNS is the differentiation of a specialized group of midline neural cells, termed the floor plate, in response to local inductive signals from the underlying notochord. The floor plate and notochord appear to control the pattern of cell types that appear along the dorsoventral axis of the neural tube. The fate of neuroepithelial cells in the ventral neural tube may be defined by cell position with respect to the ventral midline and controlled by polarizing signals that originate from the floor plate and notochord.

Download Full-text

Neural is Fundamental: Neural Stemness as the Ground State of Cell Tumorigenicity and Differentiation Potential

10.20944/preprints202012.0122.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Ying Cao

Keyword(s):

Ground State ◽

Cell Biology ◽

Regulatory Networks ◽

Splice Variants ◽

Tumor Biology ◽

General Rule ◽

Tumor Initiating Cells ◽

Differentiation Potential ◽

Neural Stem Progenitor Cells ◽

Long Genes

Tumorigenesis is a complex biological phenomenon that includes extensive genetic and phenotypic heterogeneities and complicated regulatory mechanisms. In the recent few years, our studies demonstrate that tumor-initiating cells are similar to neural stem/progenitor cells in regulatory networks, tumorigenicity and pluripotent differentiation potential. In the review, I will make further discussion on these observations and propose a rule of cell biology by integrating these findings with evidence from developmental biology, tumor biology and evolution, which suggests that neural stemness underlies two coupled cell properties, tumorigenicity and pluripotent differentiation potential. Tumorigenicity and phenotypic heterogeneity in tumor is a result of acquirement of neural stemness in cells. The neural stemness property of tumor-initiating cells can hopefully integrate different concepts/hypotheses underlying tumorigenesis. Neural stem cells/neural progenitors and tumor-initiating cells share regulatory networks; both exhibit neural stemness, tumorigenicity and differentiation potential; both are dependent on expression or activation of ancestral genes (the atavistic effect); both rely primarily on aerobic glycolytic metabolism; both can differentiate into various cells or tissues that are derived from three germ layers, resembling severely disorganized or more severely degenerated process of embryonic development; both are enriched in long genes with more splice variants that provide more plastic scaffolds for cell differentiation, etc. The property of neural stemness might be a key point to understand tumorigenesis and pluripotent differentiation potential, and possibly explain certain pathological observations in tumors that have been inexplicable. Therefore, behind the complexity of tumorigenesis might be a general rule of cell biology, i.e., neural stemness represents the ground state of cell tumorigenicity and pluripotent differentiation potential.

Download Full-text

Genome-wide mapping implicates R-loops in lineage-specific processes and formation of DNA break hotspots in neural stem/progenitor cells

10.1101/2021.09.20.460546 ◽

2021 ◽

Author(s):

Supawat Thongthip ◽

Annika Carlson ◽

Madzia P. Crossley ◽

Bjoern Schwer

Keyword(s):

Progenitor Cells ◽

Cluster Formation ◽

Strand Break ◽

Dna Double Strand Breaks ◽

Strand Breaks ◽

Neural Genes ◽

Genome Wide ◽

Gc Skew ◽

Neural Stem Progenitor Cells ◽

Dna Break

ABSTRACTRecent work has revealed classes of recurrent DNA double-strand breaks (DSBs) in neural stem/progenitor cells, including transcription-associated, promoter-proximal breaks and recurrent DSB clusters in late-replicating, long neural genes. However, the mechanistic factors promoting these different classes of DSBs in neural stem/progenitor cells are not understood. Here, we elucidated the genome-wide landscape of DNA:RNA hybrid structures called “R-loops” in primary neural stem/progenitor cells in order to assess their contribution to the different classes of DNA break “hotspots”. We report that R-loops in neural stem/progenitor cells are associated primarily with transcribed regions that replicate early and genes that show GC skew in their promoter region. Surprisingly, the majority of genes with recurrent DSB clusters in long, neural genes does not show substantial R-loop accumulation. We implicate R-loops in promoter-proximal DNA break formation in highly transcribed, early replicating regions and conclude that R-loops are not a driver of recurrent double-strand break cluster formation in most long, neural genes. Together, our study provides an understanding of how R-loops may contribute to DNA break hotspots and affect lineage-specific processes in neural stem/progenitor cells.

Download Full-text

Glia and Neural Stem and Progenitor Cells of the Healthy and Ischemic Brain: The Workplace for the Wnt Signaling Pathway

Genes ◽

10.3390/genes11070804 ◽

2020 ◽

Vol 11 (7) ◽

pp. 804

Author(s):

Tomas Knotek ◽

Lucie Janeckova ◽

Jan Kriska ◽

Vladimir Korinek ◽

Miroslava Anderova

Keyword(s):

Wnt Signaling ◽

Progenitor Cells ◽

Current Knowledge ◽

Wnt Signaling Pathway ◽

Cell Types ◽

Negative Effects ◽

Future Directions ◽

Ischemic Brain ◽

Stem And Progenitor Cells ◽

Neural Stem Progenitor Cells

Wnt signaling plays an important role in the self-renewal, fate-commitment and survival of the neural stem/progenitor cells (NS/PCs) of the adult central nervous system (CNS). Ischemic stroke impairs the proper functioning of the CNS and, therefore, active Wnt signaling may prevent, ameliorate, or even reverse the negative effects of ischemic brain injury. In this review, we provide the current knowledge of Wnt signaling in the adult CNS, its status in diverse cell types, and the Wnt pathway’s impact on the properties of NS/PCs and glial cells in the context of ischemic injury. Finally, we summarize promising strategies that might be considered for stroke therapy, and we outline possible future directions of the field.

Download Full-text

Impact of Lipid Nutrition on Neural Stem/Progenitor Cells

Stem Cells International ◽

10.1155/2013/973508 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 12

Author(s):

Nobuyuki Sakayori ◽

Ryuichi Kimura ◽

Noriko Osumi

Keyword(s):

Progenitor Cells ◽

Neural Development ◽

Biological Activities ◽

Neural System ◽

Extrinsic Factors ◽

Brain Functions ◽

Dietary Nutrients ◽

Neural Stem Progenitor Cells ◽

Adult Born Neurons ◽

And Function

The neural system originates from neural stem/progenitor cells (NSPCs). Embryonic NSPCs first proliferate to increase their numbers and then produce neurons and glial cells that compose the complex neural circuits in the brain. New neurons are continually produced even after birth from adult NSPCs in the inner wall of the lateral ventricle and in the hippocampal dentate gyrus. These adult-born neurons are involved in various brain functions, including olfaction-related functions, learning and memory, pattern separation, and mood control. NSPCs are regulated by various intrinsic and extrinsic factors. Diet is one of such important extrinsic factors. Of dietary nutrients, lipids are important because they constitute the cell membrane, are a source of energy, and function as signaling molecules. Metabolites of some lipids can be strong lipid mediators that also regulate various biological activities. Recent findings have revealed that lipids are important regulators of both embryonic and adult NSPCs. We and other groups have shown that lipid signals including fat, fatty acids, their metabolites and intracellular carriers, cholesterol, and vitamins affect proliferation and differentiation of embryonic and adult NSPCs. A better understanding of the NSPCs regulation by lipids may provide important insight into the neural development and brain function.

Download Full-text

Genomic Instability and the Oncohistone H3K27M Drive Gliomagenesis in a Murine Model

10.21007/etd.cghs.2020.0515 ◽

2020 ◽

Author(s):

◽

Lee Pribyl ◽

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Progenitor Cells ◽

Neural Development ◽

Genome Stability ◽

Damage Accumulation ◽

Genome Instability ◽

Cortical Development ◽

Neural Cells ◽

Repair Pathways

Maintaining genome stability is crucial for human health and it is of particular importance in neural cells during early brain development. Genome maintenance occurs at two broad stages; surveillance during DNA replication and DNA damage repair in differentiating and mature cells. Neural cells are particularly sensitive to DNA strand breaks and defective DNA damage responses can result in detrimental effects on the nervous system, including cancer. Multiple DNA repair pathways play critical roles in preventing DNA damage accumulation in stem and neural progenitor cells. The mechanisms that protect progenitor genomes also suppress DNA mutations that can result in cancer. A primary objective of this dissertation is to understand the relative contributions of key DNA repair factors that prevent tumorigenesis during cortical development. We have compared the differential effects of inhibition of homologous recombination (HR), via BRCA2-inactivation and non-homologous end-joining (NHEJ), via LIG4-inactivation towards tumorigenesis by directing their deletion specifically to early cortical progenitors using an Emx1-cre recombinase driver. We find that coincident loss of either of these repair pathways with p53 inhibition result in distinct high-grade glioma (HGG) formation resulting from elevated genome instability by DNA damage accumulation during embryogenesis. Furthermore, the presence of the oncohistone H3K27M mutation, commonly found in pediatric HGGs, enhances genome instability and accelerates cortical gliomagenesis with p53 inactivation and defective HR or NHEJ. Additionally, the H3K27M resultant gliomas showed distinctive differences in increased brain tumor penetrance and diffusion. Through RNA-sequencing and whole exome sequencing we identify upregulation of genes normally controlled by bivalent gene promoter post-translational modifications, which result in transcriptional alterations in genes important for both neural development and tumorigenesis. Mechanistically, this is done by targeting specific populations of cortical cells that are more susceptible to DNA damage and transformations that may cause additional critical mutations during a limited timeframe of early cortical development which eventually result in HGGs. We provide evidence supporting that BRCA2 functions to provide DSBR and genome stability to the early-born proliferating cortical progenitor cell population, while LIG4 provides the same function but to a lesser extent to progenitor cells and more so to post-mitotic neurons. Since, epigenetic regulation is tightly connected with neural development and differentiation, we propose the specific genes that H3K27M effects may differ depending on the time period and particular cell state from which the HGG initiates. We believe this contributes to reduced heterogeneity in glioma expression signatures with H3K27M in addition to either HR- or NHEJ-deficiency. Ultimately this work highlights the power of inducible genetically engineered mouse models as an approach to better understand the complexities of providing a connection between genome instability and gliomagenesis.

Download Full-text