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

2020 ◽  
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.

scholarly journals Neural stemness contributes to cell tumorigenicity

2021 ◽  
Vol 11 (1) ◽  
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.

scholarly journals Neural stemness contributes to cell tumorigenicity

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.

scholarly journals Neural stemness contributes to cell tumorigenicity

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.

scholarly journals SAM68: Signal Transduction and RNA Metabolism in Human Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Paola Frisone ◽  
Davide Pradella ◽  
Anna Di Matteo ◽  
Elisa Belloni ◽  
Claudia Ghigna ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Signal Transduction ◽  
Nuclear Export ◽  
Cell Biology ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Splice Variants ◽  
Human Cancer ◽  
Rna Metabolism ◽  
Regulatory Sequences

Alterations in expression and/or activity of splicing factors as well as mutations incis-acting splicing regulatory sequences contribute to cancer phenotypes. Genome-wide studies have revealed more than 15,000 tumor-associated splice variants derived from genes involved in almost every aspect of cancer cell biology, including proliferation, differentiation, cell cycle control, metabolism, apoptosis, motility, invasion, and angiogenesis. In the past decades, several RNA binding proteins (RBPs) have been implicated in tumorigenesis. SAM68 (SRC associated in mitosis of 68 kDa) belongs to the STAR (signal transduction and activation of RNA metabolism) family of RBPs. SAM68 is involved in several steps of mRNA metabolism, from transcription to alternative splicing and then to nuclear export. Moreover, SAM68 participates in signaling pathways associated with cell response to stimuli, cell cycle transitions, and viral infections. Recent evidence has linked this RBP to the onset and progression of different tumors, highlighting misregulation of SAM68-regulated splicing events as a key step in neoplastic transformation and tumor progression. Here we review recent studies on the role of SAM68 in splicing regulation and we discuss its contribution to aberrant pre-mRNA processing in cancer.

Bone Regulation of Insulin Secretion and Glucose Homeostasis

Endocrinology ◽  
2020 ◽  
Vol 161 (10) ◽  
Author(s):  
Patricia Ducy
Keyword(s):  
Cell Biology ◽  
Regulatory Networks ◽  
Bone Growth ◽  
Bone Cells ◽  
Protective Role ◽  
Brain Cell ◽  
Mouse Genetics ◽  
The Body ◽  
Lipocalin 2 ◽  
Inner Organs

Abstract For centuries our image of the skeleton has been one of an inert structure playing a supporting role for muscles and a protective role for inner organs like the brain. Cell biology and physiology modified this view in the 20st century by defining the constant interplay between bone-forming and bone resorbing cells that take place during bone growth and remodeling, therefore demonstrating that bone is as alive as any other tissues in the body. During the past 40 years human and, most important, mouse genetics, have allowed not only the refinement of this notion by identifying the many genes and regulatory networks responsible for the crosstalk existing between bone cells, but have redefined the role of bone by showing that its influence goes way beyond its own physiology. Among its newly identified functions is the regulation of energy metabolism by 2 bone-derived hormones, osteocalcin and lipocalin-2. Their biology and respective roles in this process are the topic of this review.

scholarly journals PPARγ2 Regulates a Molecular Signature of Marrow Mesenchymal Stem Cells

PPAR Research ◽  
2007 ◽  
Vol 2007 ◽  
pp. 1-13 ◽  
Author(s):  
K. R. Shockley ◽  
C. J. Rosen ◽  
G. A. Churchill ◽  
B. Lecka-Czernik
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Biology ◽  
Molecular Signature ◽  
Cell Phenotype ◽  
Differentiation Potential ◽  
Gene Markers ◽  
Therapeutic Consequences ◽  
Expression Of Genes ◽  
Stem Cell Phenotype

Bone formation and hematopoiesis are anatomically juxtaposed and share common regulatory mechanisms. Bone marrow mesenchymal stromal/stem cells (MSC) contain a compartment that provides progeny with bone forming osteoblasts and fat laden adipocytes as well as fibroblasts, chondrocytes, and muscle cells. In addition, marrow MSC provide an environment for support of hematopoiesis, including the development of bone resorbing osteoclasts. The PPARγ2 nuclear receptor is an adipocyte-specific transcription factor that controls marrow MSC lineage allocation toward adipocytes and osteoblasts. Increased expression of PPARγ2 with aging correlates with changes in the MSC status in respect to both their intrinsic differentiation potential and production of signaling molecules that contribute to the formation of a specific marrow microenvironment. Here, we investigated the effect of PPARγ2 on MSC molecular signature in respect to the expression of gene markers associated exclusively with stem cell phenotype, as well as genes involved in the formation of a stem cell supporting marrow environment. We found that PPARγ2 is a powerful modulator of stem cell-related gene expression. In general, PPARγ2 affects the expression of genes specific for the maintenance of stem cell phenotype, including LIF, LIF receptor, Kit ligand, SDF-1, Rex-1/Zfp42, and Oct-4. Moreover, the antidiabetic PPARγagonist TZD rosiglitazone specifically affects the expression of “stemness” genes, including ABCG2, Egfr, and CD44. Our data indicate that aging and antidiabetic TZD therapy may affect mesenchymal stem cell phenotype through modulation of PPARγ2 activity. These observations may have important therapeutic consequences and indicate a need for more detailed studies of PPARγ2 role in stem cell biology.

scholarly journals Multiparametric Phenotypic Screening System for Profiling Bioactive Compounds Using Human Fetal Hippocampal Neural Stem/Progenitor Cells

2015 ◽  
Vol 20 (9) ◽  
pp. 1074-1083 ◽  
Author(s):  
Yoshikuni Tabata ◽  
Norio Murai ◽  
Takeo Sasaki ◽  
Sachie Taniguchi ◽  
Shuichi Suzuki ◽  
...  
Keyword(s):  
Stem Cell ◽  
Regenerative Medicine ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Bioactive Compounds ◽  
Cell Biology ◽  
Stem Cell Biology ◽  
Screening System ◽  
Human Stem Cells ◽  
Neural Stem Progenitor Cells

Stem cell research has been progressing rapidly, contributing to regenerative biology and regenerative medicine. In this field, small-molecule compounds affecting stem cell proliferation/differentiation have been explored to understand stem cell biology and support regenerative medicine. In this study, we established a multiparametric screening system to detect bioactive compounds affecting the cell fate of human neural stem/progenitor cells (NSCs/NPCs), using human fetal hippocampal NSCs/NPCs, HIP-009 cells. We examined effects of 410 compounds, which were collected based on mechanisms of action (MOAs) and chemotypes, on HIP-009’s cell fate (self-renewal, neuronal and astrocytic differentiation) and morphology by automated multiparametric assays and profiled induced cellular phenotypes. We found that this screening classified compounds with the same MOAs into subgroups according to additional pharmacological effects (e.g., mammalian target of rapamycin complex 1 [mTORC1] inhibitors and mTORC1/mTORC2 dual inhibitors among mTOR inhibitors). Moreover, it identified compounds that have off-target effects under matrix analyses of MOAs and structure similarities (e.g., neurotropic effects of amitriptyline among tri- and tetracyclic compounds). Therefore, this automated, medium-throughput and multiparametric screening system is useful for finding compounds that affect the cell fate of human NSCs/NPCs for supporting regenerative medicine and to fingerprint compounds based on human stem cells’ multipotency, leading to understanding of stem cell biology.

Hepatic and pancreatic stellate cells in focus

2009 ◽  
Vol 390 (10) ◽  
Author(s):  
Claus Kordes ◽  
Iris Sawitza ◽  
Dieter Häussinger
Keyword(s):  
Cell Biology ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Differentiation Potential ◽  
Undifferentiated Cells ◽  
Cell Niche ◽  
Space Of Disse

Abstract Stellate cells are vitamin A-storing cells of liver and pancreas and have been described in all vertebrates ranging from lampreys (primitive fish) to humans, demonstrating their major importance. This cell type is thought to contribute to fibrosis, a condition characterized by an excess deposition of extracellular matrix proteins. Recently, the expression of stem/progenitor cell markers, such as CD133 (prominin-1) and Oct4, was discovered in hepatic stellate cells (HSCs) of rats. Moreover, HSCs possess signaling pathways important for maintenance of stemness and cell differentiation, such as hedgehog, β-catenin-dependent Wnt, and Notch signaling, and are resistant to CD95-mediated apoptosis. In analogy to a stem cell niche, some characteristics of quiescent HSC are maintained by aid of a special microenvironment located in the space of Dissé. Finally, stellate cells display a differentiation potential as investigated in vitro and in vivo. Collectively all these properties are congruently found in stem/progenitor cells and support the concept that stellate cells are undifferentiated cells, which might play an important role in liver regeneration. The present review highlights findings related to this novel aspect of stellate cell biology.

scholarly journals The Characteristics Variation of Hepatic Progenitors after TGF-β1-Induced Transition and EGF-Induced Reversion

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Ping Wang ◽  
Min Cong ◽  
Tianhui Liu ◽  
Aiting Yang ◽  
Guangyong Sun ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Cytokeratin 19 ◽  
Oval Cells ◽  
Tumor Initiating Cells ◽  
Deficient Diet ◽  
Differentiation Potential ◽  
Mesenchymal Transition ◽  
Hepatic Oval Cells

Profibrogenesis cytokine, transforming growth factor- (TGF-)β1, induces hepatic progenitors experiencing epithelial to mesenchymal transition (EMT) to matrix synthesis cells, even tumor initiating cells. Our previous data found that epidermal growth factor (EGF) blocks and reverses TGF-β1-induced transition. The aim of this study is to determine the characteristic changes of hepatic progenitors after TGF-β1-induced transition and EGF-induced reversion. Hepatic oval cells, rat hepatic progenitors, were isolated from rats fed a choline-deficient diet supplemented with ethionine. TGF-β1-containing medium was used for inducing EMT, while EGF-containing medium was used for reversing EMT. During TGF-β1-induced transition and EGF-induced reversion, hepatic oval cells sustained their progenitor cell marker expression, includingα-fetoprotein, albumin, and cytokeratin-19. The proliferation ability and differentiation potential of these cells were suppressed by TGF-β1, while EGF resumed these capacities to the level similar to the control cells. RNA microarray analysis showed that most of the genes with significant changes after TGF-β1 incubation were recovered by EGF. Signal pathway analysis revealed that TGF-β1 impaired the pathways of cell cycle and cytochrome P450 detoxification, and EGF reverted TGF-β1 effects through activating MAPK and PI3K-Akt pathway. EGF reverses the characteristics impaired by TGF-β1 in hepatic oval cells, serving as a protective cytokine to hepatic progenitors.

A recessive screen for genes regulating hematopoietic stem cells

Blood ◽  
2010 ◽  
Vol 116 (26) ◽  
pp. 5849-5858 ◽  
Author(s):  
Peter Papathanasiou ◽  
Robert Tunningley ◽  
Diwakar R. Pattabiraman ◽  
Ping Ye ◽  
Thomas J. Gonda ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Cell Biology ◽  
Regulatory Networks ◽  
Novel Mutation ◽  
Chemical Mutagenesis ◽  
Myb Transcription Factor ◽  
Cell Sorter ◽  
Hematopoietic Stem

Abstract Identification of genes that regulate the development, self-renewal, and differentiation of stem cells is of vital importance for understanding normal organogenesis and cancer; such knowledge also underpins regenerative medicine. Here we demonstrate that chemical mutagenesis of mice combined with advances in hematopoietic stem cell reagents and genome resources can efficiently recover recessive mutations and identify genes essential for generation and proliferation of definitive hematopoietic stem cells and/or their progeny. We used high-throughput fluorescence-activated cell sorter to analyze 9 subsets of blood stem cells, progenitor cells, circulating red cells, and platelets in more than 1300 mouse embryos at embryonic day (E) 14.5. From 45 pedigrees, we recovered 6 strains with defects in definitive hematopoiesis. We demonstrate rapid identification of a novel mutation in the c-Myb transcription factor that results in thrombocythemia and myelofibrosis as proof of principal of the utility of our fluorescence-activated cell sorter–based screen. Such phenotype-driven approaches will provide new knowledge of the genes, protein interactions, and regulatory networks that underpin stem cell biology.

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