Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Nov 23;8(12):1500.
doi: 10.3390/cells8121500.

TGFβ Family Signaling Pathways in Pluripotent and Teratocarcinoma Stem Cells' Fate Decisions: Balancing Between Self-Renewal, Differentiation, and Cancer

Affiliations
Free PMC article
Review

TGFβ Family Signaling Pathways in Pluripotent and Teratocarcinoma Stem Cells' Fate Decisions: Balancing Between Self-Renewal, Differentiation, and Cancer

Olga Gordeeva. Cells. .
Free PMC article

Abstract

The transforming growth factor-β (TGFβ) family factors induce pleiotropic effects and are involved in the regulation of most normal and pathological cellular processes. The activity of different branches of the TGFβ family signaling pathways and their interplay with other signaling pathways govern the fine regulation of the self-renewal, differentiation onset and specialization of pluripotent stem cells in various cell derivatives. TGFβ family signaling pathways play a pivotal role in balancing basic cellular processes in pluripotent stem cells and their derivatives, although disturbances in their genome integrity induce the rearrangements of signaling pathways and lead to functional impairments and malignant transformation into cancer stem cells. Therefore, the identification of critical nodes and targets in the regulatory cascades of TGFβ family factors and other signaling pathways, and analysis of the rearrangements of the signal regulatory network during stem cell state transitions and interconversions, are key issues for understanding the fundamental mechanisms of both stem cell biology and cancer initiation and progression, as well as for clinical applications. This review summarizes recent advances in our understanding of TGFβ family functions in naїve and primed pluripotent stem cells and discusses how these pathways are involved in perturbations in the signaling network of malignant teratocarcinoma stem cells with impaired differentiation potential.

Keywords: BMP; TGFbeta; cancer stem cells; cell signaling; pluripotent stem cells; teratocarcinoma.

Conflict of interest statement

The author declares no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
The transforming growth factor-β (TGFβ) family signaling pathways contribute to the context-dependent regulation of basic cellular processes though their interplay with the MEK/ERK, phosphatidylinositol 3′-kinase (PI3K)/ protein kinase B (Akt) (purple), WNT/GSK (brown), JAK/STAT (yellow), NOTCH (light blue), and NF-κB (orange) signaling pathways. TGFβ family ligands (TGFβ, Activins, Nodal, Lefties, bone morphogenic proteins (BMPs), and GDFs) bind to type I and type II transmembrane receptors and form an activated receptor complex, which phosphorylates R-Smads (Smad1-3,5,8) proteins. R-Smads-Smad4 complexes are translocated into the nucleus and directly or indirectly regulate the expression of numerous transcriptional factors that support proliferation, differentiation, the epithelial-mesenchymal transition, cell death, and survival. Smad6 and Smad7 antagonize signaling activation by binding to R-Smads and preventing their interaction with Smad4. The canonical TGFβ family signaling pathway contains two branches, TGFβ/ActivinA/Nodal/Smad2/3 (red) and BMP/GDF/Smad1/5/8 (blue), whereas non-canonical TGFβ cascades act through pathways activated by MAPKs (MKK/Jun/p38) (black). TGFβ family signaling pathways are modulated by various agonists and antagonists at different cellular levels.
Figure 2
Figure 2
Signaling and gene regulatory networks in pluripotent (naїve and primed) and teratocarcinoma stem cells. Schematic representation of the TGF-β family, Leukemia inhibiting factor (LIF)/JAK/STAT, MEK/ERK, PI3K/AKT, and WNT/β-catenin/GSK3 signaling pathways and their targets that are involved in the regulation of self-renewal and differentiation of pluripotent and teratocarcinoma stem cells. The LIF/JAK/STAT3 pathway (yellow) activates core pluripotency factors (Oct4, Nanog, and Sox2) and Klf4 and promotes the naїve pluripotent state. The BMP contributes to the self-renewal of naїve pluripotent cells by inducing Id1-3 expression. Suppression of MEK and GSK3β with chemical inhibitors, together with LIF supplementation, facilitates the stabilization of naїve pluripotency and blocks differentiation stimuli. The reversal primed-to-naїve state conversion is achieved through the activation of ectopic expression of OCT4, SOX2, NANOG, KLF4, and KLF2 or exposure to various combinations of small molecule inhibitors and growth factors. The RTK/ PI3K/AKT signaling pathway (purple) supports the self-renewal of both the naїve and primed pluripotent states, whereas the receptor tyrosine kinases (RTK)/MEK/ERK signaling pathway (green) facilitates the transition from the naїve to the primed state. WNT signaling (brown) blocks GSK3 activity and stabilizes β-catenin, which reduces TCF3-mediated repression of pluripotency-specific genes. The bFGF/PI3K/Akt and TGFβ/ActivinA/Nodal signaling pathways stimulate the self-renewal of primed pluripotent stem cells. The TGFβ/Activin/Nodal/Smad2/3 (red) and BMP/GDF/Smad1/5/8 (blue) signaling branches are involved in the maintenance of the naїve and primed pluripotent states and in differentiation into different embryonic and extraembryonic lineages. Crosstalk between the TGFβ family and other signaling pathways and feedback within the TGFβ family signaling branches provide a dynamic equilibrium in the signal network of pluripotent stem cells, whereas TGFβ family signaling pathway rearrangements impair the differentiation of teratocarcinoma stem cells.
Figure 3
Figure 3
The balance of signaling pathways in the regulatory networks of pluripotent and teratocarcinoma stem cells. The LIF/JAK/STAT3, ActivinA/Nodal/Lefty/Smad2/3, PI3K/AKT, and BMP/Smad2/58 signaling pathways promote the maintenance of pluripotent stem cell identity and self-renewal, although the BMP/Smad1/5/8 signaling branch contributes to the regulation of pluripotent stem cell proliferation and differentiation. The MAPK pathway supports viability and induces differentiation. WNT signaling blocks GSK3 activity and stabilizes the expression of pluripotency-specific genes. The increased activity of the ActivinA/Nodal/TGFβ/Smad2/3 and BMP/Smad1/5/8 signaling pathways activates lineage-specific gene expression and thus induces different embryonic lineages. The activity of both the PI3K/AKT and MAPK signaling pathways is significantly attenuated during differentiation, but they contribute to the proliferation and viability of stem cell descendants. WNT/β-catenin signaling induces differentiation through the TCF3-mediated expression of lineage-specific genes. In teratocarcinoma stem cells, both the PI3K/AKT and MAPK signaling pathways are up-regulated, whereas ActivinA/Nodal/TGFβ/Smad2/3 signaling pathway activity is reduced. Reduced TGFβ family signaling pathway activity leads to various rearrangements in gene regulatory networks and impairs the differentiation potential of teratocarcinoma stem cells.

Similar articles

See all similar articles

Cited by 2 articles

References

    1. Derynck R., Miyazono K. TGF-β and the TGF-β family. In: Derynck R., Miyazono K., editors. The TGF-β family. Cold Spring Harbor Laboratory Press; New York, NY, USA: 2008. pp. 29–43.
    1. Schilling S.H., Hjelmeland A.B., Rich J.N., Wang X. TGF-β: A multipotential cytokine. In: Derynck R., Miyazono K., editors. The TGF-β Family. Cold Spring Harbor Laboratory Press; New York, NY, USA: 2008. pp. 45–77.
    1. Mullen A.C., Wrana J.L. TGF-β Family Signaling in Embryonic and Somatic Stem-Cell Renewal and Differentiation. Cold Spring Harb. Perspect. Boil. 2017;9:a022186. doi: 10.1101/cshperspect.a022186. - DOI - PMC - PubMed
    1. Oshimori N., Fuchs E. The harmonies played by TGF-β in stem cell biology. Cell Stem Cell. 2012;11:751–764. doi: 10.1016/j.stem.2012.11.001. - DOI - PMC - PubMed
    1. Caisander G., Park H., Frej K., Lindqvist J., Bergh C., Lundin K., Hanson C. Chromosomal integrity maintained in five human embryonic stem cell lines after prolonged in vitro culture. Chromosome Res. 2006;14:131–137. doi: 10.1007/s10577-006-1019-8. - DOI - PubMed

Publication types

Feedback