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.
Highlights
The transforming growth factor-β (TGFβ) family factors are involved in the regulation of most normal and pathological cellular processes from early development, morphogenesis and histogenesis to various metabolic diseases and cancers
A significant advance in understanding the TGFβ family signaling-based regulation of these basic cellular processes was achieved using in vitro cell models of pluripotent stem cells, which were obtained from early embryos and by reprogramming somatic cells, as well as embryonal carcinoma (teratocarcinoma) cell lines (ECCs) lines that were previously isolated from germ cell tumors
Normal and adapted pluripotent stem and ECC lines are the only well-standardized models for studying the role of TGFβ family signaling in various aspects of cancer stem cell biology: the mechanisms of cancer transformation, cancer evolution and progression, restructuring of signaling pathways and gene regulatory networks, and interactions with various signaling pathways that stabilize normal and abnormal cellular statuses
Summary
The transforming growth factor-β (TGFβ) family factors are involved in the regulation of most normal and pathological cellular processes from early development, morphogenesis and histogenesis to various metabolic diseases and cancers. The activity of different branches of TGFβ family signaling pathways and their interactions with other signaling pathways and intracellular targets govern the fine regulation of the self-renewal, differentiation onset, and step-by-step specialization processes of stem cell descendants in various cell derivatives [3,4]. Pluripotent and teratocarcinoma stem cells are well characterized and stable cell lines that represent unique models for studying the initiation, progression, and development of cancer. These paired models of normal and cancerous stem cells allow us to uncover the normal and transformed cell lineages and understand the mechanisms that regulate the signaling network during each step of multi-lineage differentiation and tumor progression [9]. This review summarizes recent advances in our understanding of the biological roles of TGFβ family factors in pluripotent stem cells and discusses how TGFβ family signaling pathways are involved in perturbations in the regulatory network of teratocarcinoma stem cells, which are the malignant counterparts of pluripotent stem cells
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