Abstract
The epithelial-to-mesenchymal transition (EMT) is an essential trans-differentiation process, which plays a critical role in embryonic development, wound healing, tissue regeneration, organ fibrosis, and cancer progression. It is the fundamental mechanism by which epithelial cells lose many of their characteristics while acquiring features typical of mesenchymal cells, such as migratory capacity and invasiveness. Depending on the contest, EMT is complemented and balanced by the reverse process, the mesenchymal-to-epithelial transition (MET). In the saving economy of the living organisms, the same (Ying-Yang) tool is integrated as a physiological strategy in embryonic development, as well as in the course of reparative or disease processes, prominently fibrosis, tumor invasion and metastasis. These mechanisms and their related signaling (e.g., TGF-β and BMPs) have been effectively studied in vitro by tissue-derived cell spheroids models. These three-dimensional (3D) cell culture systems, whose phenotype has been shown to be strongly dependent on TGF-β-regulated EMT/MET processes, present the advantage of recapitulating in vitro the hypoxic in vivo micro-environment of tissue stem cell niches and their formation. These spheroids, therefore, nicely reproduce the finely regulated Ying-Yang equilibrium, which, together with other mechanisms, can be determinant in cell fate decisions in many pathophysiological scenarios, such as differentiation, fibrosis, regeneration, and oncogenesis. In this review, current progress in the knowledge of signaling pathways affecting EMT/MET and stemness regulation will be outlined by comparing data obtained from cellular spheroids systems, as ex vivo niches of stem cells derived from normal and tumoral tissues. The mechanistic correspondence in vivo and the possible pharmacological perspective will be also explored, focusing especially on the TGF-β-related networks, as well as others, such as SNAI1, PTEN, and EGR1. This latter, in particular, for its ability to convey multiple types of stimuli into relevant changes of the cell transcriptional program, can be regarded as a heterogeneous "stress-sensor" for EMT-related inducers (growth factor, hypoxia, mechano-stress), and thus as a therapeutic target.
Highlights
Our knowledge of the shared pathways in trans-differentiation processes occurring during organogenesis, post-natal tissue repair/regeneration, and tumorigenesis has greatly expanded in the last decades, thanks to improvement of in vitro cell culture technologies, namely three-dimensional (3D) tissue-derived spheroid systems
It has been proposed that miR-200, Zeb, Lin28 and let-7 are all part of a circuit that modulates the epithelial-to-mesenchymal transition (EMT)-stemness network through common regulatory factors, which move the activation of stemness features between a more epithelial or more mesenchymal state [36]
For several tissue-derived cells of heterogeneous origin, grown in an appropriate microenvironment, the spheroid-forming capacity per se is typical of stem/progenitor cells, irrespectively of their normal or neoplastic nature [1,64,104,105]. This spheroid self-building property can be considered as an EMT-dependent process, mediated by TGF-β and its network signaling
Summary
Our knowledge of the shared pathways in trans-differentiation processes occurring during organogenesis, post-natal tissue repair/regeneration, and tumorigenesis has greatly expanded in the last decades, thanks to improvement of in vitro cell culture technologies, namely three-dimensional (3D) tissue-derived spheroid systems. In addition to oxygen gradient, allowing a SC niche-like balance of cell quiescence/proliferation in the spheroid, the specific SC features of drug sensitivity/resistance, as well as phenotypic changes and trans-differentiation ability, can be spontaneously achieved within these systems, opening a window on the natural history of the tissue they came from Their use for protocols of in vitro culture of normal and malignant tissue-derived SCs is available for disease mechanism studies, drug discovery, chemoresistance and high-throughput screening, aiming at identifying molecules that inhibit cancer stem cell (CSC). Proliferation, or at modulating tissue-derived stem cells (tSCs) growth and differentiation In this perspective, the specific trans-differentiation process of epithelial-to-mesenchymal transition (EMT), which is shared by both normal (developing/regenerating) and neoplastic tissues, can be nicely reproduced within ex vivo cultured spheroids. The key pathway of TGF-β, and its related network will be evidenced, and potential pre-clinical/clinical application highlighted
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