Abstract
Simple SummaryThis review describes mechanisms driving epithelial plasticity in carcinoma mediated by transforming growth factor beta (TGF-β) signaling. Plasticity in carcinoma is frequently induced through epithelial–mesenchymal transition (EMT), an evolutionary conserved process in the development of multicellular organisms. The review explores the multifaceted functions of EMT, particularly focusing on the intermediate stages, which provide more adaptive responses of carcinoma cells in their microenvironment. The review critically considers how different intermediate or hybrid EMT stages confer carcinoma cells with stemness, refractoriness to therapies, and ability to execute all steps of the metastatic cascade. Finally, the review provides examples of therapeutic interventions based on the EMT concept.Epithelial cell plasticity, a hallmark of carcinoma progression, results in local and distant cancer dissemination. Carcinoma cell plasticity can be achieved through epithelial–mesenchymal transition (EMT), with cells positioned seemingly indiscriminately across the spectrum of EMT phenotypes. Different degrees of plasticity are achieved by transcriptional regulation and feedback-loops, which confer carcinoma cells with unique properties of tumor propagation and therapy resistance. Decoding the molecular and cellular basis of EMT in carcinoma should enable the discovery of new therapeutic strategies against cancer. In this review, we discuss the different attributes of plasticity in carcinoma and highlight the role of the canonical TGFβ receptor signaling pathway in the acquisition of plasticity. We emphasize the potential stochasticity of stemness in carcinoma in relation to plasticity and provide data from recent clinical trials that seek to target plasticity.
Highlights
Cell plasticity can be defined as the ability of a cell to modify its phenotype in response to its microenvironment
Plasticity is primarily conferred by epithelial–mesenchymal transition (EMT), an intrinsic function in the construction of the body plan in metazoans that becomes jeopardized during carcinogenesis
EMT is highly dynamic and partially reversible, positioning carcinoma in an N-dimensional diagram reduced to three dimensions; this is often provided as a Waddington-type diagram to emphasize the epigenetic and energetic intermediate states within the EMT spectrum [1]
Summary
Cell plasticity can be defined as the ability of a cell to modify its phenotype in response to its microenvironment. Plasticity is an exquisite adaptive mechanism to respond to stressors in the microenvironment, endowing cells with the capacity to avoid apoptosis, to acquire stemness and refractoriness to therapy and to transdifferentiate into other cell types. Understanding cell plasticity in carcinoma should help to decipher the intricate mechanisms driving tumor propagation and drug resistance. A deeper understanding of the cellular and molecular mechanisms driving EMT and how these endow cells with plasticity is essential for the design of new therapeutic strategies for patients with cancer. We highlight the recent findings relevant to epithelial cell plasticity in carcinoma and discuss the transcriptional regulators and the impact of transforming growth factor beta (TGF-β) signaling on this pathway. We describe some new therapeutic interventions relevant to the plasticity phenotype of carcinoma
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