cancers Review Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance Sofia Papanikolaou, Aikaterini Vourda, Spyros Syggelos and Kostis Gyftopoulos * Department of Anatomy, University of Patras School of Medicine, Rion, 26504 Patras, Greece; [email protected] (S.P.); [email protected] (A.V.); [email protected] (S.S.) * Correspondence: [email protected] Simple Summary: Although epithelial-to-mesenchymal transition (EMT) is a well-known cellular process involved during normal embryogenesis and wound healing, it also has a dark side; it is a complex process that provides tumor cells with a more aggressive phenotype, facilitating tumor metastasis and even resistance to therapy. This review focuses on the key pathways of EMT in the pathogenesis of prostate cancer and the development of metastases and evasion of currently available treatments. Abstract: Prostate cancer, the second most common malignancy in men, is characterized by high heterogeneity that poses several therapeutic challenges. Epithelial–mesenchymal transition (EMT) is a dynamic, reversible cellular process which is essential in normal embryonic morphogenesis and Citation: Papanikolaou, S.; Vourda, wound healing. However, the cellular changes that are induced by EMT suggest that it may also A.; Syggelos, S.; Gyftopoulos, K. Cell play a central role in tumor progression, invasion, metastasis, and resistance to current therapeutic Plasticity and Prostate Cancer: The options. These changes include enhanced motility and loss of cell–cell adhesion that form a more Role of Epithelial–Mesenchymal aggressive cellular phenotype. Moreover, the reverse process (MET) is a necessary element of the Transition in Tumor Progression, Invasion, Metastasis and Cancer metastatic tumor process. It is highly probable that this cell plasticity reflects a hybrid state between Therapy Resistance. Cancers 2021, 13, epithelial and mesenchymal status. In this review, we describe the underlying key mechanisms of the 2795. https://doi.org/10.3390/ EMT-induced phenotype modulation that contribute to prostate tumor aggressiveness and cancer cancers13112795 therapy resistance, in an effort to provide a framework of this complex cellular process. Academic Editor: José Antonio Keywords: prostate cancer; EMT; metastasis; cell plasticity; therapy resistance López-Guerrero Received: 16 May 2021 Accepted: 1 June 2021 1. Introduction Published: 4 June 2021 Prostate cancer (PCa) is the second most frequently diagnosed male malignancy and the second leading cause of cancer mortality in men [1]. As a general rule, both incidence Publisher’s Note: MDPI stays neutral and mortality of PCa correlate with advancing age, with the average age at the time of with regard to jurisdictional claims in diagnosis being 66 years [2]. For African American men, the incidence rates are higher published maps and institutional affil- when compared to White men; alarmingly, they also have the highest chance of being iations. diagnosed at a younger age (<40 years) [3]. However, this is also true for men generally; the incidence of PCa in young men is rising, and their younger age poses a higher risk for metastatic disease and eventually a higher mortality [3]. It is estimated that mortality will double from 2018 to 2040, reaching 379,005 deaths worldwide. The highest mortality rates Copyright: © 2021 by the authors. are expected in Africa (+124.4%) and Asia (116.7%), while the lowest incidence is expected Licensee MDPI, Basel, Switzerland. to be registered in Europe (+58.3%) [4]. It is well known that PCa is a multifocal disease This article is an open access article with a heterogeneous cell population. This excessive heterogeneity and plasticity which distributed under the terms and characterize prostate tumors underline the regulatory phenotypic changes in individual conditions of the Creative Commons Attribution (CC BY) license (https:// cells that contribute to metastasis and therapeutic resistance [5]. The critical problem creativecommons.org/licenses/by/ in the available pharmaceutical therapeutic approach of PCa is that PCa unavoidably 4.0/). develops resistance to androgen deprivation therapy (ADT) at some stage and progresses Cancers 2021, 13, 2795. https://doi.org/10.3390/cancers13112795 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x FOR PEER REVIEW 2 of 29 Cancers 2021, 13, 2795 the available pharmaceutical therapeutic approach of PCa is that PCa unavoidably 2devel- of 29 ops resistance to androgen deprivation therapy (ADT) at some stage and progresses to castration-resistant PCa (CRPC), which is characterized by invasiveness and metastatic tospread castration-resistant of CRPC cells; PCa this (CRPC), phenomenon which isstil characterizedl represents bythe invasiveness major cause andof PCa-related metastatic spreaddeath. ofThus, CRPC understanding cells; this phenomenon the cellular and still representsmolecular mechanisms the major cause underlying of PCa-related the pro- death.cess of Thus, metastatic understanding dissemination the cellular of PCa and remains molecular a challenge mechanisms for underlyingbetter management the process of ofPCa. metastatic dissemination of PCa remains a challenge for better management of PCa. Recently,Recently, ample ample evidence evidence of of epithelial–mesenchymal epithelial–mesenchymal plasticity plasticity playing playing a a role role in in both both PCaPCa metastatic metastatic progression progression and and treatment treatment resistance resistance has has been been provided provided in in severalseveral reports.reports. Epithelial–mesenchymalEpithelial–mesenchymal transitiontransition (EMT) is is a a molecular molecular cellular cellular program program essential essential for for de- development,velopment, and and the the relevant relevant processes processes are are reac reactivatedtivated during during wound wound healing, healing, fibrosis, fibrosis, and andcancer cancer progression progression [6,7]. [6 During,7]. During EMT, EMT, epithelial epithelial cells cells lose losetheir their junctions junctions and andapical–basal apical– basalpolarity, polarity, restructure restructure their their cytoskeleton, cytoskeleton, unde undergorgo changes changes in the in thesignaling signaling programs programs that thatspecify specify cell cellshape, shape, and andreprogram reprogram gene gene expression; expression; this thisenhances enhances the motility the motility of individ- of in- dividualual cells cellsand empowers and empowers the progression the progression of a mo of are more invasive invasive phenotype phenotype [8,9]. [ 8EMT,9]. EMT is iden- is identifiedtified by a by loss a loss of epithelial of epithelial markers markers such such as ascytokeratins cytokeratins and and E-ca E-cadherin,dherin, followed followed by by a aconcurrent concurrent increase increase in in mesenchymal markers such asas N-cadherinN-cadherin andand vimentinvimentin [ 10[10].]. In In cancercancer progression, progression, this this is is connected connected with with poor poor clinical clinical outcome outcome and and therapy therapy resistance resistance in in severalseveral cancer cancer types types [ 11[11].]. InIn PCa,PCa, for for instance, instance, lossloss ofof E-cadherin E-cadherin expressionexpression andand overex-overex- pressionpression of of N-cadherin N-cadherin correlate correlate with with tumor tumor grade grade and and recurrence recurrence after after surgery, surgery, providing provid- aing clinically a clinically significant significant link oflink EMT of EMT to aggressive to aggressive clinical clinical behavior behavior in advanced in advanced disease disease [12]. The[12]. cellular The cellular processes processes of EMT of areEMT coordinated are coordinated by several by several key transcription key transcription factors factors (e.g., TWIST,(e.g., TWIST, SNAI1, SNAI1, SNAI2, SNAI2, ZEB 1/2) ZEB that 1/2) act that in unisonact in unison with several with several epigenetic epigenetic mechanisms mecha- andnisms post-translational and post-translational protein protein modifications modifications to arrange to arrange the cellular the cellular alterations alterations [13]. The[13]. mainThe main molecular molecular events events are depicted are depicted in Figure in Figure1. 1. FigureFigure 1. 1.Schematic Schematic representationrepresentation of of cellular cellular changes changes and and main main molecular molecular events events during during epithelial– epithelial– mesenchymal transition (EMT) and the reverse MET. mesenchymal transition (EMT) and the reverse MET. DifferentDifferent critical critical signaling signaling pathways pathways including including TGF- TGF-ββ,, WNT, WNT, NOTCH, NOTCH, and and growth growth factorsfactors are are involved involved in in inducing inducing EMT EMT under under specific specific physiological physiological conditions. conditions. Extensive Extensive researchresearch andandavailable available datadata are are suggesting suggesting that that EMT EMT facilitates facilitates tumor tumor progression progression and and metastasismetastasis inin severalseveral cancercancer types.types. InIn thisthis review,review, wewe summarizesummarize andand referrefer to to the the main main molecular events that control the EMT phenomenon in PCa, in order to better describe its role and mechanisms in PCa progression and therapeutic resistance. Cancers 2021, 13, 2795 3 of 29 2. Molecular Events Governing EMT in Cancer