Elsevier

Phytomedicine

Volume 55, 1 March 2019, Pages 125-136
Phytomedicine

Epithelial-mesenchymal transition as a target for botanicals in cancer metastasis

https://doi.org/10.1016/j.phymed.2018.07.001Get rights and content

Abstract

Background

The plant kingdom represents an unlimited source of phytotherapeutics with promising perspectives in the field of anticancer drug discovery.

Purpose

In this view, epithelial-mesenchymal transition (EMT) represents a novel and major target in anticancer therapy. Therefore, this narrative review aims to provide an updated overview on the bioactive phytochemicals with anti-EMT activity.

Conclusion

Among the plant products reviewed, phenylpropanoids were the most investigated at preclinical phase, thus exhibiting a promising potential as anticancer drugs, though an evidence-based clinical efficacy is still lacking.

Introduction

Epithelial-mesenchymal transition (EMT) is a physiological process in which polarized epithelial cells, which routinely interact with basement membrane via their basal surface, can undergo several biochemical and molecular alterations that enable them to acquire mesenchymal cell traits (Nisticò et al., 2012). Features of mesenchymal cells include enhanced migratory properties, invasiveness, increased resistance to apoptosis, and highly augmented production of extracellular matrix (ECM) constituents (Salehi et al., 2018c, Zeisberg and Neilson, 2009). Epithelial cells undergoing a primary EMT usually go through some or all of the following phases: (a) specialization of these cells to differentiate into a type of cell that will go through EMT; (b) patterning of the progress of the EMT within the area committed to undergo EMT; (c) epithelial morphogenesis, which results in moving toward the site of EMT; (d) change or disruption of the basal lamina; (e) alteration in cell shape, generally by an apical actin-myosin contractile mechanism and/or changes in attachment; (f) de-epithelialization, (g) ingression, withdrawal of the ingressing cell's apex from the epithelial layer and into the deep layer; (h) retaining epithelial integrity; i) turning off the remnant epithelial properties and turning on properties of a mesenchymal phenotype (Shook and Keller, 2003). Therefore, the main cellular event in the process of EMT is the conversion of epithelial cells into a mesenchymal phenotype. Epithelial cells are interconnected by cell-cell junctions, which are tight seals that can largely constrain the movement of epithelial cells to the confines of the epithelial sheet. These intercellular junctions play critical roles in epithelial function and integrity. Key components of epithelial cell junctions include E-cadherins, transmembrane proteins that connect neighboring cells, and β-catenins, part of the protein complex that physically links cadherins with the actin cytoskeleton at the adherens junctions (AJ). Mesenchymal cells, in contrast to epithelial cells, can migrate easily in three dimensions, leading to migration along collagen molecules and interaction with ECM components (Cukierman et al., 2001, Marcucci et al., 2016, Voulgari and Pintzas, 2009). There are three different EMT subtypes, each with very functional differences. Type 1 EMT is recognized as a normal physiological process that affects embryogenesis, implantation, and organ development. Type 2 EMT occurs in association with wound healing and organ fibrosis. Type 3 EMT is related to cancer progression and metastasis (Kalluri, 2009, Shu et al., 2010). Fig. 1 describes the biological pathways involved in the transition. Conversion of epithelial cells to mesenchymal phenotype was first described by Elizabeth Hay as an “epithelial-mesenchymal transformation” . Subsequently, the term “transformation” was replaced with “transition”. The latter term indicates that the process of EMT is reversible and is different from neoplastic transformation. The phenotypic convertibility of EMT is revealed by the occurrence of the reverse process, the MET, which involves the conversion of mesenchymal cells to epithelial phenotype (Kalluri and Weinberg, 2010). At metastatic site, MET can stimulate EMT-transited cells to form a tumor which resemble the primary tumor, with the disappearance of mesenchymal phenotype. This EMT-MET interconversion is a realistic model for explaining the mechanism of cancer cell metastasis: EMT induces alterations in epithelial cell features to facilitate the evasion of these cells from their structural constraints imposed by tissue architecture, whereas MET reverses these alterations and facilitates colonization in secondary metastatic sites (Friedl and Gilmour, 2009, Hugo et al., 2007, Micalizzi et al., 2010).

Section snippets

Phytochemicals involved in Epithelial-mesenchymal transition

In the last few years, the interest in natural products with biological activities (i.e. antioxidant, antimicrobial, anticancer, anti-inflammatory and so on) has increased (Asthana et al., 2015, Bagheri et al., 2016, Sahraie-Rad et al., 2015, Salehi et al., 2018a, Salehi et al., 2018b, Salehi et al., 2018c, Sharifi-Rad et al., 2018a, Sharifi-Rad et al., 2018b, Sharifi-Rad et al., 2018c, Zucca et al., 2015, Zucca et al., 2016). Indeed, phytochemicals usually show lower toxic effects than

Phenylpropanoids

Phenylpropanoids are a group of plant secondary metabolites abundant in medicinal and food plants and including simple phenols and polyphenols (Sanjust et al., 2008). In turn, polyphenols can be further divided into flavonoids, stilbenes and proanthocyanidins (or condensed tannins). These phenylalanine derivatives exert a pivotal ecological role in planta, due to their involvement in pollination, seed dispersal, protection from UV and solar irradiation, and defense against pathogens and

Isoprenoids

A number of isoprenoids or terpenes have been involved in EMT as well. These phytochemicals derive from the oligomerization of isopentenyl pyrophosphate and dimethylallyl pyrophosphate building blocks (both arising from mevalonate pathway, through the key enzyme 3‑hydroxy‑3-methyl-glutaryl-CoA reductase, E.C. 1.1.1.88), thus presenting the typical isoprene (C5H8) unit (Fig. 6) (Iriti and Varoni, 2015). Terpenes are widely distributed among the plant kingdom, and some compounds belonging to this

Alkaloids

Alkaloids are naturally occurring chemicals mostly presenting nitrogen atoms, with very variable chemical structure, typically sharing the behavior as weak bases (Iriti and Faoro, 2009). The concept of alkaloids was introduced in 1819 by the German chemist Carl Friedrich Wilhelm Meissner (Barbieri et al., 2017). The first isolated alkaloid was morphine from opium, followed by strychnine, emetine, caffeine, quinine and so on. The definition of alkaloids is not very clear. Usually, amino acids,

Miscellanea

Other phytochemicals, not belonging to the previously mentioned chemical classes, were able to suppress EMT.

For instance, indole-3-carbinol and indole[3,2-b]carbazole were associated to increased epithelial marker E-cadherin and decreased mesenchymal marker vimentin (Ho et al., 2013). These bioactive compounds are indole derivatives produced by the breakdown of glucosinolates (such as glucobrassicin), present at high concentration in many cruciferous vegetables (broccoli, cauliflower, brussels

Conclusion

At the end of this survey, it seems evident that phytochemicals represent a promising source of anti-EMT agents in the development of innovative anticancer drugs. Among the plant products reviewed, phenylpropanoids were the most investigated at preclinical phase, thus exhibiting a potential as novel anticancer drugs, though an evidence-based clinical efficacy is still lacking. Indeed, the paucity of in human studies represents a major drawback in this field of research. In addition, our

Conflict of interest

We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

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