Epithelial-mesenchymal transition as a target for botanicals in cancer metastasis
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.
References (165)
- et al.
Honokiol inhibits epithelial-mesenchymal transition in breast cancer cells by targeting signal transducer and activator of transcription 3/Zeb1/E-cadherin axis
Mol. Oncol.
(2014) - et al.
Phytochemicals for human disease: an update on plant-derived compounds antibacterial activity
Microbiol. Res.
(2017) - et al.
Quercetin reverses EGF-induced epithelial to mesenchymal transition and invasiveness in prostate cancer (PC-3) cell line via EGFR/PI3K/Akt pathway
J. Nutr. Biochem.
(2014) - et al.
Dietary flavonoids and modulation of natural killer cells: implications in malignant and viral diseases
J. Nutr. Biochem.
(2017) - et al.
Novel merosesquiterpene exerts a potent antitumor activity against breast cancer cells in vitro and in vivo
Eur. J. Med. Chem.
(2014) - et al.
Luteolin attenuates TGF-β1-induced epithelial-mesenchymal transition of lung cancer cells by interfering in the PI3K/Akt-NF-κB-Snail pathway
Life Sci.
(2013) - et al.
Baicalin and baicalein inhibit transforming growth factor-β1-mediated epithelial-mesenchymal transition in human breast epithelial cells
Biochem. Biophys. Res. Commun.
(2015) - et al.
Silibinin inhibits fibronectin induced motility, invasiveness and survival in human prostate carcinoma PC3 cells via targeting integrin signaling
Mutat. Res. Fundam. Mol. Mech. Mutagen.
(2014) - et al.
In vitro inhibitory effects of terpenoids from Chloranthus multistachys on epithelial-mesenchymal transition via down-regulation of Runx2 activation in human breast cancer
Phytomedicine
(2015) - et al.
Diosmetin prevents TGF-β1-induced epithelial-mesenchymal transition via ROS/MAPK signaling pathways
Life Sci.
(2016)
Rubus idaeus L. reverses epithelial-to-mesenchymal transition and suppresses cell invasion and protease activities by targeting ERK1/2 and FAK pathways in human lung cancer cells
Food Chem. Toxicol.
Cardioprotective effects of moderate red wine consumption: polyphenols vs. ethanol
J. Appl. Biomed.
Anti-metastatic potential of resveratrol and its metabolites by the inhibition of epithelial-mesenchymal transition, migration, and invasion of malignant cancer cells
Phytomedicine
Curcumin and treatment of melanoma: The potential role of microRNAs
Biomed. Pharmacother.
Honokiol suppresses renal cancer cells’ metastasis via dual-blocking epithelial-mesenchymal transition and cancer stem cell properties through modulating miR-141/ZEB2 signaling
Mol. Cells
Targeting cancer stem cells by curcumin and clinical applications
Cancer Lett.
N-hydroxycinnamide derivatives of osthole inhibit cell migration and invasion by suppressing smad2 and akt pathways in human colorectal adenocarcinoma cells
Chem. Biol. Interact.
Resveratrol limits epithelial to mesenchymal transition through modulation of KHSRP/hnRNPA1-dependent alternative splicing in mammary gland cells
Biochim. Biophys. Acta–Gene Regul. Mech.
Berberine induces neuronal differentiation through inhibition of cancer stemness and epithelial-mesenchymal transition in neuroblastoma cells
Phytomedicine
Emodin suppresses Wnt signaling in human colorectal cancer cells SW480 and SW620
Eur. J. Pharmacol.
Garcinol regulates EMT and Wnt signaling pathways in vitro and in vivo, leading to anticancer activity against breast cancer cells
Mol. Cancer Ther.
Resveratrol: potential as anticancer agent
J. Diet. Suppl.
Role of the microtubule-targeting drug vinflunine on cell-cell adhesions in bladder epithelial tumour cells
BMC Cancer
Biological influence of Hakai in cancer: a 10-year review
Cancer Metastasis Rev.
Structure-activity relationship study of hydroxycoumarins and mushroom tyrosinase
J. Agric. Food Chem.
Curcumin inhibits hypoxia-induced angiogenesis via down-regulation of HIF-1
Oncol. Rep.
Cytotoxic and antioxidant activities of Alstonia scholaris, Alstonia venenata and Moringa oleifera plants from India
Jundishapur. J. Nat. Pharm. Prod.
Gold nanoparticle–conjugated quercetin inhibits epithelial–mesenchymal transition, angiogenesis and invasiveness via EGFR/VEGFR‐2‐mediated pathway in breast cancer
Cell Prolif.
Resveratrol and myopathy
Nutrients
A controlled study of a lecithinized delivery system of curcumin (meriva®) to alleviate the adverse effects of cancer treatment
Phytother. Res.
Effect of tea polyphenol compounds on anticancer drugs in terms of anti-tumor activity, toxicology, and pharmacokinetics
Nutrients
Curcumin inhibits hypoxia-induced epithelial'mesenchymal transition in pancreatic cancer cells via suppression of the hedgehog signaling pathway
Oncol. Rep.
Black tea polyphenols reverse epithelial-to-mesenchymal transition and suppress cancer invasion and proteases in human oral cancer cells
J. Agric. Food Chem.
Curcumin suppresses metastasis via Sp-1, FAK inhibition, and E-cadherin upregulation in colorectal cancer
Evid. Based Complement. Altern. Med.
Resveratrol inhibits transforming growth factor-β2-induced epithelial-to-mesenchymal transition in human retinal pigment epithelial cells by suppressing the smad pathway
Drug Des. Dev. Ther.
Resveratrol inhibits LPS-induced epithelial-mesenchymal transition in mouse melanoma model
Innate Immun.
The ERK-ZEB1 pathway mediates epithelial-mesenchymal transition in pemetrexed resistant lung cancer cells with suppression by vinca alkaloids
Oncogene
Natural polyphenols and their synthetic analogs as emerging anticancer agents
Curr. Drug Targets
Taking cell-matrix adhesions to the third dimension
Science
Chemopreventive activity of systemically administered curcumin on oral cancer in the 4‐nitroquinoline 1‐oxide model
J. Cell. Biochem.
Dietary pterostilbene is a novel MTA1-targeted chemopreventive and therapeutic agent in prostate cancer
Oncotarget
Curcumin inhibits prostate cancer bone metastasis by up-regulating bone morphogenic protein-7 in vivo
J. Cancer Ther.
Naturally occurring compounds acting as potent anti-metastatic agents and their suppressing effects on Hedgehog and WNT/β-catenin signalling pathways
Cell Prolif.
Osthole inhibited TGF β-induced epithelial–mesenchymal transition (EMT) by suppressing NF-κB mediated Snail activation in lung cancer A549 cells
Cell Adhes. Migr.
Antitumor effects of saffron-derived carotenoids in prostate cancer cell models
BioMed Res. Int.
Collective cell migration in morphogenesis, regeneration and cancer
Nat. Rev. Mol. Cell Biol.
Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex
Nat. Cell Biol.
Oleanolic acid suppresses migration and invasion of malignant glioma cells by inactivating MAPK/ERK signaling pathway
PLoS ONE
Low-dose paclitaxel inhibits the induction of epidermal-mesenchymal transition in the human cholangiocarcinoma CCKS-1 cell line
Oncol. Lett.
I3C and ICZ inhibit migration by suppressing the EMT process and FAK expression in breast cancer cells
Mol. Med. Rep.
Cited by (24)
Repurposing of plant alkaloids for cancer therapy: Pharmacology and toxicology
2021, Seminars in Cancer BiologyCitation Excerpt :Certain transcription factors, e.g. SNAIL-1/2 and SLUG, orchestrate the expression of these invasion and metastasis factors. Numerous investigations pointed to the inhibition of metastatic tumors by phytochemicals [55–59]. We report here on papers, which describe either the inhibition of metastases by plant alkaloids in vivo or the inhibition of primary tumors in vivo and mechanisms of metastasis inhibition in vitro (Table 8).
Natural alkaloid 8-oxo-epiberberine inhibited TGF-β1-triggred epithelial-mesenchymal transition by interfering Smad3
2020, Toxicology and Applied PharmacologyCitation Excerpt :EMT and its signaling pathways have provided novel strategies and potential targets for cancer treatment (Voon et al., 2017; Singh et al., 2018; Cho et al., 2019; Pearson, 2019). Especially, a panel of bioactive phytochemicals and small molecules with EMT-inhibitory properties have demonstrated therapeutic potentials for cancer and fibrosis (Salehi et al., 2019; Feng et al., 2020). 8-Oxo-epiberberine (OPB) (Fig. 1), a protoberberine alkaloid, was firstly isolated from the natural source of the rhizome of Coptis japonica Makino (Ranunculaceae) in 2006 (Min et al., 2006).
Therapeutic targeting of SNAIL, RKIP, and YY1 in tumor metastasis and drug resistance
2020, Prognostic and Therapeutic Applications of RKIP in CancerDesign, synthesis, anticancer, antibacterial, and antifungal evaluation of 4-aminoquinoline-1,3,5-triazine derivatives
2020, Journal of Heterocyclic ChemistryMechanism of epithelial-mesenchymal transition in cancer and its regulation by natural compounds
2023, Medicinal Research Reviews