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Review
. 2017 Feb;50(1):e12299.
doi: 10.1111/cpr.12299. Epub 2016 Sep 27.

Naturally occurring compounds acting as potent anti-metastatic agents and their suppressing effects on Hedgehog and WNT/β-catenin signalling pathways

L Farahmand  1 , B Darvishi  2 , K Majidzadeh-A  1   3 , A Madjid Ansari  4
Affiliations
Review

Naturally occurring compounds acting as potent anti-metastatic agents and their suppressing effects on Hedgehog and WNT/β-catenin signalling pathways

L Farahmand et al. Cell Prolif. 2017 Feb.

Abstract

Despite numerous remarkable achievements in the field of anti-cancer therapy, tumour relapse and metastasis still remain major obstacles in improvement of overall cancer survival, which may be at least partially owing to epithelial-mesenchymal transition (EMT). Multiple signalling pathways have been identified in EMT; however, it appears that the role of the Hedgehog and WNT/β-catenin pathways are more prominent than others. These are well-known preserved intracellular regulatory pathways of different cellular functions including proliferation, survival, adhesion and differentiation. Over the last few decades, several naturally occurring compounds have been identified to significantly obstruct several intermediates in Hedgehog and WNT/β-catenin signalling, eventually resulting in suppression of signal transduction. This article highlights the current state of knowledge associated with Hedgehog and WNT/β-catenin, their involvement in metastasis through EMT processes and introduction of the most potent naturally occurring agents with capability of suppressing them, eventually overcoming tumour relapse, invasion and metastasis.

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Figures

Figure 1
Figure 1
EMT in microenvironment and metastasis. (1) In carcinoma, there exist a primary epithelial phenotype containing a small group of mesenchymal‐like cancer stem cells. If not stimulated, they will undergo EMT, through genetic, autocrine and paracrine factors. These cells more easily escape from tumour mass by two ways, seeding nearby vasculature or stroma taking part by EMT to achieve mesenchymal features. Through migration, they can surpass the surgical region and consequently avoid surgical removal and radiotherapy and can form local recurrence in any place where re‐epithelialization take place during MET creating new malignancies. (2) The mesenchymal form is the best form to intravasate. (3) and a mixture of phenotypes is observed in blood stream. (4) The next step is extravasation. They may stay dormant; however, in any condition, they may be finally re‐epithelialized by MET and begin a macro‐metastasis with bone destruction abilities
Figure 2
Figure 2
Signalling pathways involved in EMT and the naturally occurring compounds mechanism in suppressing them. (1) In normal condition, Wnt/β‐catenin pathway is kept inactive as the β‐catenin is in complex with APC/Axin complex. (2) by the time Wnt or other specific ligands bind with membrane receptors including frizzled and LRP, or by situations in which APC/Axin become unstable, cascade become activated and result in increasing of free form of β‐catenin and is not anymore phosphorylated and can easily accumulate in cytoplasm. (4) Eventually, this free β‐catenin associate with TCF in nuclease and promotes several Wnt target genes expression. (5) If cell remains in inactive state, APC helps Axin to phosphorylate β‐catenin and results in subsequent degradation of β‐catenin through ubiquitination. (6) Wnt/β‐catenin non‐canonical signalling pathway is transduced independent from β‐catenin activation. After ligation, Dsh by means of Doam 1 activates Rho kinase (ROCK). Dsh also activates Rac, resulting in subsequent activation of JNK. The integrity of these pathways results in cytoskeletal changes and induction of cell polarization and mutilations during “Gastrulation”. (7) In the absence of Hedgehog receptors ligand, Gli is complexed with several proteins including SUFU and create a large complex. In this condition, Ptch proteins result in Gli degradation and formation of repressor form of Gli (Rep‐Gli2/3). (8) By the time Hedgehog ligands interact with Ptch, Smo gets activated and Gli 2 and 3 suppressing events become inhibited. Consequently, Gli translocation in its long form results in inhibition of targeted genes. (9) Overall, after ligation of ligand to TGF‐β receptor, signalling takes part by oligomerization of serine/threonine receptor kinases and subsequent phosphorylation of Smad2 and Smad3. This results in their partnering with Smad4 and translocation to nucleus and activation of related genes transcription
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