Polyphenolic Nutrients in Cancer Chemoprevention and Metastasis: Role of the Epithelial-to-Mesenchymal (EMT) Pathway

Abstract

The epithelial-to-mesenchymal transition (EMT) has received significant interest as a novel target in cancer prevention, metastasis, and resistance. The conversion of cells from an epithelial, adhesive state to a mesenchymal, motile state is one of the key events in the development of cancer metastasis. Polyphenols have been reported to be efficacious in the prevention of cancer and reversing cancer progression. Recently, the antimetastatic efficacy of polyphenols has been reported, thereby expanding the potential use of these compounds beyond chemoprevention. Polyphenols may affect EMT pathways, which are involved in cancer metastasis; for example, polyphenols increase the levels of epithelial markers, but downregulate the mesenchymal markers. Polyphenols also alter the level of expression and functionality of important proteins in other signaling pathways that control cellular mesenchymal characteristics. However, the specific proteins that are directly affected by polyphenols in these signaling pathways remain to be elucidated. The aim of this review is to analyze current evidence regarding the role of polyphenols in attenuating EMT-mediated cancer progression and metastasis. We also discuss the role of the most important polyphenol subclasses and members of the polyphenols in reversing metastasis and targeting EMT. Finally, limitations and future directions to improve our understanding in this field are discussed.

Keywords: cancer; chemoprevention; epithelial mesenchymal transition; metastasis; polyphenols.

Figure 1

Polyphenol classification. The classes of polyphenols include phenolic acids, flavonoids, stilbenes, and lignans. Examples of important subfamilies of each class are shown.

Figure 2

Epithelial to mesenchymal transition (EMT) role in cancer metastasis. The tumor epithelial cells transform mesenchymal invasive cells through EMT (1. EMT). Subsequently, the mesenchymal cells enter the blood circulation to distant places (2. Intravasation) and this results in the homing of circulating tumor cells to specific organs or tissues (3. Extravasation). The metastasized mesenchymal cells transition to the epithelial phenotype through the mesenchymal–epithelial transition (4. MET). The MET-transformed cancer cells become implanted and interact to form new colonies (5. Colonization) and ultimately forming a tumor.

Figure 3

Proposed mechanisms by which dietary polyphenols inhibit EMT and cancer metastasis. The most important extracellular signals are shown, and these promote the epithelial to mesenchymal transition by binding to individual membrane receptors, eventually activating specific EMT-inducing transcription factors (snail, Zeb, and/or twist). The effect of the polyphenols on specific proteins in the signaling pathways at different levels remains to be elucidated. TGF-β: transforming growth factor β; EGF: epidermal growth factor; HGF: hepatocyte growth factor; FGF: fibroblast growth factor; PTCH1: Patched 1; SMO: smoothened; WNT: glycoprotein family; TNF-α: Tumor necrosis factor-α; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; GLI 1: glioma-associated oncogene 1; ERK: extracellular regulated protein kinases; AKT: protein kinase B.