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Flavonoids, a ubiquitous dietary phenolic subclass, exert extensive in vitro anti-invasive and in vivo anti-metastatic activities

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Abstract

Cancer metastasis refers to the spread of cancer cells from the primary neoplasm to distant sites, where secondary tumors are formed, and is the major cause of death from cancer. Natural phytochemicals containing phenolic compounds have been widely demonstrated to have the capability to prevent cancer metastasis. Among phenolic compounds, flavonoids are a very large subclass, and they are abundant in food and nutraceuticals. The number of reports demonstrating that flavonoids are an effective natural inhibitor of cancer invasion and metastasis is increasing in the scientific literature. Catechin derivatives, (−)-epigallocatechin-3-gallate, (−)-epigallocatechin, (−)-epicatechin-3-gallate, and (−)-epicatechin, are the most studied compounds in this topic so far; genistein/genistin, silibinin, quercetin, and anthocyanin have also been widely investigated for their inhibitory activities on invasion/metastasis. Other flavonoids in dietary vegetable foods that are responsible for anti-invasive and anti-metastatic activities of tumors include luteolin, apigenin, myricetin, tangeretin, kaempferol, glycitein, licoricidin, daidzein, and naringenin. To effectively overcome the metastatic cascade, including cell–cell attachment, tissue-barrier degradation, migration, invasion, cell–matrix adhesion, and angiogenesis, it is essential that a bioactive compound prevent tumor cells from metastasizing. This review summarizes the effects of flavonoids on the metastatic cascade and the related proteins, the in vitro anti-invasive activity of flavonoids against cancer cells, and the effects of flavonoids on anti-angiogenic and in vivo anti-metastatic models. The available scientific evidence indicates that flavonoids are a ubiquitous dietary phenolics subclass and exert extensive in vitro anti-invasive and in vivo anti-metastatic activities.

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Abbreviations

Ang:

Angiopoietin

AOM:

Azoxymethane

CXCR4:

CXC chemokine receptor 4

COX-2:

Cyclooxygenase-2

ECM:

Extracellular matrix

EGCG:

(−)-Epigallocatechin-3-gallate

EGFR:

Epidermal growth factor receptor

EMMPRIN:

Extracellular matrix metalloproteinase inducer

EMT:

Epithelial–mesenchymal transition

ER:

Estrogen receptor

ErbB2:

Epidermal growth factor receptor-related protein B2

FAK:

Focal adhesion kinase

FOXO3:

Forkhead box O3

HGF:

Hepatocyte growth factor

HIF:

Hypoxia-inducible factor

HRG:

Heregulin-β1

HSP:

Heat shock protein

HUVECs:

Human umbilical vein endothelial cells

iNOS:

Inducible nitric oxide synthase

KAI1:

Kangai-1

LLC:

Lewis lung carcinoma

MAPKAPK2:

MAP kinase-activated protein kinase 2

mdm2:

Murine double minute 2

MET:

Mesenchymal–epithelial transition

MMP:

Matrix metalloproteinases

MT-1 MMP:

Membrane type-1 MMP

MTA3:

Metastasis-associated protein 3

MUC1:

Mucin 1, cell surface-associated

OPG:

Osteoprotegerin

OPN:

Osteopontin

PAI:

Plasminogen activator inhibitor

PECAM:

Platelet endothelial cell adhesion molecule

PMA:

Phorbol 12-myristate 13-acetate

PKC:

Protein kinase C

PGE2:

Prostaglandin E2

PMN:

Polymorphonuclear phagocytes

PN-II:

Protease nexin-II

PSA:

Prostate-specific antigen

RANKL:

Receptor activator of nuclear factor-kB ligand

RECK:

Reversion-inducing cysteine-rich protein with kazal motifs

SLUG:

Zinc finger protein SNAI2

TIMP:

Tissue inhibitor metalloproteinase protein

TRAMP:

Transgenic adenocarcinoma of mouse prostate

uPA:

Urokinase plasminogen activator

uPAR:

Urokinase plasminogen activator receptor

VASP:

Vasodilator-stimulated phosphoprotein

VEGF:

Vascular endothelial growth factor

ZEB1:

Zinc finger E-box-binding homeobox 1

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Acknowledgments

This research work was supported by a research grant from National Science Council (NSC100-2313-B-165-001-MY3), Taiwan, Republic of China.

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  1. Graduate Institute of Applied Science of Living, Tainan University of Technology, 529 Zhongzheng Rd, Yongkang District, Tainan City, 71002, Taiwan

    Chia-Jui Weng

  2. Department of Food Science and Biotechnology, National Chung Hsing University, 250 Kuokuang Rd, Taichung, 40227, Taiwan

    Gow-Chin Yen

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Weng, CJ., Yen, GC. Flavonoids, a ubiquitous dietary phenolic subclass, exert extensive in vitro anti-invasive and in vivo anti-metastatic activities. Cancer Metastasis Rev 31, 323–351 (2012). https://doi.org/10.1007/s10555-012-9347-y

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