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Int J Exp Pathol. 2001 Dec; 82(6): 309–316.
doi: 10.1046/j.1365-2613.2001.00205.x
PMCID: PMC2517785
PMID: 11846837

Inhibition of tumour invasion and angiogenesis by epigallocatechin gallate (EGCG), a major component of green tea

YOUNG D JUNG1 and LEE M ELLIS2
Author information Article notes Copyright and License information PMC Disclaimer

Abstract

Epidemiological studies have suggested that consumption of green tea may decrease cancer risk. In addition, abundant pre-clinical data from several laboratories have provided convincing evidence that polyphenols present in green tea afford protection against cancer in both in vivo and in vitro studies. Recently, epigallocatechin gallate (EGCG), a putative chemopreventive agent and a major component of green tea, was reported to inhibit tumour invasion and angiogenesis, processes that are essential for tumour growth and metastasis. Understanding the basic principles by which EGCG inhibits tumour invasion and angiogenesis may lead to the development of new therapeutic strategies, in addition to supporting the role of green tea as a cancer chemopreventive agent.

Keywords: EGCG, tea, angiogenesis, cancer, invasion

Introduction

Second only to water, tea is the most widely consumed beverage worldwide, with a per capita consumption of approximately 120 mL of brewed tea per day (Mukhtar & Ahmad 1999). Tea preparations, although they originate from the same plant source (Camellia sinensis), differ in their processing methods. The three basic forms of tea are black tea (78%), in which most green leaf polyphenols are oxidized; green tea (20%), in which the oxidation of these polyphenols is precluded; and oolong tea (2%), in which some polyphenols are oxidized and others are not (Graham 1992). Most studies examining the usefulness of tea in the prevention of cancer have focused on green tea, although a few have explored the chemopreventive potential of black tea. Interest in green tea as a cancer chemopreventive agent in humans has intensified for several reasons. First, epidemiological evidence suggests that people who consume large amounts of green tea have a lower risk of developing various cancers (Kono et al. 1988). Second, green tea has been shown in animal models to protect against the development and progression of skin, lung, mammary gland, and gastrointestinal tract tumours (Rogers et al. 1998). Third, green tea extracts have been shown in vitro to stimulate apoptosis of various cancer cell lines, including prostate, lymphoma, colon, and lung (Yang et al. 1998). Finally, green tea consumption is associated with few adverse events, and green tea is readily available at low cost (Fujiki et al. 1998). These lines of evidence are explored in the remainder of this article.

Prevention of tumour invasion, or angiogenesis, has emerged as a promising approach for reducing cancer mortality. The chemopreventive activity of tea demonstrated in epidemiological and experimental studies may be secondary to tea's anti-invasive and antiangiogenic activities. Epidemiological studies investigating the association between tea intake and cancer risk (Hara et al. 1984; Kono et al. 1988; Tewes et al. 1990; Hara 1997; Imai et al. 1997; Bushman 1998; Gupta et al. 1999) have shown varying results that may be due to limitations inherent in population-based studies. Strong inverse correlations have been found between tea intake and the development of most digestive tract cancers in several studies (Table 1). A prospective cohort study of 8552 residents of Saitama, Japan revealed both a decrease in the relative risk of cancer and a delay in onset of cancer among individuals who consumed more than 10 cups of tea a day (Nakachi et al. 2000). However, the role of tea as a chemopreventive agent in studies of lung and rectal cancer remains controversial.

Table 1

Epidemiologic studies of chemoprevention of specific tumour types by green tea

Chemoprevention correlationOrgans affectedAuthors
Strong positiveEsophagus, stomachBushman (1998),Hara et al. (1984)
PositivePancreas, prostate, urinary bladderGupta et al. (1999),Bushman (1998)
ModerateColonHara (1997),Bushman (1998)
ControversialLung, rectumTewes et al. (1990),Bushman (1998)

The anticarcinogenic and antiproliferative effects of green tea have been attributed to the biological activities of its polyphenol components. Green tea extract contains (-) -epigallocatechin gallate (EGCG) (-) -epigallocatechin (EGC) (-) -epicatechin gallate (ECG), and (-) -epicatechin (EC) (Fig. 1). Of these components, EGCG has been considered to be the major chemopreventive constituent of tea and has been the focus of a great deal of attention (Fujiki et al. 1998). The exact mechanisms underlying the anticarcinogenic activity of tea are not well defined (Table 2) and warrant further study. Some authors consider EGCG alone to be the active anticancer component (Jankun et al. 1997a). However, others suggest that other tea constituents, particularly EGC and the aflavins, also have antiproliferative or anticarcinogenic properties (Isemura et al. 2000). Although Komori et al. (1993) reported that EGCG was the most important of the polyphenols in inhibiting the growth of the human lung cancer cell line PC-9, green tea extract, i.e. tea itself, had stronger effects than did EGCG alone (Komori et al. 1993). EGCG and EC have shown synergistic effects on the induction of apoptosis in tumour cells (Suganuma et al. 1999).

An external file that holds a picture, illustration, etc. Object name is iep0082-0309-f1.jpg

Chemical structure of green tea catechins.

Table 2

Mechanistic findings of EGCG against tumour development and progression

Induction of apoptosis and cell cycle arrest (Yang et al. 1998)
Inhibition of carcinogenesis (Yamane et al. 1995; Rogers et al. 1998)
Regulation of transcription factor
 AP-1 (Dong et al. 1997)
 NF-κB (Lin & Lin 1997)
Inhibition of gene expression
 TNF-α (Suganuma et al. 2000)
 VEGF (Jung et al. 1999)
 NOS (Lin & Lin 1997)
Modulation of enzyme activities
 Ornithine decarboxylase (Agarwal et al. 1992)
 Matrix metalloproteinase (Maeda–Yamamoto et al. 1999)
 Urokinase plasminogen activator (Jankun et al. 1997b)
 Protein kinase C and protein phosphatase 2 A (Kitano et al. 1997)
 Cyclooxygenase and lipooxygenase (Stoner & Mukhtar 1995)
 Protein tyrosine kinase
   Mitogen-activated protein kinase (Jung et al. 1999)
   EGF-R tyrosine kinase (Liang et al. 1997)
Inhibition of tumour progression
 Adhesion and invasion (Zhang et al. 2000)
 Angiogenesis (Cao & Cao 1999)
 Metastasis (Taniguchi et al. 1992)
Antioxidation (Zhang et al. 2000)
Radioprotection (Uchida et al. 1992)

In addition to having chemopreventive activity, polyphenols have been shown to inhibit tumour invasion and angiogenesis, crucial steps for the growth and metastasis of all solid tumours. Studies of this topic are reviewed briefly below.

Inhibition of tumour invasion by EGCG

Metastases are the main cause of mortality in patients with cancer. During the complicated multistep processes of cancer metastasis, tumour cell invasion of the basement membrane is one of the earliest critical steps (Gohji et al. 1997). It was proposed recently that the anticancer activity of EGCG is associated with the inhibition of invasion by inhibiting the activity of urokinase (Jankun et al. 1997b) or the matrix metalloproteinases (MMPs) (Garbisa et al. 2001), or by the removal of oxygen radicals (Zhang et al. 2000), all of which play key roles in cancer invasion and metastasis.

Inhibition of urokinase activity

Urokinase, a hydrolase implicated in tumour cell invasion (Huang et al. 2000), facilitates degradation of the basement membrane and extracellular matrix. Urokinase is overexpressed in breast, ovarian, and prostate malignancies and has clearly been demonstrated to play an essential role in metastasis formation (Gohji et al. 1997). Inhibition of urokinase-type plasminogen activator (uPA) activity can reduce tumour size or even cause complete remission of tumours in mice (Jankun et al. 1997a). EGCG directly impairs the activity of urokinase, interfering with its enzymatic activity and thus its role in the degradation of extracellular matrix. Jankun et al. (1997b) used computer-based molecular modelling to demonstrate that EGGC binds to urokinase, blocking the histidine 57 and serine 195 residues of the urokinase catalytic triad and extending towards arginine 35 from a positively charged loop of urokinase. Binding of EGCG at such a location would interfere with the ability of uPA to recognize its substrates, thereby inhibiting its enzymatic activity. The inhibitory activity of EGCG on uPA was verified with a spectrophotometiric amidolytic assay. Notably, however, the EGCG concentration effective in that study (4 mm) far exceeds the levels found in vivo after tea consumption (Cao & Cao 1999).

Inhibition of matrix metalloproteinases

MMP-2 and MMP-9, the MMPs most frequently overexpressed in cancer and in activated endothelial cells, are instrumental in degrading the basement membrane and facilitating cell invasion (Liotta et al. 1980). In experimental systems, cellular invasion is reduced by the presence of endogenous tissue inhibitors of metalloproteinases (TIMPs) and synthetic inhibitors of MMPs (Li et al. 2001). Some synthetic MMP inhibitors are currently being used in clinical trials for cancer therapy. Unfortunately, initial results have been disappointing due to undesirable side-effects, particularly musculoskeletal pain. Recently, Gabrisa et al. (2001) showed that the concentration of EGCG that effectively inhibits MMP-2 and MMP-9 in vitro is orders of magnitude lower than that reported for inhibition of urokinase activity (1/500) and that still lower concentrations —equivalent to those found in the plasma of people who consume moderate amounts of green tea — can reduce tumour cell invasion by 50% (Garbisa et al. 2001). Because EGCG can form complexes with proteins and metal ions, the inhibition of MMP activities by EGCG may be partially related to its ability to chelate zinc, which is essential for MMP enzymatic activity (Maeda–Yamamoto et al. 1999). However, in another study the addition of excess zinc to EGCG failed to restore full gelatinolytic activity and in fact augmented MMP inhibition by EGCG (Garbisa et al. 2001). Understanding the molecular mechanisms by which EGCG interacts with and inhibits MMP enzymatic activities is critical in exploiting its properties for cancer prevention and treatment. That understanding will serve as a basis for designing effective anti-invasion drugs.

Antioxidant activity of EGCG

Tumour cells can produce large amounts of reactive oxygen species (ROS) that are associated with cancer invasion and metastasis (Nonaka et al. 1993). ROS are important messenger molecules in downstream signalling pathways and can ultimately lead to the induction of invasion-related genes including those for the MMPs (Brenneisen et al. 1997). Zhang and colleagues reported that exogenous ROS produced by the hypoxanthine–xanthine oxidase system increased the invasion of the rat ascites hepatoma cell line AH109A through a mesothelial cell monolayer (Zhang et al. 2000). Asc-2-O-phosphate-6-O-palmitate (Asc2P6Plm), a lipophilic and auto-oxidation-resistant derivative of ascorbic acid, was shown to inhibit invasion by fibrosarcoma HT-1080 cells by means of its potent antioxidant activity (Liu et al. 1999). Carotenoids also inhibited the ROS-potentiated invasion of AH109A cells (Kozuki et al. 2000). In addition, administration of Cu-Zn superoxide dismutase, an enzyme that scavenges superoxide, successfully reduced lung metastasis of mouse MethA sarcoma and Lewis lung carcinoma cell lines (Kogawa et al. 1999). These results suggest that antioxidants such as EGCG may be potentially useful as antimetastatic agents. EGCG has strong antioxidative capacity, high affinity for the lipid bilayers of the cell membrane, and can easily enter the nuclei of cancer cells (Okabe et al. 1997). Like other catechins, EGCG is colourless, astringent, water-soluble, and readily oxidizable (Graham 1992). Its catechol structure also makes EGCG a strong chelator of metal ions (Guo et al. 1996). EGCG can bind the transition metal ions, prevent formation of hydroxyl radicals, and thus inhibit exogenous ROS-potentiated tumour invasion (Zhang et al. 2000). The oxygen-scavenging effects of EGCG are superior to those of ascorbic acid (vitamin C) and tocopherol (vitamin E) with respect to some active oxygen radicals but are less pronounced with hydroxyl free radicals (Zhao et al. 1989). Thus, EGCG could inhibit tumour cell invasion by scavenging oxygen radicals.

Inhibition of angiogenesis by EGCG

Angiogenesis is necessary not only for nourishing growing tumour masses but also for metastasis (Fidler & Ellis 1994). Experimental evidence suggests that green tea consumption by mice significantly inhibits angiogenesis. Cao and Cao used several measures of corneal neovascularization (blood vessel length, clock-hours of corneal neovascularization, and area of neovascularization) to demonstrate that oral consumption of green tea by mice inhibited angiogenesis (Cao & Cao 1999). Studies from our laboratory showed that treating nude mice with EGCG resulted in marked inhibition of growth, vascularity, and proliferation of human colon cancer xenografts (Jung et al. 2001). In these studies, the human colon carcinoma cell line HT29 was inoculated into the subcutis of athymic nude mice and treated with daily intraperitoneal injections of epicatechin (EC, negative control) or EGCG at 1.5 mg/day/mouse. Treatment with EGCG inhibited tumour growth (58%), microvessel density (30%), and tumour cell proliferation (27%) relative to the control condition (Figs 2 and ​and3).3). As described further below, EGCG may exert at least part of its anticancer effect by inhibiting angiogenesis through blocking the induction of vascular endothelial growth factor (VEGF). We also found that EGCG induced significant endothelial cell apoptosis (Fig. 2b), a result that supports our earlier contention that VEGF is an in vivo survival factor for tumour endothelium (Shaheen et al. 1999). These findings suggest that down-regulation of VEGF by EGCG may lead to endothelial cell apoptosis within tumours, which could not only inhibit new blood vessel formation and tumour growth, but could also lead to tumour cell apoptosis. Using another tumour system, Bertolini and others demonstrated that giving mice green tea to drink led to an inhibition of angiogenesis and induction of endothelial and tumour cell apoptosis in an animal model of human high-grade non-Hodgkin's lymphoma (Bertolini et al. 2000). The mechanism by which EGCG inhibits angiogenesis is not fully elucidated, although several hypotheses have been proposed. These hypotheses are discussed further below.

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Effect of EGCG on tumour volume and weight in mice bearing human colon carcinoma cells. Nude mice were inoculated with HT29 cells into the subcutis and treated with EGCG or EC (negative control). EGCG inhibited tumour volume by 61% (a) and tumour weight by 58% (b) relative to tumours from mice treated with EC. Bars indicate standard error of the mean. *P < 0.05 (10 mice per group). (Reproduced with permission from Jung YD, Kim MS, Shin BA, Chay KO, Ahn BW, Liu W, Bucana CD, Gallick GE &amp; Ellis LM. (2001) EGCG, a major component of green tea, inhibits tumour growth by inhibiting VEGF induction in human colon carcinoma cells. British Journal of Cancer, 84, 844–850).

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EGCG inhibits tumour vascularity and tumour cell proliferation. Nude mice were inoculated with HT29 cells into the subcutis and treated with EGCG or EC (negative control). Immunohistochemical staining of tumour sections for CD31 and proliferating cell nuclear antigen (PCNA) was used to quantify tumour vessels and tumour cell proliferation. EGCG inhibited tumour vascularity by 30% and tumour cell proliferation by 27% (a). Immunofluorescent double staining of tumour sections for CD31 and TdT-mediated dUTP nick-end labelling (TUNEL) were performed to quantify the percentages of tumour and endothelial cells undergoing apoptosis. EGCG treatment significantly increased apoptosis of both cell types over that of controls (b). HPF, high-power field. Bars indicate standard error of the mean. *P < 0.05, **P < 0.001 (10 mice per group). (Reproduced with permission from Jung YD, Kim MS, Shin BA, Chay KO, Ahn BW, Liu W, Bucana CD, Gallick GE &amp; Ellis LM. (2001) EGCG, a major component of green tea, inhibits tumour growth by inhibiting VEGF induction in human colon carcinoma cells. British Journal of Cancer, 84, 844–850).

EGCG inhibition of endothelial cell proliferation

Cao & Cao (1999) used a chick chorioallantoic membrane assay to demonstrate that green tea and EGCG prevented the formation of new blood vessels (Cao & Cao 1999). In that study, EGCG inhibited bovine capillary endothelial cell proliferation that had been stimulated with fibroblast growth factor. Importantly, this growth inhibition was restricted to endothelial cells; nonendothelial cells, including murine T241 fibrosarcoma tumour cells, murine fibroblast cells, and rat smooth muscle cells, were insensitive to EGCG treatment at the concentrations used.

EGCG inhibition of vascular endothelial growth factor (VEGF) expression

VEGF is a unique, potent angiogenic protein that has specific mitogenic and chemotactic effects on vascular endothelial cells (Plate et al. 1992). Various regulators and signal transduction pathways have been implicated in regulating VEGF expression. Recently, we reported that Erk-1 and Erk-2 are important in the signalling cascade that leads to overexpression of VEGF mRNA (Jung et al. 1999). In human colon cancer cells, EGCG inhibited angiogenesis by blocking Erk-1 and Erk-2 activation and VEGF expression. The exact mechanism by which ECGC inhibits the activation of Erk-1 and − 2 is not known. One possible explanation is that EGCG could inhibit kinases that are involved in Erk-1 and − 2 activation (Jung et al. 2001). EGCG is also known to be a strong metal ion chelator (Yang & Wang 1993). Since some receptor kinases depend on divalent cations for their activity, EGCG could inhibit the activity of receptor kinases by chelating these cations (Mahadevan et al. 1995). Dong and others demonstrated that EGCG inhibited activator protein-1 (AP-1)-dependent transcriptional activity and DNA-binding activity (Dong et al. 1997). Since the VEGF gene promoter has several AP-1 binding sites, EGCG could inhibit the induction of VEGF by decreasing the activation of the transcription factor AP- 1.

Taken together, the data reviewed above suggest that EGCG may block the early event of VEGF induction by inhibiting both the activation of Erk-1 and − 2 and the binding of transcription factor AP-1 to the VEGF promoter, thereby inhibiting the induction of VEGF transcription.

EGCG inhibition of epidermal growth factor receptor signalling

The epidermal growth factor receptor (EGFR) is an upstream mediator of mitogenic factors such as VEGF and IL-8. Anti-EGFR antibody has been shown to inhibit angiogenesis and decrease VEGF and IL-8 in human transitional-cell and pancreatic carcinoma implants growing orthotopically in nude mice (Perrotte et al. 1999; Bruns et al. 2000). Liang and colleagues used phosphoamino-acid analysis of EGFR in the human epidermoid carcinoma cell line A431 to show that EGCG inhibited the EGF-stimulated increase in phosphotyrosine level. They also found that EGCG blocked EGF binding to its receptor and subsequent EGFR kinase activity (Liang et al. 1997). Although the exact mechanisms by which ECGC inhibits EGFR signalling are not known, the inhibition of EGFR signalling suggests that the antitumour effect of EGCG is mediated in part by inhibition of angiogenesis.

Conclusions

Inhibition of tumour invasion and angiogenesis are important areas of research in tumour biology. The usefulness of tea as a natural, non-toxic chemopreventive agent has been appreciated for at least 10 years. Recently, several laboratory studies have indicated that green tea, more specifically EGCG, offers beneficial effects with regard to inhibiting tumour progression and angiogenesis. Further research is necessary to define the molecular mechanism(s) by which green tea, and EGCG in particular, inhibit angiogenesis and tumour growth.

Acknowledgments

The authors thank Christine Wogan for the Department of Scientific Publishing and Kristine Faraj for the Department of Surgical Oncology, U.T. M. D. Anderson Cancer Center, for editorial assistance.

Funding

This study was supported in part by the Chonnam University Research Institute of Medical Sciences (CURIMS 98-B-130) (YDJ), the Gillsohn Longenbaugh Foundation (LME), the Jon and Susie Hall Fund for Colon Cancer Research (LME), and the University Cancer Foundation (YDJ, LME).

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