EGCG Suppresses Melanoma Tumor Angiogenesis and Growth without Affecting Angiogenesis and VEGF Expression in the Heart and Skeletal Muscles in Mice


  • Kevan B. Tucker Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA
  • Kristina L. Makey Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA
  • Edmund Chinchar Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA
  • Min Huang Department of Physiology & Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA
  • Natale Sheehan Department of Medicine University of Mississippi Medical Center, Jackson, Mississippi 39216, USA
  • Srinivasan Vijayakumar Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA
  • Jian-Wei Gu Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA



Melanoma, angiogenesis, proliferation, migration, EGCG, green tea polyphenols,VEGF,HIF-1α, NFκB, and capillary density in the heart.


 Melanoma is a highly malignant cancer with a potent capacity to metastasize distantly and has a higher mortality. There is no effective therapy for high risk melanoma patients to prevent relapse or distant metastasis. Therefore effective chemoprevention strategies are needed. The present study mainly evaluates the effects of EGCG on melanoma angiogenesis, growth, and capillary density (CD) in the heart and skeletal muscles of mice. 5 x 10^5 B16F10 cells were inoculated into the right proximal dorsal of the back in the eight week old male mice (n=12). Then, 6 mice received EGCG at 50-100 mg/kg/d in drinking water for 4 weeks and 6 control mice received drinking water only. Tumor size was monitored using dial calipers. At the end of the experiment, blood samples, tumors, hearts, and limb muscles were collected and measured for VEGF expression using ELISA and capillary density (CD) using CD31 immunohistochemistry. Compared to the control, EGCG treatment significantly reduced tumor weight (2.9±0.5 vs. 5.9±1.1 g; P<0.01; n=6), melanoma CD (117±9 vs. 167±23; P<0.01), and melanoma VEGF expression (32±1.5 vs. 42±2 pg/mg; P < 0.01), respectively. Also EGCG had no effects on body weight, heart weight, angiogenesis or VEGF expression in the heart and skeletal muscle of mice. EGCG (20-50 µg/ml) significantly inhibited the proliferation, migration, VEGF expression, and the activation of HIF-1α and NFαB in cultured B16F10 cells, respectively. These findings support the hypothesis that EGCG, a major green tea polyphenol, directly targets tumor cells and tumor vasculature, thereby inhibiting tumor growth, proliferation, migration, and angiogenesis of melanoma, and that the down-regulation of VEGF expression by EGCG is associated with the inhibition of HIF-1α and NFkB activation. EGCG has great potential as a chemopreventive agent because it has no effect on angiogenesis in normal tissue and has low toxicity.


Kim RH, Armstrong AW. Nonmelanoma skin cancer. Dermatol Clin 2012; 30: 125-39.

Karim-Kos HE, de Vries E, Soerjomataram I, et al. Recent trends of cancer in Europe: a combined approach of incidence, survival and mortality for 17 cancer sites since the 1990s. Eur J Cancer 2008; 44: 1345-89.

American Academy of Dermatology (2010) Available at: http: // 2010.

Markovic SN, Erickson LA, Rao RD, et al. Malignant melanoma in the 21st century, part 1: epidemiology, risk factors, screening, prevention, and diagnosis. Mayo Clin Proc 2007; 82: 364-80.

van der Leest RJ, Liu L, Coebergh JW, et al. Risk of second primary in situ and invasive melanoma in a Dutch population-based cohort: 1989-2008. Br J Dermatol 2012; 167: 1321-30.

Meyskens FL Jr, Farmer PJ, Yang S, Anton-Culver H. New perspectives on melanoma pathogenesis and chemoprevention. Recent Results Cancer Res 2007; 174: 191-5.

Hara Y. Fermentation of tea. Y. Hara (Ed.), Green tea, health benefits and applications, Marcel Dekker, New York 2001; pp. 16-21.

Harbowy ME, Balentine DA. Tea Chemistry. Crit Rev Plant Sci 1997; 10: 415-80.

Qin J, Xie LP, Zheng XY, et al. A component of green tea, (−)-epigallocatechin-3-gallate, promotes apoptosis in T24 human bladder cancer cells via modulation of the PI3K/Akt pathway and Bcl-2 family proteins. Biochem Biophys Res Commun 2007; 354: 852-57.

Fong HH. Integration of herbal medicine into modern medical practices: issues and prospects. Integr Cancer Ther 2002; 1: 287-93.

Huffman MA. Animal self-medication and ethno-medicine: exploration and exploitation of the medicinal properties of plants. Proc Nutr Soc 2003; 62: 371-81.

Miller KL, Liebowitz RS, Newby LK. Complementary and alternative medicine in cardiovascular disease: a review of biologically based approaches. Am Heart J 2004; 24: 703-10.

Khan N, Afaq F, Saleem M, Ahmad N, Mukhtar H. Targeting multiple signaling pathways by green tea polyphenol (−)-epigallocatechin-3-gallate. Cancer Res 2006; 66: 2500-505.

Ahn WS, Yoo J, Huh SW, et al. Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions. Eur J Cancer Prev 2003; 12: 383-90.

Shanafelt TD, Call TG, Zent CS, et al. Phase 2 trial of daily, oral Polyphenon E in patients with asymptomatic, Rai stage 0 to II chronic lymphocytic leukemia. Cancer 2013; 119: 363-70.

Wang ZY, Huang MT, Ferraro T, et al. Inhibitory effect of green tea in the drinking water on tumorigenesis by ultraviolet light and 12-O-tetradecanoylphorbol-13-acetate in the skin of SKH-1 mice. Cancer Res. 1992; 52: 1162-70.

Mantena SK, Meeran SM, Elmets CA, Katiyar SK. Orally administered green tea polyphenols prevent ultraviolet radiation-induced skin cancer in mice through activation of cytotoxic T cells and inhibition of angiogenesis in tumors. J Nutr 2005; 135: 2871-7.

Meeran SM, Mantena SK, Elmets CA, Katiyar SK. (-)-Epigallocatechin-3-gallate prevents photocarcinogenesis in mice through interleukin-12-dependent DNA repair. Cancer Res 2006; 66: 5512-20.

Katiyar S, Elmets CA, Katiyar SK. Green tea and skin cancer: photoimmunology, angiogenesis and DNA repair. J Nutr Biochem 2007; 18: 287-96.

Katiyar SK, Vaid M, van Steeg H, Meeran SM. Green tea polyphenols prevent UV-induced immunosuppression by rapid repair of DNA damage and enhancement of nucleotide excision repair genes. Cancer Prev Res 2010; 3: 179-89.

Katiyar SK, Matsui MS, Elmets CA, Mukhtar H. Polyphenolic antioxidant (-)-epigallocatechin-3-gallate from green tea reduces UVB-induced inflammatory responses and infiltration of leukocytes in human skin. Photochem Photobiol 1999; 69: 148-53.

Katiyar SK, Afaq F, Perez A, Mukhtar H. Green tea polyphenol (-)-epigallocatechin-3-gallate treatment of human skin inhibits ultraviolet radiation-induced oxidative stress. Carcinogenesis 2011; 22: 287-94.

Ravindranath MH, Ramasamy V, Moon S, Ruiz C, Muthugounder S. Differential growth suppression of human melanoma cells by tea (Camellia sinensis) epicatechins (ECG, EGC and EGCG. Evid Based Complement Alternat Med 2009; 6(4): 523-30.

Singh T, Katiyar SK. Green Tea Catechins Reduce Invasive Potential of Human Melanoma Cells by Targeting COX-2, PGE2 Receptors and Epithelial-to-Mesenchymal Transition. PLoS One 2011; 6(10): e25224.

Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971; 285: 1182.

Ferrara N, Gerber HP, LeCouter J. The biological properties of VEGF and its receptors. Nat Med 2003; 9: 669-76.

Brown NS, Bicknell R. Hypoxia and oxidative stress in breast cancer. Oxidative stress: its effects on the growth, metastatic potential and response to therapy of breast cancer. Breast Cancer Res 2001; 3: 323-27.

Brandon EL, Gu JW, Cantwell L, He Z, Wallace G, Hall JE. Obesity promotes melanoma tumor growth: role of leptin. Cancer Biol Ther 2009; 8: 1871-9.

Young E, Miele L, Tucker KB, Huang M, Wells J, Gu JW. SU11248, a selective tyrosine kinases inhibitor suppresses breast tumor angiogenesis and growth via targeting both tumor vasculature and breast cancer cells. Cancer Biol Ther 2010; 10: 703-11.

Gu JW, Fortepiani L, Reckelhoff JF, Adair TH, Wang J, Hall JE. Increased expression of vascular endothelial growth factor and capillary density in hearts of spontaneously hypertensive rats. Microcirculation 2004; 11: 689-97.

Gu JW, Bailey AP, Sartin A, Makey I, Brady AL. Ethanol stimulates tumor progression and expression of vascular endothelial growth factor in chick embryos. Cancer 2005; 103: 422-31.

Gu JW, Young E, Busby B, Covington J, Tan W, Johnson JW: Oral Administration of Pyrrolidine Dithiocarbamate (PDTC) Inhibits VEGF Expression, Tumor Angiogenesis, and Growth of Breast Cancer in Female Mice. Cancer Biol Ther 2009; 8: 514-21.

Kuphal S, Winklmeier A, Warnecke C, Bosserhoff AK. Constitutive HIF-1 activity in malignant melanoma. Eur J Cancer 2010; 46(6): 1159-69.

Ullmann U, Haller J, Decourt JP, et al. A single ascending dose study of epigallocatechin gallate in healthy volunteers. J Int Med Res 2003; 31: 88-101.

Kaegi E. Unconventional therapies for cancer: 2. Green tea. The Task Force on Alternative Therapies of the Canadian Breast Cancer Research Initiative. Can Med Assoc J 1998; 158: 1033-5.

Nagle D, Ferreira D, Zhou YD. Epigallocatechin-3-gallate (EGCG): chemical and biomedical perspectives. J Phytochemistry 2006; 67: 1849-55.

Sun B, Zhang D, Zhang S, Zhang W, Guo H, Zhao X. Hypoxia influences vasculogenic mimicry channel formation and tumor invasion-related protein expression in melanoma. Cancer Lett 2007; 249: 188-97.

Kuphal S, Poser I, Jobin C, Hellerbrand C, Bosserhoff AK. Loss of E-cadherin leads to upregulation of NFkappaB activity in malignant melanoma. Oncogene 2004; 23: 8509-19.

Szatrowski TP, Nathan CF. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res 1991; 51: 974-98.

Comito G, Giannoni E, Di Gennaro P, Segura CP, Gerlini G, Chiarugi P. Stromal fibroblasts synergize with hypoxic oxidative stress to enhance melanoma aggressiveness. Cancer Lett 2012; 324(1): 31-41.

Bronkhorst IH, Jager MJ. Uveal melanoma: the inflammatory microenvironment. J Innate Immun 2012; 4(5-6): 454-62.

Simons AL, Mattson DM, Dornfeld K, Spitz DR. Glucose deprivation-induced metabolic oxidative stress and cancer therapy. J Cancer Res Ther 2009; 5(Suppl 1): S2-6.

Tan W, Bailey AP, Shparago M, et al. Chronic alcohol consumption stimulates VEGF expression, tumor angiogenesis and progression of melanoma in mice. Cancer Biol Therapy 2007; 6(8): 1211-17.

Streit M, Detmar M. Angiogenesis, lymphangiogenesis, and melanoma metastasis. Oncogene 2003; 22: 3172-9.

Lacal PM, Failla CM, Pagani E, et al. Human melanoma cells secrete and respond to placenta growth factor and vascular endothelial growth factor. J Invest Dermatol 2000; 115: 1000-7.

Lacal PM, Ruffini F, Pagani E, D'Atri S. An autocrine loop directed by the vascular endothelial growth factor promotes invasiveness of human melanoma cells. Int J Oncol 2005; 27: 1625-32.

Jung YD, Kim MS, Shin BA, et al. EGCG, major component of green tea, inhibits tumor growth by inhibiting VEGF production in human colon carcinoma cells. Br J Cancer 2001; 84: 844-50.

Shimizu M, Shirakami Y, Sakai H, et al. (−)-Epigallocatechin gallate inhibits growth and activation of the VEGF/ VEGFR axis in human colorectal cancer cells. Chem Biol Interact 2010; 185: 247-52.

Fujiki H, Suganuma M, Okabe S, et al. Cancer inhibition by green tea. Mutat Res 1998; 402: 307-10.

Singh BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin-3-gallat (EGCG): mechanisms, perspective and clinical applications. Biochem Pharmacol 2011; 82: 1807-21.

Ohga N, Hida K, Hida Y, et al. Inhibitory effects of epigallocatechin-3 gallate, a polyphenol in green tea, on tumor-associated endothelial cells and endothelial progenitor cells. Cancer Sci 2009; 100: 1963-70.




How to Cite

Kevan B. Tucker, Kristina L. Makey, Edmund Chinchar, Min Huang, Natale Sheehan, Srinivasan Vijayakumar, & Jian-Wei Gu. (2014). EGCG Suppresses Melanoma Tumor Angiogenesis and Growth without Affecting Angiogenesis and VEGF Expression in the Heart and Skeletal Muscles in Mice. Journal of Cancer Research Updates, 3(1),  19–29.