Radiation Induced-Tubulogenesis in Endothelial Cells is Antagonized by the Antiangiogenic Properties of Green Tea Polyphenol (-) Epigallocatechin-3-Gallate

Abstract

Radiation therapy is a widely-used option for the treatment of a variety of solid tumors. Although effective, ionizing radiation (IR) may give rise to various side effects, including secondary tumors. In agreement with this, recent reports have demonstrated increased invasive potential in different tumor-derived cell lines following radiation treatment. Many of the molecular effects of IR specifically on the endothelial cells involved in tumor neovascularization remain unknown. In this study, we found that low sublethal single doses of IR applied to human umbilical vein endothelial cells stimulated cell migration and in vitro tubulogenesis. This correlated with an increase in membrane type-1 matrix metalloproteinase (MT1-MMP) protein expression, a crucial enzyme that promotes endothelial cell migration and tube formation, and of caveolin-1, a protein that regulates tube formation. Cell adhesion was also promoted by IR, reflected in increased gene expression levels of cell surface beta (3) integrin. Pretreatment of the cells with epigallocatechin-3gallate (EGCg), a green tea catechin that possesses anti-angiogenic properties, prevented most of the IR-induced cellular and molecular events. These observations suggest that current protocols involving radiation therapy for the treatment of cancer can paradoxically promote angiogenesis, but can be improved by combination with anti-angiogenic molecules such as EGCg to target those tumor-derived endothelial cells that escaped IR-induced apoptosis.

Oral Consumption of Green Tea Polyphenols Inhibits Insulin-Like Growth Factor-I–Induced Signaling in an Autochthonous Mouse Model of Prostate Cancer

“…Although apparently an inhibition in the expression of TIMP-1 and TIMP-2 was observed with green tea polyphenol, an estimation of the ratios of MMP to TIMP revealed that in green tea polyphenol-fed TRAMP mice, the balance between MMP and TIMP significantly favored TIMP levels. The balance between MMP-9 and MMP-2 to TIMP-1 and TIMP-2 expression was shown to be an essential factor in the aggressiveness of several cancers (47,48). In this study, the ratio of MMP to TIMP was greater than 1 in water-fed TRAMP mice and less than 1 in green tea polyphenol-fed TRAMP mice.…”

“…In this study, the ratio of MMP to TIMP was greater than 1 in water-fed TRAMP mice and less than 1 in green tea polyphenol-fed TRAMP mice. Several studies have observed inhibition in the expression of MMPs by green tea (47)(48)(49)(50), and tumor cell invasion of a reconstituted basement membrane matrix was reduced by 50% with EGCG a green tea component at concentrations equivalent to that in the plasma of moderate green tea drinker (50).…”

Tumor Environment Dictates Medulloblastoma Cancer Stem Cell Expression and Invasive Phenotype

“…When MMP-9 gene expression was silenced in DAOY medulloblastoma-derived cells, experimental in vivo tumor growth was inhibited in an intracranial animal model (12). Moreover, in line with the CD133(+) tumor cell phenotype that accounts for glioma stem cells' radioresistance (13), the expression of MT1-MMP expression was also increased in several cell line models that escaped radiationinduced apoptosis (14,15). Previous reports from our laboratory have documented the contribution of MT1-MMP to the infiltrative and invasive phenotype of brain tumorderived cells (16,17), and strategies which inhibit either MMP-9 or MT1-MMP activities and/or expression may, furthermore, be envisioned to reduce tumorigenicity (17)(18)(19).…”

A prostate secretory protein94‐derived synthetic peptide PCK3145 inhibits VEGF signalling in endothelial cells: Implication in tumor angiogenesis

“…The extent of capillary-like structure formation was quantified by analysis of digitized images using a commercially available image analysis software (Northern Eclipse). 26 …”