EGCG Inhibits Adipose-Derived Mesenchymal Stem Cells Differentiation into Adipocytes and Prevents a STAT3-Mediated Paracrine Oncogenic Control of Triple-Negative Breast Cancer Cell Invasive Phenotype

Abstract

Obese subjects have an increased risk of developing triple-negative breast cancer (TNBC), in part associated with the chronic low-grade inflammation state. On the other hand, epidemiological data indicates that increased consumption of polyphenol-rich fruits and vegetables plays a key role in reducing incidence of some cancer types. Here, we tested whether green tea-derived epigallocatechin-3-gallate (EGCG) could alter adipose-derived mesenchymal stem cell differentiation into adipocytes, and how this impacts the secretome profile and paracrine regulation of the TNBC invasive phenotype. Here, cell differentiation was performed and conditioned media (CM) from preadipocytes and mature adipocytes harvested. Human TNBC-derived MDA-MB-231 real-time cell migration was performed using the exCELLigence system. Differential gene arrays and RT-qPCR were used to assess gene expression levels. Western blotting was used to assess protein expression and phosphorylation status levels. In vitro vasculogenic mimicry (VM) was assessed with Matrigel. EGCG was found to inhibit the induction of key adipogenic biomarkers, including lipoprotein lipase, adiponectin, leptin, fatty acid synthase, and fatty acid binding protein 4. Increased TNBC-derived MDA-MB-231 cell chemotaxis and vasculogenic mimicry were observed in response to mature adipocytes secretome, and this was correlated with increased STAT3 phosphorylation status. This invasive phenotype was prevented by EGCG, the JAK/STAT inhibitors Tofacitinib and AG490, as well as upon STAT3 gene silencing. In conclusion, dietary catechin-mediated interventions could, in part through the inhibition of adipogenesis and modulation of adipocytes secretome profile, prevent the onset of an obesogenic environment that favors TNBC development.

Histone Demethylase JMJD2D: A Novel Player in Colorectal and Hepatocellular Cancers

“…Mechanistically, JMJD2D contributes to HSC activation and hepatic fibrosis progression by facilitating the transcription of toll-like receptor 4 (TLR4) through H3K9me2/3 demethylation, subsequently activating TLR4/NF-κB signaling in HSC [ 85 ]. Hepatic steatosis is also one of the mechanisms of pathogenesis of primary HCC, in which the abnormal or excessive differentiation of mesenchymal stem cells (MSC) to adipocytes may be a potential risk factor [ 86 , 87 , 88 ]. Intriguingly, JMJD2D has been reported as a critical regulator for the adipogenic differentiation of C3H10T1/2 MSCs [ 89 ].…”

Pharmacological Effects of Polyphenol Phytochemicals on the JAK-STAT Signaling Pathway

“…EGCG is a catechin monomer isolated from green tea. STAT3 participates in adipocyte secretomemediated Paracrine regulation of Human MDA-MB-231 (TNBC-derived) cell invasive phenotype, EGCG inhibits p-STAT3 (Gonzalez Suarez et al, 2021). And in IFNγ-stimulated human oral cancer cells, p-JAK1 and p-JAK2 are inhibited by EGCG, and EGCG inhibits STAT1 translocation to the nucleus (Cheng et al, 2010).…”

Nutraceuticals in the Mediterranean Diet: Potential Avenues for Breast Cancer Treatment

“…A very recent study [ 159 ] investigated whether green tea-derived EGCG could modify adipose-derived mesenchymal stem cell differentiation into adipocytes and eventually alter the secretome profile and paracrine regulation of the triple negative breast cancer invasive phenotype. EGCG was able to antagonize the increase of lipoprotein lipase, adiponectin, leptin, fatty acid synthase and fatty acid binding protein.…”