Abstract
Background: Triple-negative breast cancer (TNBC) cells secretome induces a pro-inflammatory microenvironment within the adipose tissue, which hosts both mature adipocytes and adipose-derived mesenchymal stem/stromal cells (ADMSC). The subsequent acquisition of a cancer-associated adipocyte (CAA)-like phenotype is, however, unknown in ADMSC. While epidemiological studies suggest that consuming a polyphenol-rich diet reduces the incidence of some obesity-related cancers, the chemopreventive impact of green tea-derived epigallocatechin-3-gallate (EGCG) against the cues that trigger the CAA phenotype remain undocumented in ADMSC. Methods: Human ADMSC were exposed to human TNBC-derived MDA-MB-231 conditioned media (TNBC cells secretome) supplemented or not with EGCG. Differential gene expression was assessed through RNA-Seq analysis and confirmed by RT-qPCR. Protein expression levels and the activation status of signal transduction pathways mediators were determined by Western blotting. ADMSC chemotaxis was assessed by a real-time cell migration assay. Results: The TNBC cells secretome induced in ADMSC the expression of the CAA cytokines CCL2, CCL5, IL-1β, and IL-6, and of immunomodulators COX2, HIF-1α, VEGFα, and PD-L1. The epithelial-to-mesenchymal biomarker Snail was found to control the CAA phenotype. EGCG inhibited the induction of CAA genes and the activation status of Smad2 and NF-κB. The induced chemotactic response was also inhibited by EGCG. Conclusion: The induction of an inflammatory and CAA-like phenotype in ADMSC can be triggered by the TNBC cells secretome, while still efficiently prevented by diet-derived polyphenols.
Highlights
Introduction published maps and institutional affilThe acquisition of a cancer-associated adipocyte (CAA) phenotype can be viewed as an adaptive characteristic of cells residing within the adipose tissue and that respond to cues that originate from the tumor microenvironment (TME) [1,2]
In order to first identify the genes and molecular pathways involved in the acquisition of a CAA phenotype, human adiposederived mesenchymal stem/stromal cells (ADMSC) were cultured for 24 h in conditioned media (CM)
We found a total of 13,284 genes differentially expressed in both conditions (FDR < 0.05), from which roughly two thirds were downregulated in the presence of EGCG (Figure 1A)
Summary
Introduction published maps and institutional affilThe acquisition of a cancer-associated adipocyte (CAA) phenotype can be viewed as an adaptive characteristic of cells residing within the adipose tissue and that respond to cues that originate from the tumor microenvironment (TME) [1,2]. Adipocytes tumor infiltration has been reported in breast, ovarian, colorectal, and pancreatic cancers, leading to the instauration of a pro-inflammatory state that promotes carcinogenic events in return [3,4]. Such pro-malignancy role of the adipose tissue has been described primarily in breast cancer, where the residing adipocytes represent the most abundant stromal cell type and constitute the main source of pro-inflammatory cytokines and growth factors [5–7]. The CAA phenotype characterizes adipose tissue-derived cells with morphologically smaller and irregular sizes, as well as with decreased content and dispersed pattern of lipid droplets [8] These cells present an activated state attributable to the overexpression iations
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