Glucose Enhances Pro-Tumorigenic Functions of Mammary Adipose-Derived Mesenchymal Stromal/Stem Cells on Breast Cancer Cell Lines

Simple Summary Metabolic alterations (i.e., high glucose levels) enhance cancer cell aggressiveness by acting on tumor and on its environment. Mammary adipose tissue-derived mesenchymal stromal/stem cells (MAT-MSCs) stand in close proximity of breast cancer (BC) cells but have a still unclear role. We investigated whether changes in glucose concentration may impact on the interaction between human MAT-MSCs and BC cells. We provided evidence that in presence of cancer cells and high glucose levels, MAT-MSCs display pro-tumorigenic functions, while cancer cells become more aggressive. These results highlight that a metabolic control helps to reduce cancer outgrowth, at least in part preserving the functions of the adipose microenvironment. Adiposity and diabetes affect breast cancer (BC) progression. We addressed whether glucose may affect the interaction between mammary adipose tissue-derived mesenchymal stromal/stem cells (MAT-MSCs) and BC cells. Two-dimensional co-cultures and spheroids were established in 25 mM or 5.5 mM glucose (High Glucose-HG or Low Glucose-LG) by using MAT-MSCs and MCF7 or MDA-MB231 BC cells. Gene expression was measured by qPCR, while protein levels were measured by cytofluorimetry and ELISA. CD44(high)/CD24(low) BC stem-like sub-population was quantified by cytofluorimetry. An in vivo zebrafish model was assessed by injecting spheroid-derived labeled cells. MAT-MSCs co-cultured with BC cells showed an inflammatory/senescent phenotype with increased abundance of IL-6, IL-8, VEGF and p16(INK4a), accompanied by altered levels of CDKN2A and LMNB1. BC cells reduced multipotency and increased fibrotic features modulating OCT4, SOX2, NANOG, alpha SMA and FAP in MAT-MSCs. Of note, these co-culture-mediated changes in MAT-MSCs were partially reverted in LG. Only in HG, MAT-MSCs increased CD44(high)/CD24(low) MCF7 sub-population and promoted their ability to form mammospheres. Injection in zebrafish embryos of HG spheroid-derived MCF7 and MAT-MSCs was followed by a significant cellular migration and caudal dissemination. Thus, MAT-MSCs enhance the aggressiveness of BC cells in a HG environment.

Automated summary

This study demonstrates that high glucose levels enhance the aggressiveness of breast cancer cells and promote a pro-tumorigenic phenotype in mammary adipose tissue-derived mesenchymal stromal/stem cells (MAT-MSCs). The findings suggest that metabolic control may be important for reducing cancer outgrowth and preserving the functions of the adipose microenvironment.