Breast Tumor Microenvironment Can Transform Naive Mesenchymal Stem Cells into Tumor-Forming Cells in Nude Mice

Abstract

How mesenchymal stem cells (MSCs) interact with tumor cells and promote tumor growth is not well understood. In this study, we demonstrate that when naive MSCs and malignant breast cancer cells (MDA-MB231) were injected into opposing mammary glands of an immunodeficient nude mouse, both cell types formed tumor-like masses within 8 weeks at the injected site. Surprisingly, MDA-MB231 cells were detected in the opposing mammary gland injected with the naive MSCs, indicating migration and crosstalk between naive MSCs and MDA-MB231 cells. Furthermore, when naive MSCs preexposed to MDA-MB231-derived conditioned medium (CM; MSC CM ) or purified exosomes (Exo; MSC Exo ) were injected into mammary glands of nude mice, they too formed a tumor-like mass with stromal tissue within 14 weeks. Interestingly, cells dissociated from these primary explants also formed tumor-like masses. Finally, injecting MSC CM or MSC Exo and naive MSCs into opposing mammary glands formed tumor-like masses on the naive MSC-injected side, suggesting migration and crosstalk between MSC CM or MSC Exo with naive MSCs, similar to that observed between malignant MDA-MB231 cells and naive MSCs. Importantly, molecular analysis of MSC CM and MSC Exo revealed DNA hypermethylation. These data demonstrate that MSCs and breast cancer cells communicate, resulting in the transformation of naive MSCs into cells capable of forming explants in nude mice. Our data also suggest that DNA hypermethylation might have contribute to their migration. Understanding the crosstalk between MSCs and tumor cells, and identifying the players involved in their interaction, will help us develop novel therapeutics for breast cancer regression and elimination.