Regulation of Breast Cancer Stem Cells by Mesenchymal Stem Cells in the Metastatic Niche

Despite recent advances in breast cancer diagnosis and treatment, metastatic breast cancer remains incurable and is a leading cause of cancer-related death among women. There is now substantial evidence that breast cancer metastasis to distant organs is mediated by a cellular subpopulation that displays stem cell properties. These breast cancer stem cells (CSCs) maintain the plasticity to transition between epithelial and mesenchymal states. Furthermore, transition between epithelial (EMT) and mesenchymal (MET) CSC states is regulated by the tumour microenvironment. This microenvironment includes mesenchymal stem cells (MSCs), which are recruited from the bone marrow to growing sites of tumour metastasies. In vitro and in vivo studies demonstrate significant crosstalk between metastatic breast cancer cells and bone marrow-derived mesenchymal stem cells, which facilitate metastasis by mediating EMT/MET cell-state transitions. At distant organs such as bone, stromal cells, including osteoclasts and mesenchymal stem cells, may play important roles in regulating EMT/MET CSC transistions. EMT stem cells, by virtue of their quiescence, may contribute to tumour dormancy. In contrast, conversion of EMT to self-renewing MET-like stem cells may facilitate growth at metastatic sites. In this review, we discuss recent advances in understanding the role of the tumour microenvironment in general, and mesenchymal stem cells in particular, in regulating breast CSCs. We discuss the role of these interactions in facilitating tumour metastasis, as well as in generating therapeutic resistance. We provide a review of current preclinical and clinical strategies designed to specifically target BCSCs, as well as the microenvironmental signals regulating these cells. It is hoped that selective targeting of breast CSCs will improve the outcome for women with metastatic and early-stage breast cancers.