Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells
The bone marrow delivers dormancy signals in exosomes to metastatic cancer cells. Promoting Cancer Cell Dormancy with Exosomes Metastatic disease often develops long after treatment of the primary tumor because of cells that spread into metastatic niches, particularly the bone marrow. Because these "dormant" cells have a slow rate of cell cycling, they are not killed by traditional chemotherapies that target rapidly dividing cells. Ono et al. examined how cells present in the bone marrow niche trigger dormancy of metastatic breast cancer cells. They found that exosomes (vesicles shed by cells) from bone marrow derived mesenchymal stem cells were taken up by cancer cells, in which they inhibited proliferation and promoted other characteristics associated with dormancy, in part through the delivery of a microRNA that suppressed the expression of a gene encoding a protein that promotes cell proliferation and motility. Thus, the bone marrow niche releases exosomes that deliver signals promoting metastatic cancer cell dormancy. Breast cancer patients often develop metastatic disease years after resection of the primary tumor. The patients are asymptomatic because the disseminated cells appear to become dormant and are undetectable. Because the proliferation of these cells is slowed, dormant cells are often unresponsive to traditional chemotherapies that exploit the rapid cell cycling of most cancer cells. We generated a bone marrow metastatic human breast cancer cell line (BM2) by tracking and isolating fluorescent labeled MDA MB 231 cells that disseminated to the bone marrow in mice. Coculturing BM2 cells with bone marrow mesenchymal stem cells (BM MSCs) isolated from human donors revealed that BM MSCs suppressed the proliferation of BM2 cells, decreased the abundance of stem cell like surface markers, inhibited their invasion through Matrigel Transwells, and decreased their sensitivity to docetaxel, a common chemotherapy agent. Acquisition of these dormant phenotypes in BM2 cells was also observed by culturing the cells in BM MSC conditioned medium or with exosomes isolated from BM MSC cultures, which were taken up by BM2 cells. Among various microRNAs (miRNAs) increased in BM MSC derived exosomes compared with those from adult fibroblasts, overexpression of miR 23b in BM2 cells induced dormant phenotypes through the suppression of a target gene, MARCKS, which encodes a protein that promotes cell cycling and motility. Metastatic breast cancer cells in patient bone marrow had increased miR 23b and decreased MARCKS expression. Together, these findings suggest that exosomal transfer of miRNAs from the bone marrow may promote breast cancer cell dormancy in a metastatic niche.
Science Signaling