Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells

Abstract

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.

Protease-activated Receptor-2 (PAR-2)-mediated Nf-κB Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma

“…miR-23b is a known suppressor of cancer metastasis. Putative target genes that are up-regulated in oral cancer include the proliferation and motility gene MARCKS, the RAS oncogene RAP1B, and the growth factor HDGFRP3 (58,63). miR-23b also suppresses EMT by reduction of vimentin and Snail and up-regulation of E-cadherin (64 -66).…”

Tumour-derived miRNAs and bone metastasis

“…Further, exosomes were isolated from bone marrow mesenchymal stem cellsand co-cultured with CD44 þ -expressing MDA-MB-231 breast cancer cells, as a model of DTCs, to investigate interactions between cancer cells and the bone microenvironment. 59 In another study, the growth of CD44-expressing cells injected into the bone compartment was impaired in the presence of exosomes isolated from bone marrow mesenchymal stem cells. This was postulated to be due to elevated expression of exosome-derived miRNAs such as miR-23b, and was further substantiated when miR-23b overexpression partially recapitulated the tumour inhibitory effect in vivo.…”

Bone marrow as a metastatic niche for disseminated tumor cells from solid tumors

“…As expected, exosome-treated or miR-23b-overexpressing MDA-BM-231-BM2 cells both exhibit dormancy in mice. 28 It has been demonstrated that bone marrow-derived MSCs are capable of transforming into cancer-associated fibroblasts (CAFs) within the primary tumor, 29,30 whereupon CAFs promote lung metastases of human breast cancer cell line MDA-MB-231 through the Chemokine (C-C motif) ligand 5 (CCL5)/ C-C chemokine receptor type 5 (CCR5) axis, 29 and bone metastases of murine prostate cancer cell line RM-1 through the chemokine (C-X-C motif) ligand 16 (CXCL16)/ C-X-C chemokine receptor type 6 (CXCR6) axis. 30 In fact, MSC-derived CAFs may select for Src hyperactive, bone metastatic and triple negative breast cancer.…”

“…When the bone metastatic clone of human breast cancer cell line MDA-BM-231-BM2 is cocultured with human MSC line R14, the proliferation and migration of MDA-BM-231-BM2 cells are reduced, evidently by R14-derived exosomes. 28 The mechanism behind this transition is the high expression of microRNA mir-23b in the exosomes, which causes suppression of the MARCKS gene and subsequently its encoded protein, myristoylated alaninerich C kinase substrate. As expected, exosome-treated or miR-23b-overexpressing MDA-BM-231-BM2 cells both exhibit dormancy in mice.…”