Glioblastoma multiforme (GBM), the most common and lethal tumor of the adult brain, generally shows chemo- and radioresistance. MicroRNAs (miRs) regulate physiological processes, such as resistance of GBM cells to temozolomide (TMZ). Although miRs are attractive targets for cancer therapeutics, the effectiveness of this approach requires targeted delivery. Mesenchymal stem cells (MSCs) can migrate to the sites of cancers, including GBM. We report on an increase in miR-9 in TMZ-resistant GBM cells. miR-9 was involved in the expression of the drug efflux transporter, P-glycoprotein. To block miR-9, methods were developed with Cy5-tagged anti-miR-9. Dye-transfer studies indicated intracellular communication between GBM cells and MSCs. This occurred by gap junctional intercellular communication and the release of microvesicles. In both cases, anti-miR-9 was transferred from MSCs to GBM cells. However, the major form of transfer occurred with the microvesicles. The delivery of anti-miR-9 to the resistant GBM cells reversed the expression of the multidrug transporter and sensitized the GBM cells to TMZ, as shown by increased cell death and caspase activity. The data showed a potential role for MSCs in the functional delivery of synthetic anti-miR-9 to reverse the chemoresistance of GBM cells.
Bone marrow (BM) metastasis of breast cancer (BC) can recur even decades after initial diagnosis and treatment, implying the long-term survival of disseminated cancer cells in a dormant state. Here we investigated the role of microRNAs (miRNA) transmitted from BM stroma to BC cells via gap junctions and exosomes in tumor cell quiescence. MDA-MB-231 and T47D BC cells arrest in G 0 phase of the cell cycle when cocultured with BM stroma. Analyses of miRNA expression profiles identified numerous miRNAs implicated in cell proliferation including miR-127, -197, -222, and -223 targeting CXCL12. Subsequently, we showed that these CXCL12-specific miRNAs are transported from BM stroma to BC cells via gap junctions, leading to reduced CXCL12 levels and decreased proliferation. Stroma-derived exosomes containing miRNAs also contributed to BC cell quiescence, although to a lesser degree than miRNAs transmitted via gap junctions. This study shows that the transfer of miRNAs from BM stroma to BC cells might play a role in the dormancy of BM metastases.
Mesenchymal stem cells (MSCs) have been shown to support breast cancer growth. Because MSCs also increase the frequency of regulatory T cells (Tregs), this study tested the hypothesis that human MSCs, via Tregs, protect breast cancer cells (BCCs) from immune clearance MSCs suppressed the proliferation of PBMCs when the latter were exposed to gamma-irradiated BCCs. Similarly, MSCs showed significant inhibition of PBMC migration toward BCCs and a corresponding decrease in CXCL12. MSCs also inhibited NK cell and CTL functions, which correlated with reduced numbers of CD8+ and CD56+ cells compared with parallel cultures without MSCs. The reduced NK and CTL activities correlated with a decrease in intracellular and secreted granzyme B. To explain these immunosuppressive findings, we compared Treg levels after coculture with MSCs and found an ∼2-fold increase in Tregs, with associated decreases in antitumor Th1 cytokines and increases in Th2 cytokines. MSC-derived TGF-β1 was largely responsible for the increase in Tregs based on knockdown studies. In the presence of Treg depletion, PBMC proliferation and effector functions were partially restored. Together, these studies show an MSC-mediated increase in Tregs in cocultures of PBMCs and BCCs. The results could be explained, in part, by the increase in Th2-type cytokines and MSC-generated TGF-β1. These findings demonstrate immune protection by MSCs to BCCs. The reduction in immune cell proliferation and recruitment mediated by MSCs has implications for treatment of breast cancer with chemotherapy.
Dormant breast cancers resurge as metastatic disease after a long dormancy period in the bone marrow, where cancer cells interact with mesenchymal stem cells (MSC). However, the nature of early interactions between breast cancer cells and MSCs in the bone marrow microenvironment that facilitate adaptation to a quiescent state remains poorly understood. Here, we report that breast cancer cells prime MSC to release exosomes containing distinct miRNA contents, such as miR-222/223, which in turn promotes quiescence in a subset of cancer cells and confers drug resistance. Building on these results, we developed a novel, nontoxic therapeutic strategy to target dormant breast cancer cells based on systemic administration of MSC loaded with antagomiR-222/223. In an immunodeficient mouse model of dormant breast cancer, this therapy sensitized breast cancer cells to carboplatin-based therapy and increased host survival. Overall, our findings illuminate the nature of the regulatory interactions between breast cancer cells and MSCs in the evolution of tumor dormancy and resurgence in the micrometastatic microenvironment of the bone marrow.
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