Mesenchymal Stem Cells in Early Entry of Breast Cancer into Bone Marrow

Abstract

BackgroundAn understanding of BC cell (BCC) entry into bone marrow (BM) at low tumor burden is limited when compared to highly metastatic events during heavy tumor burden. BCCs can achieve quiescence, without interfering with hematopoiesis. This occurs partly through the generation of gap junctions with BM stroma, located close to the endosteum. These events are partly mediated by the evolutionary conserved gene, Tac1.Methodogy/Principal FindingsThis study focuses on the role of mesenchymal stem cells (MSCs), Tac1, SDF-1 and CXCR4 in BCC entry into BM. The model is established in studies with low numbers of tumor cells, and focuses on cancer cells with low metastatic and invasion potential. This allowed us to recapitulate early event, and to study cancer cells with low invasive potential, even when they are part of larger numbers of highly metastatic cells. A novel migration assay showed a facilitating role of MSCs in BCC migration across BM endothelial cells. siRNA and ectopic expression studies showed a central role for Tac1 and secondary roles for SDF-1α and CXCR4. We also observed differences in the mechanisms between low invasive and highly metastatic cells. The in vitro studies were verified in xenogeneic mouse models that showed a preference for low invasive BCCs to BM, but comparable movement to lung and BM by highly metastatic BCCs. The expressions of Tac1 and production of SDF-1α were verified in primary BCCs from paired samples of BM aspirates and peripheral blood.Conclusions/SignificanceMSC facilitate BCC entry into BM, partly through Tac1-mediated regulation of SDF-1α and CXCR4. We propose a particular population of BCC with preference for BM could be isolated for characterization. This population might be the subset that enter BM at an early time period, and could be responsible for cancer resurgence and resistance to current therapies.

Potential role of mesenchymal stem cells (MSCs) in the breast tumour microenvironment: stimulation of epithelial to mesenchymal transition (EMT)

“…Reports from this laboratory and others have shown a significant increase in migration of breast cancer cells in response to factors secreted by MSCs [25,26], and this was reflected by increased expression of migratory genes seen here including MMP11 and CXCL12 [27]. Oncogenes and proto-oncogenes were upregulated both in a cell specific manner and, in the case of FOS and JUN, across all breast cancer cells retrieved following co-culture with MSCs.…”

“…Mesenchymal Stem Cells have been reported to interact with breast cancer cells that have metastasised to bone marrow [25] as well as being actively recruited to the primary tumour stromal interface [15]. This tumour homing quality has prompted investigators to assess MSCs as possible delivery vectors for anti-cancer therapies [13].…”

Mesenchymal Stem Cells Protect Breast Cancer Cells through Regulatory T Cells: Role of Mesenchymal Stem Cell-Derived TGF-β

“…MSCs were cultured from BM aspirates, as described (20). Briefly, unfractionated aspirates were diluted in DMEM.…”

“…Transmigration assay was performed as described (20). Briefly, Boyden chambers with 8-mm inserts (BD Falcon) were used to evaluate PBMC migration toward BCCs and/or MSCs.…”

Therapeutically targeting SELF‐reinforcing leukemic niches in acute myeloid leukemia: A worthy endeavor?

“…Thus, it can be argued that MSCs might significantly affect MRD persistence either through their angiogenic or immunosuppressive/anti-inflammatory properties [60,61]. It is well-known that MSCs actively participate in the "angiogenic switch" not only by releasing various angiogenic factors [62], but also by recruiting circulating vascular progenitor cells [63]. MSCs may inhibit adaptive and innate immunity by releasing immunosuppressive cytokines and effectors including tumor necrosis a (TNF-a) and interferon-g (IFN-g) either directly or under the influence of leukemic cells [64][65][66][67].…”