Mesenchymal stem cell secretion of chemokines during differentiation into osteoblasts, and their potential role in mediating interactions with breast cancer cells

Abstract

Over 70% of patients with advanced breast cancer will develop bone metastases for which there is no cure. Mesenchymal Stem Cells (MSCs) and their derivative osteoblasts are subpopulations of cells within the bone marrow environment, postulated as potential interacting targets for disseminating cancer cells because of their ability to secrete a range of chemokines. This study aimed to investigate chemokine secretion throughout MSC differentiation into osteoblasts and their effect on the breast cancer cells. Primary MSCs and osteoblast progenitors were cultured in appropriate conditions to induce differentiation into mature osteoblasts. Chemokines secreted throughout differentiation were detected using ChemiArray and ELISA. Migration of breast cancer cells in response to the bone-derived cells was quantified using Transwell inserts. Breast cancer cells were cocultured with MSCs, retrieved using magnetic beads, and changes in CCL2 expression were analyzed. MSCs secreted a range of factors including IL-6, TIMP-1 and CCL2, the range and level of which changed throughout differentiation. CCL2 secretion by MSCs increased significantly above control cells as they differentiated into mature osteoblasts (p < 0.05). The bone-derived cells stimulated migration of breast cancer cells, and this was inhibited (21-50%) in the presence of a CCL2 antibody. CCL2 gene expression in breast cancer cells was upregulated following direct coculture with MSCs. The varying levels of chemokines secreted throughout MSC differentiation may play an important role in supporting tumor cell homing and progression. These results further highlight the distinct effect MSCs have on breast cancer cells and their potential importance in supporting development of metastases.

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.…”

“…This tumor homing ability has prompted researchers to analyse MSCs as possible vectors for the targeted delivery of anti-cancer agents to tumor microenvironments [13]. However evidence suggests that interactions between MSCs and breast cancer cells may impact upon the phenotype of the cancer cell and promote their metastatic potential [7][8][9][14][15][16]. Understanding these interactions has become fundamental to determining whether the homing ability of MSCs should be harnessed for delivery of therapeutic agents or whether the MSC-tumour interactions should be considered a target for intervention.…”

Modeling sarcomagenesis using multipotent mesenchymal stem cells

“…MSCs are frequently recruited to the site of tissue injury or tumor growth and sometimes, in the appropriate and permissive environment and under stress conditions, this could also represent a potential source of malignancy. Thus, MSCs within the tumor stroma facilitate breast cancer metastasis through the secretion of the chemokines CCL5 [89] and CCL2 [90]. Likewise, hMSCs target osteosarcoma and promote its growth and pulmonary metastasis through secretion of CCL5 [91].…”

Targeting multiple tyrosine kinase receptors with Dovitinib blocks invasion and the interaction between tumor cells and cancer-associated fibroblasts in breast cancer

“…7,8 It was also shown that CAFs support the malignant properties of cancer spreading by secreting soluble factors such as pro-angiogenic factors, matrix metalloproteinases (MMPs), cytokines as well as chemokines and growth factors. 9 Among these cytokines, CCL2 and CCL5, which are known inflammatory mediators, were demonstrated to play important role in the mediation of the interaction between CAFs and breast cancer cells beyond SDF-1 [10][11][12][13] Dovitinib (formerly CHIR-258, TKI-258, Novartis pharmaceuticals) is an investigational new inhibitor of multiple tyrosine kinases that has in vitro inhibitory activity against basic fibroblast growth factor receptor (bFGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR) kinases with IC 50 values of approximately 10 nM. Further in vivo and in vitro data indicate that this drug blocked PDGFR/FGFR/VEGFR signaling in advanced melanoma, 4 pancreatic cancer, 14 breast carcinoma, 15 urothelial carcinoma, 16 impaired tumor growth, angiogenesis, and metastasis by effects on tumor cells, endothelial cells, and pericytes in vitro.…”