Abstract
Mesenchymal stromal cells (MSCs) are multipotent adult stem cells which are recruited to the tumor microenvironment (TME) and influence tumor progression through multiple mechanisms. In this study, we examined the effects of MSCs on the tunmorigenic capacity of 4T1 murine mammary cancer cells. It was found that MSC-conditioned medium increased the proliferation, migration, and efficiency of mammosphere formation of 4T1 cells in vitro. When co-injected with MSCs into the mouse mammary fat pad, 4T1 cells showed enhanced tumor growth and generated increased spontaneous lung metastasis. Using in vivo fluorescence color-coded imaging, the interaction between GFP-expressing MSCs and RFP-expressing 4T1 cells was monitored. As few as five 4T1 cells could give rise to tumor formation when co-injected with MSCs into the mouse mammary fat pad, but no tumor was formed when five or ten 4T1 cells were implanted alone. The elevation of tumorigenic potential was further supported by gene expression analysis, which showed that when 4T1 cells were in contact with MSCs, several oncogenes, cancer markers, and tumor promoters were upregulated. Moreover, in vivo longitudinal fluorescence imaging of tumorigenesis revealed that MSCs created a vascularized environment which enhances the ability of 4T1 cells to colonize and proliferate. In conclusion, this study demonstrates that the promotion of mammary cancer progression by MSCs was achieved through the generation of a cancer-enhancing microenvironment to increase tumorigenic potential. These findings also suggest the potential risk of enhancing tumor progression in clinical cell therapy using MSCs. Attention has to be paid to patients with high risk of breast cancer when considering cell therapy with MSCs.
Highlights
Mesenchymal stromal cells (MSCs) are adult stem cells that possess multipotent differentiation potential
Several growth factors and cytokines secreted by MSCs, such as vascular endothelial growth factor (VEGF), angiopoietin, Interleukin 6, Interleukin 8, transforming growth factor b (TGF-b), PDGF, bFGF, and FGF-7 may act on endothelial cells and directly contribute to tumor vessel formation [13]
To determine whether MSCs influence cancer cell proliferation, cells were counted at various time points after 4T1 or JC cells were cultured in regular medium or MSC-conditioned medium (MSC-CM)
Summary
Mesenchymal stromal cells (MSCs) are adult stem cells that possess multipotent differentiation potential. When MSCs are systemically injected into tumor-bearing animals, they target tumors [6,7,8]. Factors such as stromal cell-derived factor 1 (SDF-1) and its receptor C-X-C chemokine receptor type 4 (CXCR-4), plateletderived growth factor a (PDGF-a) and vascular endothelial growth factor (VEGF) may be involved in MSC targeting to tumors [9,10]. The recruited MSCs within the tumor microenvironment (TME) may further differentiate into various types of cells, such as fibroblasts, pericytes and cancer-associated fibroblasts (CAFs) [11,12] which influence cancer progression. MSCs enhanced in vitro mammosphere formation by breast cancer cells and reduced the latency time of in vivo tumor formation [15]
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