Abstract
BackgroundMesenchymal stromal cells (MSCs) represent heterogeneous cell population suitable for cell therapies in regenerative medicine. MSCs can also substantially affect tumor biology due to their ability to be recruited to the tumor stroma and interact with malignant cells via direct contacts and paracrine signaling. The aim of our study was to characterize molecular changes dictated by adipose tissue-derived mesenchymal stromal cells (AT-MSCs) and the effects on drug responses in human breast cancer cells SKBR3.MethodsThe tumor cells were either directly cocultured with AT-MSCs or exposed to MSCs-conditioned medium (MSC-CM). Changes in cell biology were evaluated by kinetic live cell imaging, fluorescent microscopy, scratch wound assay, expression analysis, cytokine secretion profiling, ATP-based viability and apoptosis assays. The efficiency of cytotoxic treatment in the presence of AT-MSCs or MSCs-CM was analyzed.ResultsThe AT-MSCs altered tumor cell morphology, induced epithelial-to-mesenchymal transition, increased mammosphere formation, cell confluence and migration of SKBR3. These features were attributed to molecular changes induced by MSCs-secreted cytokines and chemokines in breast cancer cells. AT-MSCs significantly inhibited the proliferation of SKBR3 cells in direct cocultures which was shown to be dependent on the SDF-1α/CXCR4 signaling axis. MSC-CM-exposed SKBR3 or SKBR3 in direct coculture with AT-MSCs exhibited increased chemosensitivity and induction of apoptosis in response to doxorubicin and 5-fluorouracil.ConclusionsOur work further highlights the multi-level nature of tumor-stromal cell interplay and demonstrates the capability of AT-MSCs and MSC-secreted factors to alter the anti-tumor drug responses.
Highlights
Mesenchymal stromal cells (MSCs) represent heterogeneous cell population suitable for cell therapies in regenerative medicine
adipose tissue-derived mesenchymal stromal cells (AT-MSCs) stimulate an epithelial-to-mesenchymal transition (EMT) and mammosphere formation in the breast cancer cells SKBR3 Previously we have described that AT-MSCs secrete a plethora of chemokines and growth factors which might affect the tumor cell behavior [23]
The EMT process was previously linked to contribute to increased stemness [35] and an upregulation of Oct and Nanog was detected in MSCs-conditioned medium (MSC-CM) exposed enhanced green fluorescent protein (EGFP)-SKBR3 (Figure 1C)
Summary
Mesenchymal stromal cells (MSCs) represent heterogeneous cell population suitable for cell therapies in regenerative medicine. MSCs can substantially affect tumor biology due to their ability to be recruited to the tumor stroma and interact with malignant cells via direct contacts and paracrine signaling. The aim of our study was to characterize molecular changes dictated by adipose tissue-derived mesenchymal stromal cells (AT-MSCs) and the effects on drug responses in human breast cancer cells SKBR3. MSCssecreted factors increased mammosphere formation and the exosomes from MSCs were sufficient to support the growth of tumor xenografts [24,25,26]. Taken together these data suggest that BM-MSCs promote breast cancer growth and/or metastatic spread. The introduction of specific transgene(s) into the AT-MSCs sensitized the breast cancer cells MDA-MB-231 to the chemotherapeutic drug 5FU for in vitro [33]
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