Altered features and increased chemosensitivity of human breast cancer cells mediated by adipose tissue-derived mesenchymal stromal cells

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.

Human Mesenchymal Stroma/Stem Cells Exchange Membrane Proteins and Alter Functionality During Interaction with Different Tumor Cell Lines

“…Furthermore, these findings are substantiated by a previous work demonstrating enhanced tumor cell growth by MSC [34][35][36][37], although there are also controversial studies suggesting a reduced tumor cell proliferation in the presence of MSC [38,39]. The divergent effects of MSC on tumor cells may be caused, in part, by a different activation status within the heterogeneous MSC population involving interference with the b-catenin pathway such as DKK-1-mediated depression of Wnt signaling [40].…”

Differential properties of human stromal cells from bone marrow, adipose, liver and cardiac tissues

“…In our co-culture, stromal cells from liver and adipose also supported the proliferation of K562 cells. Recent reports have demonstrated that adipose tissue and associated stroma can maintain breast cancer cells and induce pharmacological resistance [34,35]. Additionally, the links between adipose tissue and activation of inflammation and chemokine pathways with regard to oncogenesis is becoming more recognized [36].…”

Adipose Tissue-Derived Stem Cell Therapy for Post-Surgical Breast Reconstruction - More Light than Shadows

“…Actually, major attention has been focused in order to clarify if the transfer of ASCs-containing SVF may increase the risk of breast cancer development or relapse [14]. Tumor microenvironment consists in a complex signaling network which influences the behavior of both resident stem cells and tumor cells [15]. Angiogenesis is one of the crucial events for cancer development and growth, and VEGF secretion plays a pivotal role in this process, thereby becoming a main target for antitumor strategies [16,17].…”