Abstract
Adipose-derived stem cells are capable of differentiating into multiple cell types and thus considered useful for regenerative medicine. However, this differentiation feature seems to be associated with tumor initiation and metastasis raising safety concerns, which requires further investigation. In this study, we isolated adipose-derived stem cells from subcutaneous as well as from visceral adipose tissues of the same donor and systematically compared their features. Although being characteristic of mesenchymal stem cells, subcutaneous adipose-derived stem cells tend to be spindle form-like and are more able to home to cancer cells, whereas visceral adipose-derived stem cells incline to be "epithelial"-like and more competent to differentiate. Moreover, compared to subcutaneous adipose-derived stem cells, visceral adipose-derived stem cells are more capable of promoting proliferation, inducing the epithelial-to-mesenchymal transition, enhancing migration and invasion of breast cancer cells by cell-cell contact and by secreting interleukins such as IL-6 and IL-8. Importantly, ASCs affect the low malignant breast cancer cells MCF-7 more than the highly metastatic MDA-MB-231 cells. Induction of the epithelial-to-mesenchymal transition is mediated by the activation of multiple pathways especially the PI3K/AKT signaling in breast cancer cells. BCL6, an important player in B-cell lymphoma and breast cancer progression, is crucial for this transition. Finally, this transition fuels malignant properties of breast cancer cells and render them resistant to ATP competitive Polo-like kinase 1 inhibitors BI 2535 and BI 6727.
Highlights
Breast cancer is the second most common cancer worldwide with 1.7 million cases and over 522,000 deaths per year [1]
Indirect immunofluorescence staining in adipose-derived stem cell (ASC) further underscored the positive signals of CD90 and CD73 (Figure 1B), which were negative in MCF-7 cells (Figure S1A)
After 14 days of neurogenic induction, 43% of visceral ASCs showed lineage specific staining of Tuj1, a marker for class III β-tubulin, and DCX, a marker for developing neurons, in addition to neuronal branching among differentiated cells (Figure 1C, 1st panel and Figure 1D). 34% of visceral ASCs were positively stained for adiponectin, one of the adipokines secreted by adipocytes, confirming the adipogenic differentiation capacity (Figure 1C, 2nd panel and Figure 1D)
Summary
Breast cancer is the second most common cancer worldwide with 1.7 million cases and over 522,000 deaths per year [1]. ASCs are capable of differentiating into multiple cell types such as adipocytes, neurons, osteoblasts and retain the ability of self-renewing [3] By virtue of their regenerative features like pro-angiogenic, anti-apoptotic, pro-proliferative and multipotent differentiation, ASCs are widely considered as a promising tool for regenerative medicine application and tissue engineering [4, 5], such as breast reconstruction after breast ablation in cancer patients. While numerous investigations indicate that ASCs promote tumor growth and malignant phenotypes in multiple cancer types [7], supported by in vivo studies showing increased tumor growth, metastatic spread and angiogenesis [7, 8], other studies reveal a therapeutic potential of ASCs in breast cancer models in vitro and in vivo [9, 10]. Visceral ASCs are more potent to induce the epithelial-to-mesenchymal transition in breast cancer cells mediated by activating multiple pathways in particular the PI3K/AKT signaling
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