Abstract
ObjectiveAlthough adipocytes are the most abundant stromal cell component in breast cancer tissues, their interaction with breast cancer cells has been less investigated compared to cancer-associated fibroblasts or macrophages. Exosomes are a novel way of cell-cell communication and have been demonstrated to play an important role in various biological processes. However, to our knowledge, only a few studies have reported the effects of adipocyte exosomes on tumor development. Here, utilizing exosomes isolated from in vitro mesenchymal stromal/stem cell (MSC)-differentiated adipocytes, we systematically investigated this issue in a breast cancer model.Material and methodsExosomes were isolated from MSC-differentiated adipocytes and added to breast cancer cells MCF7. Cell proliferation was detected by MTS, and migration was analyzed by wound healing and transwell assay. An in vivo mouse xenograft model was used to evaluate MSC-differentiated adipocyte exosomes’ contribution to tumor growth. Signaling pathway activation was evaluated by western blot and immunofluorescence staining.ResultsWe found MSC-differentiated adipocyte-derived exosomes are actively incorporated by breast cancer cell MCF7 and subsequently promote MCF7 proliferation and migration as well as protect MCF7 from serum derivation or chemotherapeutic drug-induced apoptosis in vitro. In the in vivo mouse xenograft model, depletion of exosomes reduces tumor-promoting effects of adipocytes. Transcriptomic analysis of MSC-differentiated adipocyte exosome-treated MCF7 identified several activated signaling pathways, among which we confirm the Hippo signaling pathway and found a blockade of this pathway leads to a reduced growth-promoting effect of adipocyte exosomes.ConclusionTaken together, our findings provide new insights into the role of adipocyte exosomes in the tumor microenvironment.
Highlights
Breast cancer is one of the most common cancers and the second leading cause of cancer-related mortality in women worldwide [1]
We found mesenchymal stromal/stem cells (MSCs)-differentiated adipocyte-derived exosomes are actively incorporated by breast cancer cell MCF7 and subsequently promote MCF7 proliferation and migration as well as protect MCF7 from serum derivation or chemotherapeutic drug-induced apoptosis in vitro
In vitro differentiation of adipocytes from AD-MSCs To investigate the role of adipocyte exosomes in tumor development, we first explored the feasibility of using human in vitro differentiated adipocytes as a new cellular model since most studies use mouse cell line 3T3-L1differentiated adipocytes. hAD-MSCs were cultured under an adipogenic induction medium for 12 days, and differentiated cells exhibited typical adipocyte phenotypes as demonstrated by morphology and staining(Fig. 1a)
Summary
Breast cancer is one of the most common cancers and the second leading cause of cancer-related mortality in women worldwide [1] Various factors such as genetic and epigenetic mutations, abnormal hormone levels, and environmental stimulus contribute to breast cancer development [2, 3]. Studies focusing on interactions between cancer cells and tumor microenvironment have emphasized the important roles of stromal compartments such as cancer-associated fibroblasts and cancer-associated macrophages [6]. Adipocytes could transfer free fatty acids (FFAs) to stimulate breast cancer invasion via metabolic remodeling of tumor cells [11]. These studies suggest there is an intimate interaction between breast cancer cells and adipocytes. The underlying mechanism governing adipocyte crosstalk with breast cancer cells is not fully understood
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