Breast cancer-derived extracellular vesicles stimulate myofibroblast differentiation and pro-angiogenic behavior of adipose stem cells

Abstract

Adipose-derived stem cells (ASCs) are abundantly present in the mammary microenvironment and can promote breast cancer malignancy by differentiating into myofibroblasts. However, it remains largely unclear which role tumor-derived extracellular vesicles (TEVs) play in this process. Here, we used microfabricated, type I collagen-based 3-D tissue culture platforms to investigate the effect of breast cancer cell-derived TEVs on ASCs myofibroblast differentiation and consequential changes in extracellular matrix remodeling and vascular sprouting. TEVs collected from MDA MB-231 human metastatic breast cancer cells (MDAs) promoted ASC myofibroblast differentiation in both 2-D and 3-D culture as indicated by increased alpha smooth muscle actin (α-SMA) and fibronectin (Fn) levels. Correspondingly, TEV-treated ASCs were more contractile, secreted more vascular endothelial growth factor (VEGF), and promoted angiogenic sprouting of human umbilical vein endothelial cells. These changes were dependent on transforming growth factor beta (TGF-β)-related signaling and tumor cell glutaminase activity as their inhibition decreased TEV-related myofibroblastic differentiation of ASCs and related functional consequences. In summary, our data suggest that TEVs are important signaling factors that contribute to ASC desmoplastic reprogramming in the tumor microenvironment, and suggest that tumor cell glutamine metabolism may be used as a therapeutic target to interfere with this process.

CD44v6 increases gastric cancer malignant phenotype by modulating adipose stromal cell-mediated ECM remodeling

“…This was confirmed by the higher proliferative capacity of ASCs determined through BrdU staining, as well as increased levels of α-SMA, fibronectin, and type I collagen, whose up-regulation is known to accompany the neoplastic transformation of the stomach. 57 Our findings are consistent with previous reports 27–29,34 and suggest that CD44v6 expression up-regulates TGF-β secretion, 50,51 which may function in a paracrine manner to stimulate the production of ECM components 58,59 and modulate the levels of α-SMA independent of pre-existing or newly deposited ECM. 60 Nevertheless, further investigation is warranted to understand the functional link between TGF-β and CD44v6 expression and to identify additional growth factors and cytokines that may contribute to CD44v6-mediated changes in ASC-associated ECM deposition and remodeling.…”

“…Similarly, stromal cells have previously been shown to differentiate into myofibroblasts under the influence of tumor-derived factors. 27,29,47,48 Among these factors, transforming growth factor-beta (TGF-β) plays a key role in myofibroblastic differentiation 49 and is secreted at higher levels by more malignant tumor cells. 27 Interestingly, comparison of Control media as well as TCM from MKN74 and CD44v6 cells via ELISA revealed that TGF-β is significantly enhanced in the TCM of CD44v6 expressing tumor cells (Fig.…”

Extracellular Vesicles as Signaling Mediators and Disease Biomarkers across Biological Barriers

“…The EVs released by cancer cells have been intensely studied and play key roles in the organization of the tumor microenvironment. For example, they are implicated in the reprogramming of normal stromal fibroblasts to activated cancer-associated fibroblasts (CAFs) [155][156][157][158][159]. In turn, CAFs secrete EVs that boost tumorigenesis by instigating metabolic changes, proliferation, epithelial-mesenchymal transition (EMT), motility, and migration in cancer cells, endothelial cells, and other stromal fibroblasts [160][161][162][163].…”

New insights into extracellular vesicle biogenesis and function

“…Similarly, treating cancer cells with chemotherapeutic agents, or radiation, significantly enhances the number of EVs produced and shed by the cells (Kreger et al, 2016a;Lv et al, 2012;Pavlyukovms et al, 2018;Yu et al, 2006). A possible explanation for these observations comes from the findings that an important contributor to the ability of cancer cells to generate increased numbers of EVs is the metabolic re-programming that these cells undergo (Song et al, 2017;Santana et al, 2014;Dorai et al, 2018). The vast majority of cancer cells exhibit marked changes in their metabolic activities, including significantly increased glycolytic fluxes (Lukey et al, 2018).…”