Breast cancer-derived extracellular vesicles stimulate myofibroblast differentiation and pro-angiogenic behavior of adipose stem cells.
Breast cancer-derived extracellular vesicles stimulate myofibroblast differentiation and pro-angiogenic behavior of adipose stem cells.
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DOI：
10.1016/j.matbio.2016.11.008
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发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
Fischbach C
中科院分区：
文献类型：
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作者：
Song YH;Warncke C;Choi SJ;Choi S;Chiou AE;Ling L;Liu HY;Daniel S;Antonyak MA;Cerione RA;Fischbach C
脂肪来源的干细胞(ASCs)广泛存在于乳腺微环境中，通过分化为肌成纤维细胞促进乳腺癌的恶性转化。然而，肿瘤来源的细胞外小泡(TEV)在这一过程中扮演的角色仍很不清楚。在这里，我们使用微制的、基于I型胶原的三维组织培养平台来研究乳腺癌细胞来源的TEV对ASCs肌成纤维细胞分化的影响，以及由此导致的细胞外基质重塑和血管萌发的变化。从mda MB-231人转移性乳腺癌细胞(MDA)收集的TEV可促进ASC肌成纤维细胞在二维和三维培养中的分化，表现为α-平滑肌肌动蛋白(α-SMA)和纤维连接蛋白(FN)水平的增加。相应地，经TEV处理的ASCs收缩更快，分泌更多的血管内皮生长因子(VEGF)，并促进人脐静脉内皮细胞的血管新生萌发。这些变化依赖于转化生长因子-β(TGFR-β)相关信号和肿瘤细胞谷氨酰胺酶活性，因为它们的抑制降低了与转化生长因子-β相关的肌成纤维细胞分化和相关功能后果。综上所述，我们的数据表明，TEV是在肿瘤微环境中促进ASC结缔组织再生重编程的重要信号因子，并提示肿瘤细胞的谷氨酰胺代谢可能被用作干预这一过程的治疗靶点。
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.