The in vitro and in vivo effects of human umbilical cord mesenchymal stem cells on the growth of breast cancer cells
The in vitro and in vivo effects of human umbilical cord mesenchymal stem cells on the growth of breast cancer cells
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DOI：
10.1007/s10549-011-1774-x
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发表时间：
2012-06-01
影响因子：
3.8
通讯作者：
Zhang, Jin
中科院分区：
文献类型：
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作者：
Ma, Yi;Hao, Xiaomeng;Zhang, Jin
本研究旨在探讨人脐带间充质干细胞（human umbilical cord mesenchymal stem cells，hUCMSCs）对人乳腺癌原代细胞、乳腺癌细胞株MDA-MB-231和MCF-7的干细胞体内外生长的影响及其可能机制。采用流式细胞术对原代人乳腺癌细胞、MDA-MB-231和MCF-7细胞进行体外分选，分离出ESA+、CD 44+、CD 24-/low细胞作为乳腺癌干细胞（CSC）。使用Cell Counting Kit-8细胞增殖和软琼脂集落形成测定来检查hUCMSCs对CSC的抑制作用。使用移植有MDA-MB-231乳腺CSC的严重联合免疫缺陷异种移植小鼠模型研究体内肿瘤抑制。采用免疫组织化学方法检测移植瘤中磷脂酰肌醇3-激酶（PI 3 K）和AKT的表达。与hUCMSCs共培养的乳腺CSCs在软琼脂底层形成的集落数明显低于对照组（P < 0.01）。与对照组相比，与hUCMSCs共培养的CSCs中G2-M期细胞数明显增多（P < 0.05），凋亡细胞数明显增多（P < 0.01）。与对照组相比，中浓度和高浓度hUCMSC治疗组的小鼠表现出明显减小的肿瘤体积和肿瘤重量（P < 0.01）。与生理盐水组相比，不同浓度hUCMSCs处理的小鼠的异种移植瘤组织显示PI 3 K和AKT蛋白水平显著降低（P < 0.001）。总之，hUCMSC在体外和体内均显著抑制乳腺CSC的生长。其机制可能与细胞周期阻滞、诱导肿瘤细胞凋亡、抑制PI 3 K和AKT蛋白激酶活性有关。
The purpose of the study was to detect the effect and possible mechanism of human umbilical cord mesenchymal stem cells (hUCMSCs) on the in vitro and in vivo growth of stem cells isolated from primary human breast cancer cells and cell lines MDA-MB-231 and MCF-7. Primary human breast cancer cells and MDA-MB-231 and MCF-7 cells were sorted in vitro using flow cytometry, and the ESA+, CD44+, CD24-/low cells were isolated as breast cancer stem cells (CSCs). The inhibitory effect of hUCMSCs on CSCs was examined using the Cell Counting Kit-8 cell proliferation and soft agar colony formation assay. In vivo tumor inhibition was studied using a severe combined immunodeficient xenograft mouse model transplanted with MDA-MB-231 breast CSCs. The expression of phosphoinositide 3-kinase (PI3K) and AKT was examined in the xenograft tumors using immunohistochemistry. The number of colonies formed by breast CSCs co-cultured with hUCMSCs at the bottom of soft agar was significantly lower than those formed by the control group (P < 0.01). Compared with the control group, the CSCs co-cultured with hUCMSCs showed a higher number of cells in the G2-M phase (P < 0.05) and an increased number of apoptotic cells (P < 0.01). The mice in the medium- and high-concentration hUCMSC treatment groups exhibited clearly reduced tumor volume and tumor weight, compared with the control group (P < 0.01). Compared with the saline group, the xenograft tumor tissues from the mice treated with different concentrations of hUCMSCs showed significantly reduced levels of PI3K and AKT proteins (P < 0.001). In conclusion, hUCMSC significantly inhibited the growth of breast CSCs in vitro and in vivo. The underlying mechanism is likely related to cell cycle arrest, induction of tumor cell apoptosis, and suppressed activities of PI3K and AKT protein kinases.