Human umbilical cord matrix mesenchymal stem cells suppress the growth of breast cancer by expression of tumor suppressor genes [human]. Homo sapiens

Human and rat umbilical cord matrix mesenchymal stem cells (UCMSC) possess the ability to control the growth of breast carcinoma cells. Comparative analyses of two types of UCMSC suggest that rat UCMSC-dependent growth regulation is significantly stronger than that of human UCMSC. Their different tumoricidal abilities were clarified by analyzing gene expression profiles in the two types of UCMSC. Microarray analysis revealed differential gene expression between untreated naïve UCMSC and those co-cultured with species-matched breast carcinoma cells. The analyses screened 17 differentially expressed genes that are commonly detected in both human and rat UCMSC. The comparison between the two sets of gene expression profiles identified two tumor suppressor genes, adipose-differentiation related protein (ADRP) and follistatin (FST), that were specifically up-regulated in rat UCMSC, but down-regulated in human UCMSC when they were co-cultured with the corresponding species' breast carcinoma cells. Over-expression of FST, but not ADRP, in human UCMSC enhanced their ability to suppress the growth of MDA-231 cells. The growth of MDA-231 cells was also significantly lower when they were cultured in medium conditioned with FST, but not ADRP over-expressing human UCMSC. In the breast carcinoma lung metastasis model generated with MDA-231 cells, systemic treatment with FST-overexpressing human UCMSC significantly attenuated the tumor burden. These results suggest that FST may play an important role in exhibiting stronger tumoricidal ability in rat UCMSC than human UCMSC and also implies that human UCMSC can be transformed into stronger tumoricidal cells by enhancing tumor suppressor gene expression. Overall design: Human UCMSC and MDA-231 breast carcinoma cells were cultured indirectly for 48 hours using Transwell culture dish. Naïve human UCMSC were cultured under same condition without the addition of carcinoma cells.

人类与大鼠脐带基质间充质干细胞（umbilical cord matrix mesenchymal stem cells，UCMSC）具备调控乳腺癌细胞增殖的能力。对两类UCMSC的比较分析显示，大鼠UCMSC的增殖调控能力显著强于人类UCMSC。借助对两类UCMSC的基因表达谱分析，阐明了二者抗肿瘤活性的差异。基因芯片分析显示，未处理的初始UCMSC与同源乳腺癌细胞共培养的UCMSC之间存在基因表达差异。本次分析筛选出17个在人类和大鼠UCMSC中均存在差异表达的共有基因。对两组基因表达谱的比对发现，两个肿瘤抑制基因——脂肪分化相关蛋白（adipose-differentiation related protein，ADRP）和卵泡抑素（follistatin，FST）——在与对应物种乳腺癌细胞共培养时，于大鼠UCMSC中特异性上调，而在人类UCMSC中则下调。在人类UCMSC中过表达FST（而非ADRP）可增强其抑制MDA-231细胞增殖的能力。当MDA-231细胞在经FST过表达（而非ADRP过表达）的人类UCMSC条件培养基中培养时，其增殖水平也显著降低。在MDA-231细胞构建的乳腺癌肺转移模型中，全身递送过表达FST的人类UCMSC进行干预可显著减轻肿瘤负荷。上述结果表明，FST可能是大鼠UCMSC抗肿瘤活性强于人类UCMSC的关键调控因子，同时也提示可通过上调肿瘤抑制基因的表达，将人类UCMSC改造为更强效的抗肿瘤细胞。实验整体设计：采用Transwell培养板间接共培养人类UCMSC与MDA-231乳腺癌细胞，共培养时长为48小时；同时设置对照组，在相同条件下培养初始人类UCMSC，不添加乳腺癌细胞。