Carcinoma Associated Fibroblast Like Differentiation of Human Mesenchymal Stem Cells

Carcinoma associated fibroblasts (CAFs) have recently been implicated in important aspects of epithelial solid tumor biology such as neoplastic progression, tumor growth, angiogenesis, and metastasis. However, neither the source of CAFs nor the differences between CAFs and fibroblasts from non-neoplastic tissue have been well defined. In this study we demonstrate that human bone marrow-derived mesenchymal stem cells (hMSCs) exposed to tumor-conditioned medium (TCM) over a prolonged period of time assume a CAF-like myofibroblastic phenotype. More importantly, these cells exhibit functional properties of CAFs including sustained expression of stromal derived factor 1 (SDF-1) and the ability to promote tumor cell growth both in vitro and in an in vivo co-implantation model and expression of myofibroblast markers including α-smooth muscle actin and fibroblast surface protein. hMSCs induced to differentiate to a myofibroblast-like phenotype using 5-azacytidine do not promote tumor cells growth as efficiently as hMSCs cultured in tumor-conditioned medium nor do they demonstrate increased SDF-1 expression. Furthermore, gene expression profiling revealed similarities between TCM exposed hMSCs and carcinoma associated fibroblasts. Taken together these data suggest that hMSCs are a source of carcinoma associated fibroblasts and can be used in the modeling of tumor-stroma interactions. To our knowledge this is the first report demonstrating that hMSCs become activated and resemble carcinoma associated myofibroblasts upon prolonged exposure to conditioned medium from MDAMB231 human breast cancer cells. Keywords: differentiation The experiment was done to test the differentiation of hMSCs upon exposure to tumor condition media or epigenetic modifiers.

癌相关成纤维细胞（Carcinoma associated fibroblasts，CAFs）近年来被发现与上皮性实体瘤生物学的诸多关键环节密切相关，包括肿瘤进展、增殖、血管生成及转移。然而，学界尚未明确CAFs的来源，也未阐明其与非肿瘤组织来源成纤维细胞之间的差异。
本研究证实，长期暴露于肿瘤条件培养基（tumor-conditioned medium，TCM）的人骨髓间充质干细胞（human bone marrow-derived mesenchymal stem cells，hMSCs）可获得类似CAFs的肌成纤维细胞表型（myofibroblastic phenotype）。更重要的是，这类细胞展现出CAFs的功能特性：可持续表达基质细胞衍生因子1（stromal derived factor 1，SDF-1），可在体外及体内共移植模型中促进肿瘤细胞增殖，同时表达α-平滑肌肌动蛋白（α-smooth muscle actin）、成纤维细胞表面蛋白（fibroblast surface protein）等肌成纤维细胞标志物。
使用5-氮杂胞苷（5-azacytidine）诱导分化为肌成纤维细胞样表型的hMSCs，其促进肿瘤细胞增殖的效率远低于在TCM中培养的hMSCs，且未出现SDF-1表达上调的情况。此外，基因表达谱分析显示，经TCM处理的hMSCs与CAFs具有相似的基因表达特征。
综合上述结果表明，hMSCs可作为CAFs的来源细胞，亦可用于构建肿瘤-间质相互作用的研究模型。据我们所知，本研究首次证实，长期暴露于MDAMB231人乳腺癌细胞的条件培养基后，hMSCs可被激活并表现出类似癌相关肌成纤维细胞的特征。
关键词：分化。本实验旨在探究hMSCs在暴露于肿瘤条件培养基或表观遗传修饰剂后的分化情况。