Lanza Denise Grant, Ma Jun, Guest Ian, Uk-Lim Chang, Glinskii Anna, Glinsky Gennadi, Sell Stewart
Translational and Functional Genomics Laboratory, Ordway Research Institute, Albany, NY 12208, USA.
Tumour Biol. 2012 Dec;33(6):1997-2005. doi: 10.1007/s13277-012-0459-3. Epub 2012 Jul 27.
The ability to transplant mammary cancer stem cells, identified by the phenotype CD24(+)CD29(+)CD49f(+)Sca-1(low), is dependent on the microenvironment in which the cells are placed. Using the MMTV-PyMT mouse model of mammary cancer, we now report two methods of tumor growth enhancement: contributions of tumor stroma in the form of tumor-derived mesenchymal stem cells and orthotopic vs. heterotopic transplantation sites. To support evidence of stem cell function, tumor-derived mesenchymal stem cells differentiated into adipocyte- and osteocyte-like cells after culture in specific medium. Co-injection of tumor-initiating cells with tumor-derived mesenchymal stem cells significantly increased tumor initiation compared to subcutaneous injection of TICs alone; co-injection also allowed tumor initiation with a single TIC. Interestingly, we observed the formation of sarcomas after co-injections of tumor-derived mesenchymal stem cells or mouse embryonic fibroblasts with TICs; sarcomas are not observed in spontaneous MMTV-PyMT tumors and rarely observed in injections of TICs alone. Tumor initiation was also significantly increased in the orthotopic injection site compared to heterotopic injections. We conclude that tumor stroma and orthotopic sites both enhance tumor initiation by mammary cancer stem cells.
通过CD24(+)CD29(+)CD49f(+)Sca-1(low)表型鉴定的乳腺癌干细胞的移植能力取决于细胞所处的微环境。利用MMTV-PyMT乳腺癌小鼠模型，我们现在报告两种增强肿瘤生长的方法：肿瘤来源的间充质干细胞形式的肿瘤基质的贡献以及原位与异位移植部位。为了支持干细胞功能的证据，肿瘤来源的间充质干细胞在特定培养基中培养后分化为脂肪细胞样和骨细胞样细胞。与单独皮下注射肿瘤起始细胞相比，将肿瘤起始细胞与肿瘤来源的间充质干细胞共同注射显著增加了肿瘤起始；共同注射还允许单个肿瘤起始细胞引发肿瘤。有趣的是，我们观察到在将肿瘤来源的间充质干细胞或小鼠胚胎成纤维细胞与肿瘤起始细胞共同注射后形成了肉瘤；在自发性MMTV-PyMT肿瘤中未观察到肉瘤，在单独注射肿瘤起始细胞时也很少观察到肉瘤。与异位注射相比，原位注射部位的肿瘤起始也显著增加。我们得出结论，肿瘤基质和原位部位都增强了乳腺癌干细胞的肿瘤起始能力。
