Department of Molecular Pathology and Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Int J Cancer. 2012 Sep 1;131(5):1023-31. doi: 10.1002/ijc.26493. Epub 2012 Jan 30.
Epithelial-mesenchymal transition (EMT) generates tumor cells with stem cell properties. The aim of our study was to investigate the effects of adipose tissue-derived stem cells (ASCs) on EMT of cancer cells and to further investigate the mechanisms involved. We demonstrate that conditioned medium from ASCs induces breast cancer cells (4T1) to express mesenchymal markers such as fibronectin, alpha smooth muscle actin and vimentin. Flow cytometry analyses show that ASC-conditioned medium promotes the expansion of CD44high/CD24low cancer stem cells. Soft agar assays using T47D, BT474 and MCF-7 breast cancer cells reveals that ASC conditioned medium promotes the anchorage-independent growth of cancer cells. These effects were inhibited by a neutralizing antibody against platelet-derived growth factor-D (PDGF-D). Furthermore, PDGF-D treated breast cancer cells grow faster in a mouse model, and this effect could be neutralized by a PDGF antibody. In conclusion, our data show that tissue-resident stem cells interact with the cancer microenvironment via PDGF-D, induce EMT in the cancer cells in a paracrine fashion, thereby increasing the number of cancer stem cells and increase tumor growth in a PDGF dependent manner. Our findings shed new light on mechanisms where local tissue-resident stem cells are able to promote the growth of breast cancer cells. Possibly this could open up a novel selective therapeutic strategy targeting EMT pathways and the specific communication between tissue-resident normal stem cell and cancer stem cells, assuming that the blockage of PDGF-D pathways is critical for tumor growth but would not affect normal tissue homeostasis.
上皮-间充质转化 (EMT) 可产生具有干细胞特性的肿瘤细胞。我们的研究旨在探讨脂肪组织来源的干细胞 (ASCs) 对癌细胞 EMT 的影响，并进一步探讨相关机制。我们证明 ASC 的条件培养基可诱导乳腺癌细胞 (4T1) 表达间充质标志物，如纤连蛋白、α 平滑肌肌动蛋白和波形蛋白。流式细胞术分析表明 ASC 条件培养基促进 CD44high/CD24low 癌症干细胞的扩增。使用 T47D、BT474 和 MCF-7 乳腺癌细胞进行软琼脂实验表明，ASC 条件培养基促进了癌细胞的无锚定生长。这些作用可被血小板衍生生长因子-D (PDGF-D) 的中和抗体所抑制。此外，PDGF-D 处理的乳腺癌细胞在小鼠模型中生长更快，而这种作用可被 PDGF 抗体中和。总之，我们的数据表明，组织驻留干细胞通过 PDGF-D 与肿瘤微环境相互作用，以旁分泌的方式诱导癌细胞 EMT，从而增加癌症干细胞的数量，并以 PDGF 依赖的方式增加肿瘤生长。我们的研究结果揭示了局部组织驻留干细胞能够促进乳腺癌细胞生长的机制。可能这为靶向 EMT 途径和组织驻留正常干细胞与癌症干细胞之间特定通讯的新型选择性治疗策略开辟了道路，假设 PDGF-D 途径的阻断对肿瘤生长至关重要，但不会影响正常组织稳态。
