骨髓间充质干细胞对鼻咽癌肿瘤干细胞特性的调控及机制研究

Epithelial-mesenchymal transition (EMT) constitutes one of the important mechanisms contributing to the acquisition of cancer stem cell-like properties. Even though recent evidence has highlighted the critical role of tumor microenvironment, particularly the complex interactions among tumor cells and stromal components including mesenchymal stem cells, in the regulation of EMT and CSC development, the underlying mechanisms remain largely unknown. In our preliminary studies, we have demonstrated the reciprocal proliferation-promoting effects between human nasopharyngeal carcinoma (NPC) cells and bone marrow-derived mesenchymal stem cells (BMSCs), e.g. BMSC can significantly promote proliferation of NPC cells through the secretion of soluble factors, such as interleukin-6 (IL-6). In this application, we propose to further explore the mechanisms involved in the regulation of EMT in NPC cells through the interactions between BMSCs and NPC-derived cancer stem cells (NPC-CSCs). Specifically, we will characterize cancer-associated fibroblasts differentiated from BMSCs induced by NPC and NPC-CSCs (NPC-CAFs), and investigate the effects of BMSCs and BMSC-derived CAFs on the proliferation, cell migration/invasion, EMT in NPC cells, as well as the acquisition and properties of NPC-CSCs. The completion of the proposed studies will partially reveal the mechanisms underlying the generation and differentiation of NPC-CSCs, which might be closely associated with the recruited BMSCs within the tumor microenvironment. Therefore, information obtained from this study has the potential for the development of novel therapeutic strategies for NPC therapy by specifically targeting NPC-CSCs.

上皮-间质转化(EMT)是肿瘤干细胞产生的重要机制，而肿瘤微环境特别是间充质干细胞与肿瘤细胞的相互作用可以促进EMT的发生，但其机制不明，也受到了极大的关注。我们的前期结果表明：鼻咽癌细胞与骨髓间充质干细胞相互促进增殖，骨髓间充质干细胞可通过释放某些细胞因子，比如说IL-6，促进鼻咽癌细胞的增殖。因此，本项目试图对肿瘤微环境中间充质干细胞与鼻咽癌肿瘤干细胞相互作用对鼻咽癌细胞EMT的调控机制进行深入研究，观察鼻咽癌肿瘤干细胞对间充质干细胞的诱导分化作用，包括鼻咽癌发生相关成纤维细胞(NPC-CAFs)的形成和鉴定；间充质干细胞及其分化来源的成纤维细胞对鼻咽癌细胞生长、转移、EMT转化及肿瘤干细胞形成和特性的影响。本项目的完成将部分揭示鼻咽癌肿瘤干细胞的产生和分化机制，可能与肿瘤微环境特别是间充质干细胞密切相关，为特异性地靶向清除鼻咽癌干细胞提供新的思路。

上皮-间质转化(EMT)是肿瘤干细胞产生的重要机制，而肿瘤微环境特别是间充质干细胞与肿瘤细胞的相互作用可以促进EMT的发生，但其机制不明，也受到了极大的关注。本项目试图揭示了肿瘤微环境中间充质干细胞与鼻咽癌肿瘤干细胞相互作用对鼻咽癌细胞EMT的调控机制，发现鼻咽癌肿瘤干细胞对间充质干细胞有诱导分化作用；间充质干细胞及其分化来源的成纤维细胞对鼻咽癌细胞生长、转移、EMT转化及肿瘤干细胞形成和特性有重要影响。本项目的完成将部分揭示鼻咽癌肿瘤干细胞的产生和分化机制，可能与肿瘤微环境特别是间充质干细胞密切相关，为特异性地靶向清除鼻咽癌干细胞提供新的思路。本项目实施以来在国内杂志发表相关文章23篇，其中SCI收录论文8篇（Int J Oncol. 2017；Oncol Rep. 2016；Mediators Inflamm. 2016; Am J Transl Res. 2016 ;Int J Oncol. 2015；Asian Pac J Cancer Prev. 2014;15(4):1851-7；J BUON. 2013; J BUON. 2013），申请发明专利1项（一种人鼻咽癌肿瘤干细胞系建立方法），培养硕士研究生9名（蒋东辉，张鑫，蔚帅帅，崔仲宜，张勤，马晓娟，刘付梅，黄振河，黄博），完成学位论文9篇，培养青年科研骨干4名（李祥勇，李彩虹，张美红，曾今诚）。