Osteopontin-CCL5-Wnt参与肺癌相关间充质干细胞促进肺癌干细胞转移的研究

Recent evidence indicates that tumor-associated mesenchymal stem cells (TMSCs) play a pival role in modulating tumor progression. However, the interaction between TMSCs and cancer stem cells (CSCs) remains unclear. Here, for the first time, we study the effect and mechanism of lung cancer-associated MSCs on the metastases of CSCs. We will compare the difference of capacity of promoting metastases between TMSCs and bone marrow-derived MSCs, detect the formation of "MSC-CSC niches" in vivo, and identify that CCL5 secrected by TMSCs is the key factor contributing to the enhanced metastases of CSCs. We will also explore the underlying mechanism that CCL5 binds its receptor CCR5 on the surface of CSCs specifically, which might result in phosphorylation of Akt in CSCs and subsequently activation of Wnt signal pathway. The ability of TMSCs to facilitate metastases of CSCs probably devotes to the education of lung cancer cells, which induce TMSCs to produce CCL5 by overexpressing osteopontin (OPN). We suggest that tumor cells are capable of encouraging their own development by educating the tumor microenvironment. Our study will provide a novel experimental foundation for investigating the interrelation among MSCs, tumor microenvironment and CSCs and may offer a potential strategy for targeted tumor therapy.

近年来研究表明肿瘤相关间充质干细胞（TMSCs）在调控肿瘤进程中起关键作用，但目前有关TMSCs与肿瘤干细胞（CSCs）相互关系的报道甚少。本研究首次探讨了肺癌TMSCs在肺癌CSCs转移中的作用及其分子机制。课题拟从比较TMSCs与骨髓来源的BM-MSCs促进CSCs转移能力的差异出发，检测体内“MSC-CSC niches”的形成，证明TMSCs可促进CSCs转移；明确CCL5的关键地位，TMSCs高表达的CCL5通过与CSCs表面CCR5结合，促进Akt磷酸化，活化Wnt信号通路，从而增强CSCs转移能力；拟阐明TMSCs的促转移能力是肺癌细胞通过表达osteopontin (OPN)对其进行“教育”的结果。由此推断肿瘤细胞可通过诱导肿瘤微环境改变以促进其自身发展。本课题将为深入研究MSCs、肿瘤微环境、CSCs三者之间的相互联系和肿瘤靶向治疗提供新的实验与理论依据。

本课题在成功分离肺癌肿瘤组织来源的间充质干细胞（tumor-derived mesenchymal stem cells，TMSCs）的基础上，以研究TMSCs对肺癌细胞生物学特征影响为切入点、TMSCs对肺癌转移为主要研究目的展开深入研究，发现肺癌细胞通过高表达OPN以促进TMSCs分泌CCL5，后者通过与肿瘤细胞表面的CCL5受体CCR5结合，促进肿瘤转移，从而证明肿瘤细胞利用间质细胞以达促进其自身发展的目的。该研究将为进一步阐明肿瘤与肿瘤间质的相互联系和肿瘤靶向治疗提供新的实验与理论依据。项目资助发表SCI论著2篇，核心论著1篇，待发表论著和综述各1篇。培养硕士生3名，其中2名已经取得硕士学位，1名在读。项目投入经费23万元，支出15.41万元，各项支出基本与预算相符。剩余经费7.59万元，剩余经费计划用于本项目研究后续支出。