肿瘤干细胞重塑微环境调控新生血管生成的研究

Recent studies support the concept that angiogenesis contribute significantly to tumor recurrence and metastasis. SOX2, which is one of the marker genes for embryonic stem cells and cancer stem cells (CSCs), plays an important role in maintaining their unique stemness properties and contributing to tumor metastasis. However, its regulatory effect on tumor microenvironment and angiogenesis still need to be explored. The applicant has been engaged in research on tumor and CSCs for many years and devoted to the exploration of novel therapeutic targets and methods for tumor. Based on previous work, we plan to apply multiple biological technologies or methods, including ChIP-Seq, bone marrow xenografts and tumor-bearing animal models as well as in vitro experiments to perform the following studys: 1). to verify the regulatory effect of SOX2 on angiogenesis; 2) to further elucidate whether SOX2 gene in tumor cells plays a key role in recruiting the endothelial progenitor/endothelial cells from tumor microenvironment through remodeling it; 3). to further enucleate the molecular mechanisms of SOX2 in promoting the participation of cancer stem cells and endothelial cells in angiogenesis. This study will help us to explore more rational and effective methods for tumor therapy.

目前的研究普遍认为肿瘤新生血管在肿瘤复发与转移中起到重要作用，作为胚胎与肿瘤干细胞（CSCs）的标识性基因之一的SOX2在调控肿瘤细胞干特性及转移中发挥着重要的功能，然而其对肿瘤微环境及新生血管生成调控的报道较少。申请者长期从事肿瘤及肿瘤干细胞的研究，并积极的探讨新的肿瘤治疗靶点及治疗方法。本课题拟在前期研究工作的基础上，结合CHIP-seq结果及活体动物骨髓移植等技术，通过体外实验及荷瘤动物模型完成以下研究： (1)明确肿瘤细胞SOX2基因在肿瘤新生血管生成中的作用；(2)明确肿瘤细胞的SOX2基因是否通过调控肿瘤微环境促进肿瘤微环境内皮祖细胞/内皮细胞的招募，从而在促进肿瘤新生血管生成中起到重要作用；(3)进一步阐明SOX2基因促进肿瘤干细胞及内皮细胞共同生成新生血管的分子机理及其调控机制。本研究将为制定更加合理有效的肿瘤治疗的方法提供必要前沿性探讨。

本课题组在四年的研究工作中按照既定的研究计划执行，较好的达到了预期目标，完成了以下工作：1）明确肿瘤细胞干性调控基因SOX2能够促进肿瘤新生血管的生成；2）明确SOX2招募肿瘤微环境中内皮/内皮祖细胞从而促血管生成的作用；3）阐明SOX2通过诱导肿瘤细胞以及内皮细胞表达促血管生成基因而促进肿瘤形成的分子机理；4）通过多种动物实验模型的建立，进一步证明靶向肿瘤微环境，抑制肿瘤细胞干性基因如SOX2的表达，能够抑制VEGF，CD31等基因的表达进而抑制了肿瘤的新生血管生成；5）已发表SCI论文3篇，影响因子大于5分的论文5篇（其中大于8分2篇）；6）已培养4名硕士研究生及3名博士研究生毕业。