CD70+亚群在乳腺癌肿瘤侵袭转移过程中作用机制研究

Cancer stem cells (CSCs) is a heterogeneous population of cancer cells responsible for tumor growth. Recently, a subpopulation of invasive CSCs (iCSCs) is found to be important for tumor invasion,metastasis and recurrence. However, the origin of iCSCs and their biological behavior,plasticity and specific markers are still unclear. In our preliminary studies, we developed a highly metastatic variant of human breast cancer cells to enrich iCSCs. The most differentially expressed gene between the metastatic variants and parental cells, CD70, was screened out and was further demonstrated to be the specific marker of iCSCs. Here, we aim to uncover the critical role of the CD70+ iCSCs in metastatic progression of breast cancer both in vitro and in vivo. Utilizing RNAi, ChIP-PCR and promoter reporter system, we attempt to clarify the involvement of CD70 and its downstream SATB1-related pathway in regulating biological behavior of iCSCs. Moreover, with a lentiviral-based knockdown approach, we try to determine whether pointing to the CD70+iCSCs is an attractive therapeutic alternative for proventing breast cancer metastasis. Thus, further support of this program would provide a novel insight into the process of tumor metastases formation and a promising perspective for anti-tumor therapy.

肿瘤干细胞（CSCs）是具有自我更新能力的异质性群体，其中高侵袭力干细胞亚群（iCSCs）在肿瘤侵袭转移和复发等过程中发挥了重要作用。目前，iCSCs的来源、生物学特性及可塑性等关键问题尚未阐明。我们在前期研究中通过建立自发性转移乳腺癌模型富集了具有高侵袭转移潜能的乳腺癌干细胞，筛选并初步证实了CD70是iCSCs亚群的表面标记物。本项目拟利用乳腺癌细胞系、人乳腺癌标本和小鼠体内模型，从体内外两方面进一步证实CD70+iCSCs在乳腺癌侵袭转移过程中的作用；采用RNAi、ChIP-PCR、启动子基因报告等方法，阐释CD70及其下游SATB1相关通路参与调控iCSCs生物学行为的机制；并通过动物实验观察以CD70+iCSCs为靶标抑制乳腺癌侵袭转移的作用，从而为临床早期诊治肿瘤复发转移提供新策略和新方法。

肿瘤干细胞在肿瘤远处转移过程中发挥了重要作用。在本项目中，我们着重关注了CD70+亚群在乳腺癌远处转移中所扮演的角色。在临床标本中，我们证实CD70在乳腺癌中的表达水平与肺转移呈正相关。从乳腺癌细胞系中分选出来的CD70+和CD70-亚群分别表达间质和上皮表型。相比于CD70-亚群，CD70+细胞具有更强的自我更新潜能和多向分化能力。CD70+细胞在体外悬浮培养更容易形成干细胞球，在体内接种后更易于成瘤。不仅如此，原位接种后CD70+细胞具有更强的肺脏转移能力。进一步的机制研究表明，CD70不仅仅是细胞表面分子标记物，还能在STAT3-SATB1介导下通过上调CD70+亚群自我更新潜能促进该亚群在肺脏中的定植。上述研究成果将会为乳腺癌患者更精准的治疗提供临床诊断依据。