SEI-1通过诱导肿瘤相关成纤维细胞TAFs活化促进卵巢癌进展的机制

Many research confirmed that the tumor microenvironment, especially its main component - tumor associated fibroblasts (TAFs) play an important role in the development of tumor. The mechanism how TAFs promotes tumor especially what is the molecular mechanism of TAFs activation is still poorly understood. Our previous study in xenograft tumor of nude mice showed that the ovarian cancer cells of high expression oncogene SE1-1 can induce genomic instability of cytogenetic marker - double minute chromosomes (DMs) appears in the karyotype of TAFs and activation of TAFs can promote the growth of xenograft tumor, shorten the time of tumor formation. Accordingly, we propose: high expression of SEI-1 in ovarian cancer can make TAFs activate through genomic instability, and then play the role of promoting tumor. So, in this study we will perform the research from the cytogenetic and molecular biology - animal model - clinical tissue specimens from patients with multiple levels, investigate the mechanism of SEI-1 induced activation of TAFs; understand effects of TAFs on promoting the development of ovarian cancer; explore the correlation of key molecules involved in "tumor -TAFs- tumor" interactions and signaling pathways in patients with clinical pathological characteristics of tumor. This project started from the phenomena observed in animal model and passaged many times in vivo, then summarize the hypothesis and mechanisms. In brief, this study is very innovative.

研究证实，肿瘤微环境尤其是其主要组分-肿瘤相关成纤维细胞（TAFs）在肿瘤发生、发展中起重要作用。但TAFs促瘤的机制尤其是TAFs活化的分子机制目前仍知之甚少。我们前期在裸鼠体内移植瘤中发现：高表达癌基因SEI-1的卵巢癌细胞可诱导TAFs核型中出现基因组不稳定的细胞遗传学标记-双微体（DMs），且活化的TAFs可以促进移植瘤的生长，缩短成瘤时间。据此我们提出：卵巢癌高表达SEI-1可使TAFs通过发生基因组不稳定而被激活，继而发挥促瘤的作用。本课题将从细胞遗传学-分子生物学-动物模型-临床患者组织标本多层次进行研究，深入探讨SEI-1诱导TAFs活化的机制；明确TAFs对卵巢癌发生发展的促进作用及相关机制；阐明“肿瘤-TAFs-肿瘤”相互作用的关键分子及信号通路与临床肿瘤患者病理特征的相关性。本项目从动物模型中观察到的现象入手，经体内多次传代，总结规律，探讨机制，立题具有一定的创新性。

卵巢癌是常见的女性生殖系统恶性肿瘤之一，虽然其发病率低于子宫颈癌和子宫体癌位列第三，但是致死率却高居各类妇科肿瘤之首。目前，卵巢癌的治疗仍依赖于手术和铂类药物化疗的常规方法，但治疗效果欠佳。肿瘤微环境TME在肿瘤发生发展中起到了关键作用。随着2018年诺贝尔生理学与医学奖的揭晓，基于TME中的免疫细胞-肿瘤细胞互作的PD-1/PD-L1抑制剂的应用，使肿瘤免疫治疗迎来了新的篇章。而在TME的多种组分中，肿瘤相关成纤维细胞TAFs作为肿瘤间质中的重要组分，与M2型巨噬细胞共同参与促进肿瘤的增殖、侵袭转移等，并可与胞外基质组成异常复杂的瘤内递送屏障，阻碍药物在肿瘤组织内渗透及其靶向肿瘤细胞的递送。我们前期在裸鼠体内移植瘤中发现：高表达癌基因SEI-1的卵巢癌细胞可诱导TAFs核型中出现基因组不稳定的细胞遗传学标记-双微体（DMs），且活化的TAFs可以促进移植瘤的生长，缩短成瘤时间。提示卵巢癌高表达SEI-1可使TAFs通过发生基因组不稳定而被激活，继而发挥促瘤的作用。本课题通过体内外实验、生物信息学分析等发现S100A4可通过转录后调控，抑制P53通路，进而引起细胞基因组不稳定，产生双微体，最终激活TAFs，促进卵巢癌的进展；而转录因子SEI-1可与S100A4启动子区域结合，从而调控S100A4的表达，并通过膜受体RAGE起到正反馈调节的作用，诱导TAFs细胞的激活。同时，本项目还发现TAFs可以通过外泌体蛋白，直接作用于卵巢癌细胞，促进其发展。阐明“肿瘤-TAFs-肿瘤”相互作用的关键分子及信号通路与临床肿瘤患者病理特征的相关性将有助于肿瘤患者的临床个体化治疗。本研究发现的S100A4、外泌体携带的SLPI蛋白等，有望成为卵巢癌治疗及预后判断的临床靶标。