伴发慢性乙肝增加结直肠癌患者肝转移风险的机制研究

About 7% of the colorectal cancer (CRC) patients in China suffers concomitant chronic hepatitis B (CHB) infection, and this percentage tops the world. The colorectal liver metastasis (CRLM) is the key prognostic factor of CRC. It was widely believed that concomitant CHB decreases the incidence of CRLM. Our previous large-scale, retrospective clinical study proves for the first time that concomitant CHB increase the risk of CRLM, but the mechanism remains unknown。The further sub-groups analysis indicates that CHB-induced cirrhosis decreases CRLM, while active hepatitis B virus (HBV) replication increases CRLM. Another study of our group proves that certain chemokine and its receptor pairs facilitate the progression of CRLM via recruiting certain subset of myeloid cells. It has been well-established that active HBV replication induces the abnormal expression of some chemokines, and some of these chemokines are proved to be pro-metastatic. Based upon our pilot study and the literature reports, we hypothesize that, CHB alters the expression of some chemokines in liver, then recruits certain subset of myeloid cells and finally increases the risk of CRLM. In this project, we plan to explore this hypothesis with our established mouse model of CRLM, technique of myeloid cell isolation and subset sorting from clinical sample, as well as the clinical CRLM samples and in situ myeloid cells reservoir. This project is significant in elucidating the mechanism of CRLM in the selected population, thus the corresponding policies of clinical surveillance, intervention and follow-up can be made to improve the prognosis.

我国结直肠癌患者伴发慢性乙肝比例全球最高，而肝转移是结直肠癌预后关键因素。普遍认为伴发慢性乙肝抑制肝转移发生，而我们前期的大样本临床横断面研究首次证实其促进肝转移，但具体机制未明。分层分析提示，慢性乙肝所致肝硬化抑制肝转移，而乙肝病毒复制则促进肝转移。而我们前期另一项研究证实，特定趋化因子及其受体可通过募集特定髓系细胞亚群促进结直肠癌肝转移进展。已知乙肝病毒活跃复制可引起若干转移相关趋化因子表达异常。我们据此提出假说：慢性乙肝通过改变肝脏局部特定趋化因子表达，募集髓系细胞亚群，促进结直肠癌肝转移发生。本研究拟利用已成熟建立的小鼠结直肠癌肝转移模型、临床肝转移瘤髓系细胞亚群分离技术，及已收集的临床结直肠癌肝转移标本，研究慢性乙肝通过趋化因子募集髓系细胞促进结直肠癌肝转移的具体机制。本课题对阐明该群患者肝转移的机制，依此制定相应的临床监测、干预与随访策略，进而提高其整体预后具有重要意义。

我国结直肠癌患者伴发慢性乙肝比例全球最高，而肝转移是结直肠癌预后关键因素，普遍认为伴发慢性乙肝抑制肝转移发生。而我们前期的大样本临床横断面研究首次证实其促进肝转移，但具体机制未明。在本课题实施过程中我们致力于先探索慢性肝病引起哪些特定相关趋化因子发生改变，并深入阐述其促进结直肠癌肝转移的机制，研究取得以下成果: ①伴发慢性乙型肝炎显著增加CRC患者肝转移风险。在大宗临床病例回顾所有CRC患者中，乙肝表面抗原阳性（HBsAg+）的慢性乙型肝炎组同时性肝转移患病率明显高于乙肝表面抗原阴性组（HBsAg-）；同时，HBsAg+也是结直肠癌同时性肝转移的独立危险因素。进一步对HBsAg+/HBeAg+活动性乙肝患者进行分析，证实HBeAg+同样是CRLM的临床危险因素，可以很容易地识别和治疗。②肝硬化显著降低CRLM风险。对HBsAg+患者进行亚组分析，伴肝硬化的慢性乙型肝炎患者发生结直肠癌肝转移风险显著低于无肝硬化的慢性乙型肝炎患者。③髓系细胞影响结直肠癌肝转移的可能机制：具有促血管生成作用的FGF2在CRLM内浸润的CD11b+髓系细胞中表达显著升高，其中M2型巨噬细胞中miR-16-5p通过与FGF2 的 3’-UTR 相互作用抑制FGF2蛋白表达的作用，进而起到抑制肝转移的重要作用。④伴发除乙肝以外的其他慢性肝病因素可导致趋化因子表达谱改变，进而招募大量MDSC入肝，促进肝转移。在小鼠酒精/非酒精性脂肪肝+结直肠癌肝转移模型中，我们通过流式分析发现某些特异趋化因子招募大量MDSC入肝，进而引起肝转移负荷的增加。这为临床治疗提供了强有力的理论依据，有望在临床进行应用。