巨噬细胞促进播散肝癌细胞休眠逃逸的机制研究

The curative effects of surgery for hepatocellular carcinoma (HCC) were mainly impeded by tumor recurrence and there's no widely accepted adjuvant therapy. Clinical analysis showed that more than 70% of tumor recurrence developed within 2 years after surgery (early recurrence). According to the conventional wisdom, early recurrence was derived from the growth of the tumor cells disseminated from the primary tumor, in which escape from dormancy was a main theory. To stop the escape becomes the key problem for the prevention of tumor recurrence. Our previous studies also found that the infiltration of macrophages (MΦ) in patients' livers was associated with early recurrence (J Clin Oncol 2008; PLoS One 2013), suggesting that MΦ promoted the disseminated HCC cells escape from dormancy. Our preliminary animal studies found that the growth of disseminated HCC cells showed a peculiar pattern with a relatively long period of dormancy followed by a rapid growth period. Also, depletion of MΦ in the liver doubled the period of dormancy of the disseminated HCC cells in liver. In this project, we will study how MΦ was recruited into the liver and how the escape of dormancy was promoted by MΦ. By investing the key mechanism and key molecules, we will explore the therapeutic values of targeting the escape from dormancy and provide new thoughts for adjuvant therapies.

复发是影响肝细胞癌（以下简称"肝癌"）术后长期疗效提高的主要障碍，目前缺乏公认的预防手段。我们的统计显示70%以上的术后复发集中于术后两年内（早期复发）。一般认为，术后早期复发来自原发肿瘤的肝内播散灶在术后的生长，休眠逃逸是播散灶获得生长能力的理论之一。阻止休眠逃逸过程成为预防复发的关键。此前我们发现癌旁肝脏内的巨噬细胞（MΦ）浸润密度与患者术后早期复发相关（J Clin Oncol 2008; PLoS One 2013），提示MΦ可能促进播散肝癌细胞的休眠逃逸。前期的动物实验中，我们已发现：播散灶的进展具备相对长期的休眠期、短期内可快速生长（休眠逃逸）的特点；去除肝脏内的MΦ可将肝内播散灶的休眠期延长至两倍。本项目中，我们拟进一步研究MΦ如何向肝脏内浸润，浸润的MΦ如何促进肝癌细胞休眠逃逸。通过探索其中的关键机制，靶向其关键分子，了解其治疗价值，为术后复发的预防提供新思路。

复发是影响肝细胞癌（以下简称"肝癌"）术后长期疗效提高的主要障碍，目前缺乏公认的预防手段。70%以上的术后复发集中于术后两年内（早期复发）。一般认为，术后早期复发来自原发肿瘤的肝内播散灶在术后的生长，休眠逃逸是播散灶获得生长能力的理论之一。阻止休眠逃逸过程成为预防复发的关键。在本项研究中，我们发现：(1) 播散肝癌细胞在进入靶器官后会存在较长时间的休眠期，在巨噬细胞的参与下，才能长成肉眼可见的转移灶；(2) 肝癌细胞表达CSF-1，与肿瘤相关巨噬细胞（TAM）表达CSF-1受体（CSF-1R）相结合，不仅促进了后者在癌周的募集还诱导了TAM内的AIF1的过表达。(3) TAM通过激活CSF-1R - MEK1/2 - Erk1/2 - c-Jun信号转导通路，反过来促进了肝癌细胞的休眠逃逸和局部进展，两者之间形成了正反馈循环的相互对话。(4) 使用肝癌裸鼠原位移植瘤模型，CSF-1R的抑制剂PLX3397可显著抑制肝癌进展，其主要机制不在于抑制TAM募集，而在于调变TAM的极化状态，使其出现抗肿瘤的M1表型是药物作用的关键机制。以这些发现为主要研究结果，已发表标注受本项目资助的SCI论文6篇，项目负责人均为共同第一作者。本研究不仅揭示了肝癌细胞与TAM之间相互对话的关键分子机制及其在促进播散肝癌细胞休眠逃逸中的作用，还明确了针对其中关键分子进行靶向干预的潜在治疗价值，具有一定的临床转化价值。