NAFLD微环境中Kupffer细胞促进结直肠癌肝转移机制研究

Metastasis is the main cause of death of colorectal cancer, and liver is one of the most common distant metastatic organs of colorectal cancer. It is of great clinical significance to study the regulation mechanism of colorectal liver metastasis. Retrospective analysis and previous animal model studies have found that patients of colorectal cancer with nonalcoholic fatty liver disease (NAFLD) have an increased occurrence of synchronous liver metastases; in colorectal stem cells (CSC)-mediated splenic vein liver metastases model, high fat-fed NAFLD mice increased liver metastasis; NAFLD-promoted liver metastasis was inhibited after removing from Kupffer cells by liposomes. These results suggest that the process of NAFLD promoting colorectal liver metastasis may be related to Kupffer cells. We propose that Kupffer cells in the NAFLD microenvironment promote the survival of colorectal cancer stem cells and maintain their stem functions and accelerate the occurrence of liver metastases in colorectal cancer. The NAFLD microenvironment regulates Kupffer cell function, which may regulate CSC function through growth factors or inflammasome mediated inflammatory factors. Clearing Kupffer in NAFLD or inhibiting inflammatory secretion of macrophages can reverse the occurrence of liver metastases in colorectal cancer promoted by NAFLD.

肿瘤转移是结直肠癌致死的主要原因，而肝脏是结直肠癌最常见的远处转移器官之一，研究结直肠癌肝转移的调控机制具有重要的临床意义。通过回顾性分析及前期动物模型研究发现，患有非酒精性脂肪肝病（NAFLD）的结直肠癌患者发生同时性肝转移风险增加；在结直肠癌肿瘤干细胞（CSC）介导的脾静脉肝转移动物模型，高脂饲养的NAFLD小鼠肝转移灶增多；脂质体去除Kupffer细胞后NAFLD促进的肝转移被抑制。这些结果提示NAFLD促进结直肠癌肝转移的过程可能与Kupffer细胞有关。我们提出科学假设：NAFLD微环境中Kupffer细胞促进结直肠癌肿瘤干细胞存活和维持其干性功能，加速结直肠癌肝转移发生。拟采用多种生物学技术和体内转移动物模型，研究Kupffer细胞调节CSC功能分子机制，为NAFLD促进的结直肠癌肝转移提供新的治疗靶点。

本研究初步探索了脂肪肝背景下结直肠癌肝转移的机制。我们的研究发现，相较于没有NAFLD的肝脏背景，NAFLD背景下的结直肠癌患者，发生肠癌肝转移的风险增加,相关性分析提示脂肪肝是肠癌肝转移的独立危险因素。动物实验研究发现，高脂饮食（HFD）促进了结肠癌肿瘤干细胞肝脏转移，而清除了肝内巨噬细胞后，可以逆转该过程。体外研究发现，在肿瘤干细胞以及肝脏脂肪背景双重作用下，通过改变巨噬细胞的脂肪代谢方式，促进肝脏内炎症介质释放，加速肝转移发生。我们也对肝癌细胞仑伐替尼耐药机制进行探究，发现了MT1JP- microRNA-24-3p- BCL2L2信号轴通过抑制凋亡水平，促进对仑伐替尼的耐药发生。我们的研究对于肠癌的转移机制，以及肠癌肝转移的防控有着借鉴作用，改变肝脏脂肪堆积的背景，可能可以降低肠癌肝转移的发生。