阿帕替尼抑制肠炎相关性结直肠癌发生发展的机制研究

Apatinib is a small-molecule anti-tumor angiogenic drug developed by our country for the treatment of advanced gastric cancer. Our previous results suggest that Apatinib could inhibit the development of Colitis-associated colorectal (CAC) in vivo, and inhibit the expression of M2 macrophage-related genes significantly in vitro. Considering the different and important roles of macrophages in various stages of the development of Colitis-associated colorectal cancer, We will further explore how Apatinib acts as an antitumor agent by regulating macrophage activation and function in the clinical, animal, cell and molecular levels. This study not only helps to further understand the regulatory mechanism of macrophage polarization, but also helps to understand the relationship between intestinal macrophage-mediated enteritis and colorectal cancer. More importantly, this study suggests that the significant antitumor effect of Apatinib not only affects angiogenesis, but may also plays an anti-tumor role by regulating the activation of macrophages.

阿帕替尼(Apatinib)是我国自主研制的一种用于治疗晚期胃癌的小分子靶向抗肿瘤血管生成药物。我们前期实验结果表明Apatinib在体内能够抑制肠炎相关性结直肠癌（CAC）的发生发展，在体外能显著抑制M2型巨噬细胞相关基因的表达。考虑到巨噬细胞在CAC发生发展的各个阶段发挥不同且重要的作用，我们将在临床、动物、细胞以及分子水平进一步探索Apatinib如何通过调控巨噬细胞的活化以及功能起到抗肿瘤的作用。该研究不仅有助于进一步了解巨噬细胞极化的调控机制，也有助于了解肠道巨噬细胞介导的肠炎与肠癌之间的关系。更重要的是，该研究提示Apatinib显著的抗肿瘤效果不仅仅是影响到血管新生，还有可能通过调控巨噬细胞的活化来实现的。

肠炎相关性结肠癌的发生发展是一个肠炎/肠癌的转化过程。其发病机制较为复杂，导致相关药物的筛选及研发任重道远。众多研究表明，巨噬细胞与炎症相关性结直肠癌的发生发展密切相关。巨噬细胞在炎症及肿瘤的发生发展中均扮演重要角色，目前已成为炎症与肿瘤相关疾病治疗的重要靶向药物靶点。近年来，在炎症与肿瘤微环境中M1/M2型巨噬细胞动态平衡的相关研究中存在许多技术困难，严重阻碍了相关靶向药物的开发。核受体作为一类重要的转录因子，在巨噬细胞极化过程中的相关研究已有报道，但其调控的分子机制仍有待进一步的研究。在这里，我们发现抗肿瘤药物阿帕替尼是一个靶向核受体PPARγ的抑制剂，能够抑制M2型巨噬细胞的极化，进而抑制炎症相关性结直肠癌的发生发展。这些研究的完成有助于进一步了解阿帕替尼抗肿瘤的机制，有助于了解巨噬细胞在炎症以及肿瘤发生发展中作用，有助于了解核受体调控巨噬细胞极化过程的机制，为相关疾病的靶向药物筛选及研究提供更好的理论依据。