Snail介导的肿瘤相关巨噬细胞表型重塑在结直肠癌转移中的作用及其干预对策

诸多研究证实，结直肠癌中肿瘤相关巨噬细胞（TAM）的浸润可显著促进其转移。TAM属于M2型巨噬细胞，并具有向M1型分化的潜能。M1型巨噬细胞对肿瘤细胞有强烈的杀伤作用，而TAM却密切介入了肿瘤的发生发展、侵袭转移及血管和淋巴管生成。因此，充分调动TAM的分化潜能，促进其向M1型巨噬细胞极化，重建其肿瘤杀伤能力，是一项值得期待的肿瘤免疫治疗新策略。Snail是决定个体发育及细胞分化方向重要的转录因子。新近研究及我们前期工作表明，转录因子Snail参与了巨噬细胞免疫抑制表型转化的过程，而敲除Snail则向M1型转化，初步揭示了TAM的转化机制。据此，本课题拟在建立体内、外诱导巨噬细胞转化模型的基础上，解析Snail介导TAM极化的作用及内在机制，阐明其过程中的核心环节及关键分子，并评价通过调控Snail及其关键分子的策略，促使TAM表型和功能逆向转化，降低结直肠癌转移风险的有效性和可行性。

Accumulated evidences indicated that the infiltration of tumor-associated macrophages (TAM) in tumor microenvironment plays an important role in promoting colorectal tumor metastasis. TAM is M2 phenotype, and can re-educate macrophages towards an M1 phenotype. M1 macrophage is an anti-tumor phenotype by killing tumor cells, while TAM is closely involved in the development, invasion, metastasis and angiogenesis of tumor. Therefore, to fully mobilization the differentiation potential of TAM and promote its polarization to M1 phenotype, reconstruction of its tumor killing capacity is a new strategy for tumor immunotherapy. Snail is an important transcription factor that determines the direction of individual development and cell differentiation. Recent studies and our preliminary studies have revealed that the expression of Snail in TAM is up-regulated. Over-expression of Snail in macrophage induced TAM polarization and knock-out Snail induced M1 polarization. Thus, on the basis of our previous established in vitro and vivo models of macrophage polarization, the major objectives of the present proposal are to evaluate the effect and molecular mechanism of Snail induced TAM polarization. Furthermore, we will search for new strategies to inhibit Snail and other related important regulatory factors, and then assess the validity and feasibility for increasing tumor immunity adjuvant therapy and reducing the risks of tumor metastasis.