肿瘤源性IL-6诱导巨噬细胞M2样极化在胃癌淋巴转移中的作用及分子机制研究

Tumor-associated macrophages were (TAMs) directly involved in lymphatic metastasis of gastric carcinoma, but it is not unclear yet how the tumor microenvironment to induce TAMs M2 polarization and lymphangiogenesis . Our previous study has found that tumor-derived IL-6 could induce monocyte TAMs polarization and new lymphatic vessels, and gastric cancer TAMs highly expressed IRF4, a key transcription factors associated with polarization, indicated that the IRF4 gene may be the target of IL-6/gp130/JAK/STAT3 signal pathway. We speculate that: a large number of gastric cancer sourced IL-6 effects on TAMs through activation of JAK / STAT3 signal pathway, enhances the expression of IRF4, and induces M2 polarization, which directly involved in gastric cancer lymphangiogenesis and lymph node metastasis. This study combines the cell model with clinical specimens of gastric cancer, and takesTAMs as the object, using immunohistochemistry, reporter gene and ChIP and other methods, to clarify the effects of tumor-derived IL-6 on TAMs polarization, explore the molecular mechanism of IL-6 regulation of TAMs polarization, and finally uses the mouse gastric cancer xenograft model to explore the relationship between TAMs polarization and lymph node metastasis of gastric cancer. The research will deepen the understanding of mechanism of lymph metastasis and provide a new target for early clinical treatment and prevention of gastric cancer transfer.

肿瘤相关巨噬细胞（TAMs）直接参与胃癌淋巴转移，但肿瘤微环境诱导其 M2样极化并参与淋巴管新生的分子机制尚不清楚。我们前期研究发现胃癌源性IL-6可诱导单核巨噬细胞发生M2样极化并诱生新淋巴管，且胃癌TAMs高表达极化关键转录因子IRF4，预实验还提示IRF4基因可能是IL-6/gp130/JAK/STAT3信号的靶标。由此推测：大量胃癌来源的IL-6作用于TAMs，通过激活JAK／STAT3信号，增强IRF4表达，诱导其M2样极化，进而直接参与胃癌的淋巴管新生和淋巴转移。本研究拟通过细胞模型并结合胃癌临床标本，以TAMs为研究对象，采用免疫组化、报告基因和ChIP 等技术，阐明肿瘤源性IL-6调控TAMs极化的分子机制，用胃癌淋巴转移小鼠模型结合活体成像技术探索TAMs极化与胃癌淋巴转移的关系。研究结果将深化对胃癌淋巴转移机制的认识，为临床早期治疗胃癌并预防其转移提供新的可能靶点。

肿瘤相关巨噬细胞（TAMs）是肿瘤发生发展的重要免疫细胞，对肿瘤患者的预后有着重要的影响。本研究通过对胃癌临床标本的研究，证实了M2型肿瘤相关巨噬细胞的表达与胃癌患者的生存呈负相关。同时本研究还发现肿瘤组织中的IL-6的表达量与M2型巨噬细胞的数量呈正相关性，进一步研究发现IL-6能诱导单核巨噬细胞向M2型极化，结合细胞模型，证实了肿瘤源性IL-6作用于TAMs，通过激活JAK／STAT3信号，增强p-STAT3表达，诱导巨噬细胞向高表达IL-10,TGF-β的M2型巨噬细胞极化，并且此诱导效应具有IL-6剂量依耐性，同时IL-6诱导的M2型巨噬细胞可以促进胃癌细胞(AGS\SGC)的增殖和迁移。因此，本研究结果充分证实了IL-6及肿瘤相关巨噬细胞对胃癌进展的重要作用，深化了对胃癌淋巴转移机制的认识，为临床早期治疗胃癌并预防其转移提供新的可能靶点。