M2型肿瘤相关巨噬细胞诱导腹膜微环境改变促进胃癌腹膜转移机制研究

Peritoneal metastasis from gastric cancers is a result of development of special cancer cell clones in the appropriate peritoneal microenvironment. Previous studies frequently focused on the peritoneal free cancer cells. However, the roles of peritoneal micro-environment changes in the procedures of the development of peritoneal metastasis remain unclear. In our previous studies, we have observed that free cancer cells in the peritoneal cavity have the ablity of recruiting and activating circular mononuclear cell to M2 polarization peritoneal tumor-associated macrophages (TAMs). Previous results in the literatures have revealed that M2 polarization TAMs produce multifarious cytokines as well as chemotactic factors, which promote tumor growth and metastasis. Nonetheless, the potential roles of M2 polarization TAMs in promoting the development of peritoneal metastasis remain unclear. In our previous studies, we found M2 polarization TAMs might have the function of inducting the changes of peritoneal micro-environment, which characterized by mesothelial-fibrosis transformation (MFT) and apoptosis of peritoneal mesothelial cells', exposure of connective tissue, and angiogenesis. On the other hand, M2 polarization TAMs might also mediate the epithelial-mesenchymal transition and cancer stem cell properties of peritoneal free cancer cells by down regulation of expression of miRNA-34 in cancer cells. According to these results, we presume the activating of M2 polarization TAMs by peritoneal free cancer cells might play a centrol role in the peritoneal micro-environment changes, which results in the promotion of peritoneal metastasis. In order to prove this presumption, the aim of the present study is to investigate the validity of peritoneal free cancer cells from gastric cancers in activiting M2 polarization TAMs and the ratio of M1/M2 polarization TAMs after activation, to investigate essentiality and its mechanisms of M2 polarization TAMs induced peritoneal micro-environment changes in promoting the development of peritoneal metastasis, and to investigate the downstream molecular mechanisms involved in the miRNA-34 mediated regulation of epithelial-mesenchymal transition and cancer stem cell properties of peritoneal free cancer cells by M2 polarization TAMs. The results of the present study will be valuable for further investigations of effective prevention and treatment of peritoneal metastasis for gastric caners.

胃癌腹膜转移是特殊癌细胞克隆在适宜的腹膜微环境中生长的结果。既往研究主要围绕癌细胞开展，针对腹膜微环境改变在腹膜转移中作用的研究甚少。前期实验我们发现癌细胞可募集并活化循环单核细胞为M2型腹腔肿瘤相关巨噬细胞（TAMs）。文献报告，M2型TAMs可分泌多种细胞因子促进肿瘤生长，但其在腹膜转移过程中的作用仍然未知。前期实验我们发现M2型TAMs一方面可能诱导以腹膜间皮细胞成纤维转化及凋亡、结缔组织暴露及血管生成为主的微环境改变，一方面又可能通过诱导miRNA-34低表达，调控癌细胞EMT及肿瘤干细胞特性。由此推测，M2型TAMs的活化可能是腹膜转移过程中微环境变化的核心机制。本研究拟通过体内外实验证实胃癌细胞可活化M2型TAMs及其比率，明确M2型TAMs诱导腹膜微环境改变及其促进腹膜转移的作用及机制，并探讨其调控癌细胞EMT及"干性"的分子机制。研究结果将为腹膜转移防治提供新的思路与靶点。

本研究的总体思路以腹膜乳斑是胃癌细胞入侵腹膜的门户这一临床现象为切入点, 以体内外条件下进一步证实胃癌细胞可活化循环单核细胞为M2 型TAMs 及其比率；探讨M2型TAMs 诱导腹膜微环境改变促进胃癌细胞粘附、侵袭的作用及其机制以及研究M2型TAMs调控腹腔游离癌细胞EMT及“干性”的 分子机制为主要研究内容。以新的视角解释了胃癌腹膜转移的成因，完善胃癌腹膜转移的分子机制。本研究通过获取不同病期胃癌腹腔冲洗液、腹腔游离癌细胞及患者腹膜标本检测腹腔冲洗液、 腹腔游离癌细胞中多种 M1、M2 型 TAMs 特异性活化因子表达水平及 M1、M2 型活化 TAMs 特异性表达因子水平明确了缺氧M2型TAM是胃癌腹膜转移的关键作用位点。HIF-1α广泛表达于胃癌原发灶及转移灶中，对胃癌生物学行为产生重要影响。HIF-1α阳性表达是影响胃癌预后的独立危险因素。HIF-1α阳性 表达与某些肿瘤干细胞标志物 OCT4 及 Nestin 的表达呈正相关，参与了缺氧微环 境对胃癌干细胞样细胞生物学行为的调控。缺氧微环境下 HIF-1α调控胃癌干细 胞样细胞，增强其自我更新能力，减弱其多向分化能力。腹膜乳斑是适合胃癌干 细胞样细胞定植的理想干细胞龛，其内部缺氧微环境调控胃癌干细胞样细胞使其 维持未分化状态，处于休眠状态。破坏乳斑缺氧微环境或者破坏乳斑内缺氧信号 传递可以减轻裸鼠腹膜转移的程度。胃癌间断性和持续性缺氧模型均可以诱导胃 癌细胞缺氧，增强其侵袭转移能力，增加胃癌细胞群体中干细胞样细胞比率。上述研究成果证明了乳斑缺氧微环境调控胃癌干细胞样细胞自我更新能力促进腹膜转移的发生发展，丰富了胃癌抚摸转移发生的理论研究，为胃癌的早期诊断或阻断治疗提供新的靶点

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