逆转乳斑微环境中TAM及TAF促转移表型阻断胃癌腹膜转移的转化研究

Gastric cancer peritoneal dissemination is the result of cross-talking between peritoneal free cancer cells and peritoneal milky spots microenvironment. Our previous studies revealed that the key pathological change of gastric cancer peritoneal dissemination is pro-metastatic soil which is composed by FAP+ tumor associated fibroblast, M2 phenotype tumor associated macrophage as well as peritoneal milky spots hypoxic microenvironment. Therefore we proposed that: the vital step to block gastric cancer peritoneal dissemination is breaking the dynamic balance between peritoneal free cancer cells and peritoneal milky spots microenvironment, eliminating the protection and supporting effect on peritoneal free cancer cells which is caused by peritoneal milky spots pro-metastasis microenvironment. By these means, the malignancy and metastatic potential of gastric cancer cells was restrained, and the sensitivity of gastric cancer cells to supportive chemical therapy may significantly enhanced. In this study, optimize the target-replacement pathway of stroma cells in peritoneal milky spots microenvironment is the key research content. We aim to block gastric cancer peritoneal dissemination by exogenous genetic remolding the tumor associated fibroblast and tumor associated macrophage. The results of present study will be valuable for further investigations of effective prevention and treatment of gastric cancer peritoneal dissemination.

胃癌腹膜转移是腹腔游离癌细胞与腹膜乳斑微环境双向作用的结果，通过前期研究我们发现由FAP+型肿瘤相关成纤维细胞、M2型肿瘤相关巨噬细胞以及乳斑缺氧微环境共同构筑的促转移微环境是胃癌腹膜转移的核心病理改变。由此我们提出：若阻断胃癌腹膜转移的病理进程，首先应该打破腹膜促转移微环境与胃癌细胞之间的动态平衡，消除腹膜促转移微环境对胃癌细胞的保护及支持机制，既可降低胃癌细胞的恶性程度及转移潜能，亦可增强胃癌细胞对辅助治疗的敏感性。本研究以优化腹膜微环境基质细胞靶向替换途径为核心研究内容，旨在通过肿瘤相关巨噬细胞、肿瘤相关成纤维细胞的外源性基因改造阻断胃癌腹膜转移病理进程。研究结果将为有效防治胃癌腹膜转移提供新的思路与靶点。

胃癌腹膜扩散(gastric cancer peritoneal dissemination, GCPD)已被公认为进展期胃癌(gastric cancer, GC)最常见的转移方式，其预后不容乐观。间皮细胞损伤在GCPD中起重要作用。然而，其分子机制尚不完全清楚。在这里，我们集中于人腹膜间皮细胞(human peritoneal mesothelial cell, HPMC)中的鞘氨醇激酶1(sphingosine kinase, SPHK1)，它在GCPD进展过程中调节HPMC的自噬。. 首先，我们用免疫组织化学方法分析了120例胃癌腹膜组织中SPHK1的表达，发现SPHK1的高表达与LC3B的表达和腹膜复发密切相关，导致预后不良。利用共培养系统，我们观察到GC细胞促进HPMC的自噬，并通过阻断GC细胞分泌的转化生长因子-β-1来抑制这一过程。自噬HPMC诱导GC细胞黏附和侵袭。我们还证实了抑制HPMC中SPHK1的表达可以抑制转化生长因子-β1诱导的自噬。此外，SPHK1驱动的HPMCs自噬在体内外加速了GC细胞GCPD的发生。此外，我们还探讨了自噬与HPMC纤维化的关系，观察到SPHK1过表达诱导HPMC纤维化，而抑制自噬则削弱HPMC纤维化。. 综上所述，我们的结果为理解GCPD的机制提供了新的见解，并确立了SPHK1作为GCPD的新靶点。