TGF-β/Smad信号通路在胃癌腹膜转移中的作用及机制研究

Peritoneal carcinomatosis severely limits the improvement of gastric cancer patients' prognoses after surgery. Peritoneal metastasis results in a metastatic cascade, usually occurring at late-stage tumor development, that significantly contributes to gastric cancer-related mortality. The"seed and soil" theory proposed that metastasis only occurs when tumor cells live and grow in a favorable environment. The peritoneal stroma environment favors proliferation of tumor cells by serving as a rich source of growth factors and chemokines known to be involved in tumor metastasis. We have previously shown that the layer of confluent, intact mesothelial cells hindered cancer cell invasion of the abdominal cavity. However, once the integrity of this barrier is disrupted, metastasis may occur because the peritoneum provides a favorable environment for gastric cancer cells to grow. Previous results also showed a significant elevation of TGF-β1 expression when mesothelial cells were co-cultured with gastric tumor cells. TGF-β1 pathway may play a role in the reciprocal communication of gastric tumor cells and mesothelial cells, and it potentially contributes to gastric tumor cells invasion through mesothelial cell layer.. In this study, we examined the effects of soluble factors released by gastric cancer cells on morphology and biological activity of peritoneal mesothelial cells in vitro and vivo. The effects of TGF-β1/Smad signaling pathway and MPK38 on the morphology and function of human peritoneal mesothelial cells to provide more information of the reciprocal interaction between tumor and mesothelial cells during peritoneal gastric cancer metastasis.

癌细胞对腹膜的浸润转移是连续而系列的过程。腹膜基质的微环境为癌细胞转移提供了丰富的生长因子和炎症因子。我们发现间皮细胞能抵御胃癌侵袭转移，胃癌腹膜转移过程中由胃癌所分泌的上清液能预先破坏间皮，导致其损伤，从而促进癌转移。"种子-土壤"学说认为癌细胞更适宜在对其生存、生长有利的微环境中形成转移。受损的腹膜为胃癌细胞转移提供了适宜的环境，成为了胃癌细胞种植适宜的"土壤"。另外，把胃癌细胞与间皮细胞共培养以后，TGF-β1的含量明显升高。说明TGF-β1及其相 关通路在胃癌腹膜转移中很可能处于活跃状态。通过本研究希望了解相关细胞因子如何诱导间皮细胞损伤，并对其进行筛选，明确TGF-β1在胃癌腹转过程中对间皮细胞的破坏作用。探讨TGF-β/Smad信号通路在胃癌腹膜转移中的作用机制，研究MPK38是否参与调节TGF-β/Smad信号通路及其对胃癌腹膜浸润的影响。为治疗胃癌腹膜转移提供新的治疗靶点。

“种子－土壤”学说认为：癌细胞更适宜在对其生存、生长有利的微环境中形成转移。研究发现：正常的腹膜间皮细胞能够作为屏障防止肿瘤细胞对于腹膜的粘附转移。本研究验证了间皮细胞对胃癌细胞的抵御作用，并发现在亚临床转移阶段，胃癌细胞能通过其上清诱导腹膜间皮凋亡及纤维化。在胃癌细胞分泌的多种细胞因子的作用下，腹膜间皮发生损伤凋亡，反过来可诱导癌细胞获得更高水平的变形转移能力。通过进一步研究我们不但注意到在多种胃癌细胞系中均呈现TGF-β1高表达状态，而且发现TGF-β1还能通过TGF-β/ Smads信号传导途径诱导腹膜间皮细胞发生凋亡。从而证明TGF-β1是胃癌诱导腹膜间皮细胞凋亡的重要靶点。而抑制TGF/Smads通路能有效降低肿瘤细胞对腹膜间皮的粘附。除此以外，我们发现黄其提取物也可以抑制胃癌上清诱导的间皮凋亡。本项目研究结果为有效的防治胃癌的腹膜转移提供新的思路与靶点，也为腹腔其他脏器恶性肿瘤腹膜转移的防治提供了依据。