基于肿瘤相关成纤维细胞SASP促胃癌细胞干性形成探讨化疗抵抗机制及扶正解毒方干预作用研究

化疗抵抗是胃癌治疗效果提升的瓶颈，至今缺乏有效干预手段。最新研究显示：化疗在清除癌细胞同时导致肿瘤相关成纤维细胞（CAFs）衰老，其衰老相关分泌表型（SASP）作用于自身及上调M2型肿瘤相关巨噬细胞（TAMs）比例引起NK细胞耗竭，从而避免被清除，继而使癌细胞获得干性是造成化疗抵抗关键机制。扶正解毒方是我院治疗胃癌有效方，前期研究表明：该方能够提高化疗效果，并能促M2型TAMs向M1型转化。扶正解毒方是否通过“CAFs-SASP-NK细胞耗竭-癌细胞干性化”逆转化疗抵抗值得进一步探讨。本课题拟利用体内、外平台，通过富集衰老CAFs，构建化疗抵抗荷瘤小鼠模型，观察扶正解毒方对cGAS-STING/NF-κB 通路介导衰老CAFs相关SASP分泌过程重塑及 WNT16B/ SFPR2/β-catenin通路促癌细胞干性化调控，从干预CAFs衰老的新视角揭示化疗抵抗分子机制和扶正解毒方干预作用。

Chemotherapy resistance is the bottleneck to improve the effect of chemotherapy for gastric cancer, and there is a lack of effective intervention so far. The latest research shows that chemotherapy not only clears cancer cells but also causes senescence of tumor-associated fibroblasts (CAFs). The key mechanism of chemotherapy resistance is that the senescence-related secretion phenotype (SASP) acts on itself and up-regulates the proportion of (TAMs) in M2 tumor-associated macrophages, which leads to the exhaustion of NK cells, thus avoiding clearance and making cancer cells stemness. Fu Zheng Jie Du Formula (FZJDF) is an empirical prescription for the treatment of gastric cancer in our hospital. previous studies have shown that it can improve the effect of chemotherapy and promote the transformation of M2 type TAMs to M1. Whether FZJDF reverse chemotherapy resistance through the axis of " CAFs-SASP- exhaustion of NK cells- cancer cells stemness " is worthy of further investigation. The purpose of this study is to establish a chemotherapy resistance tumor-bearing mouse model by enriching senescent CAFs, in vivo and in vitro, to observe the effect of FZJDF on the remodeling of senescent CAFs-related SASP secretion mediated by cGAS-STING/NF-κB pathway and the regulation of WNT16B/ SFPR2/β-catenin pathway to promote gastric cancer cells stemness, and to reveal the molecular mechanism of chemotherapy resistance and the intervention effect of FZJDF from the new perspective of senescent CAFs.