Background

Cancer progression following chemotherapy is a significant barrier to effective cancer treatment. We aimed to evaluate the role of drug-exposed cancer-associated fibroblasts (CAFs) in the growth and progression of drug-exposed gastric cancer (GC) cells and to explore the underlying molecular mechanism.

Methods

The human GC cell line 44As3 and CAFs were treated with 5-fluorouracil and oxaliplatin (5FU + OX). 5FU + OX-pretreated 44As3 cells were then cultured in a conditioned medium (CM) from 5FU + OX-pretreated CAFs, and the growth and migration/invasion ability of the cells were evaluated. We also compared the clinicopathological characteristics of the GC patients treated with S1 + OX in accordance with the properties of their resected specimens, focusing on the number of CAFs. Changes in gene expression in CAFs and 44As3 cells were comprehensively analyzed using RNA-seq analysis.

Results

The CM from 5FU + OX-pretreated CAFs promoted the migration and invasion of 5FU + OX-pretreated 44As3 cells. Although the number of cases was relatively small (n = 21), the frequency of positive cases of lymphovascular invasion and the recurrence rate were significantly higher in those with more residual CAF. RNA-seq analysis revealed 5FU + OX-pretreated CAF-derived glycoprotein 130 (gp130) as a candidate factor contributing to the increased migration of 5FU + OX-pretreated 44As3 cells. Administration of the gp130 inhibitor SC144 prevented the increased migration ability of 5FU + OX-pretreated 44As3 cells owing to drug-treated CAFs.

Conclusions

Our findings provide evidence regarding the interactions between GC cells and CAFs in the tumor microenvironment following chemotherapy, suggesting that ligands for gp130 may be novel therapeutic targets for suppressing or preventing metastasis in GC.

中文翻译：

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药物暴露的癌症相关成纤维细胞促进化疗后胃癌细胞的进展

背景

化疗后的癌症进展是有效治疗癌症的重要障碍。我们旨在评估药物暴露的癌症相关成纤维细胞 (CAF) 在药物暴露的胃癌 (GC) 细胞生长和进展中的作用，并探索潜在的分子机制。

方法

人 GC 细胞系 44As3 和 CAF 用 5-氟尿嘧啶和奥沙利铂 (5FU + OX) 处理。然后将 5FU + OX 预处理的 44As3 细胞在来自 5FU + OX 预处理的 CAF 的条件培养基 (CM) 中培养，并评估细胞的生长和迁移/侵袭能力。我们还根据其切除标本的特性比较了 S1 + OX 治疗的 GC 患者的临床病理特征，重点是 CAF 的数量。使用 RNA-seq 分析综合分析了 CAF 和 44As3 细胞中基因表达的变化。

结果

来自 5FU + OX 预处理的 CAF 的 CM 促进了 5FU + OX 预处理的 44As3 细胞的迁移和侵袭。虽然病例数相对较少（n  =21），但CAF残留较多者的淋巴血管侵犯阳性率和复发率明显较高。RNA-seq 分析显示 5FU + OX 预处理的 CAF 衍生糖蛋白 130 (gp130) 作为候选因子，有助于增加 5FU + OX 预处理的 44As3 细胞的迁移。由于药物处理的 CAF，gp130 抑制剂 SC144 的施用阻止了 5FU + OX 预处理的 44As3 细胞迁移能力的增加。

结论

我们的研究结果为化疗后肿瘤微环境中 GC 细胞和 CAF 之间的相互作用提供了证据，表明 gp130 的配体可能是抑制或预防 GC 转移的新治疗靶点。