胃癌是一种异质性肿瘤疾病，缺乏适当的治疗选择。迫切需要开发创新的药理学策略，特别是考虑到这种肿瘤的潜在分层/个性化治疗。全反式视黄酸 (ATRA) 是维生素 A 的活性代谢物之一。这种天然化合物是临床批准的细胞分化剂的第一个例子，用于治疗急性早幼粒细胞白血病。 ATRA 在实体瘤（包括胃癌）中也可能具有显着的治疗潜力。本研究提供了支持 ATRA 通过高通量方法治疗胃癌的临床前证据。我们评估了 ATRA 在 27 种胃癌细胞系和来自 13 个胃癌细胞系的组织切片培养物中的抗增殖作用。胃癌患者。我们对 13 种暴露于 ATRA 的细胞系进行了 RNA 测序研究。我们使用这些数据和 TCGA/CCLE 数据集的胃癌 RNA 测序数据进行多项计算分析。对我们的大量胃癌细胞系进行分析，了解它们对 ATRA 的抗增殖作用的定量反应，表明：大约一半的细胞系对类维生素A敏感。这些细胞系的组成型转录组图谱允许构建由 42 个基因组成的模型，其表达与 ATRA 敏感性相关。该模型预测 45% 的 TCGA 胃癌对 ATRA 敏感。在经类视黄醇处理的胃癌细胞系中进行的 RNA 测序研究提供了对 ATRA 抗肿瘤活性的基因网络的深入了解。此外，我们的数据表明 ATRA 具有显着的免疫调节作用，这似乎很大程度上是由 IRF1 上调控制的。最后，我们提供了IRF1和DHRS3之间反馈循环的证据，DHRS3是ATRA上调的另一个基因。ATRA在胃癌的分层/个性化治疗中具有显着的治疗潜力。我们的数据代表了临床试验设计的基础，重点是使用 ATRA 来个性化治疗这种异质性肿瘤。我们的基因表达模型将允许开发预测工具来选择 ATRA 敏感的胃癌患者。 ATRA 激活的免疫调节反应表明类视黄醇和免疫检查点抑制剂构成了治疗胃癌的合理组合。© 2023。作者。

Gastric-cancer is a heterogeneous type of neoplastic disease and it lacks appropriate therapeutic options. There is an urgent need for the development of innovative pharmacological strategies, particularly in consideration of the potential stratified/personalized treatment of this tumor. All-Trans Retinoic-acid (ATRA) is one of the active metabolites of vitamin-A. This natural compound is the first example of clinically approved cyto-differentiating agent, being used in the treatment of acute promyelocytic leukemia. ATRA may have significant therapeutic potential also in the context of solid tumors, including gastric-cancer. The present study provides pre-clinical evidence supporting the use of ATRA in the treatment of gastric-cancer using high-throughput approaches.We evaluated the anti-proliferative action of ATRA in 27 gastric-cancer cell-lines and tissue-slice cultures from 13 gastric-cancer patients. We performed RNA-sequencing studies in 13 cell-lines exposed to ATRA. We used these and the gastric-cancer RNA-sequencing data of the TCGA/CCLE datasets to conduct multiple computational analyses.Profiling of our large panel of gastric-cancer cell-lines for their quantitative response to the anti-proliferative effects of ATRA indicate that approximately half of the cell-lines are characterized by sensitivity to the retinoid. The constitutive transcriptomic profiles of these cell-lines permitted the construction of a model consisting of 42 genes, whose expression correlates with ATRA-sensitivity.  The model predicts that 45% of the TCGA gastric-cancers are sensitive to ATRA. RNA-sequencing studies performed in retinoid-treated gastric-cancer cell-lines provide insights into the gene-networks underlying ATRA anti-tumor activity. In addition, our data demonstrate that ATRA exerts significant immune-modulatory effects, which seem to be largely controlled by IRF1 up-regulation. Finally, we provide evidence of a feed-back loop between IRF1 and DHRS3, another gene which is up-regulated by ATRA.ATRA is endowed with significant therapeutic potential in the stratified/personalized treatment gastric-cancer. Our data represent the fundaments for the design of clinical trials focusing on the use of ATRA in the personalized treatment of this heterogeneous tumor. Our gene-expression model will permit the development of a predictive tool for the selection of ATRA-sensitive gastric-cancer patients. The immune-regulatory responses activated by ATRA suggest that the retinoid and immune-checkpoint inhibitors constitute rational combinations for the management of gastric-cancer.© 2023. The Author(s).