Targeting cancer-associated fibroblasts/tumor cells cross-talk inhibits intrahepatic cholangiocarcinoma progression via cell-cycle arrest.

IF 11.4 1区医学 Q1 ONCOLOGY Journal of Experimental & Clinical Cancer Research Pub Date : 2024-10-17 DOI:10.1186/s13046-024-03210-9

Serena Mancarella, Isabella Gigante, Elena Pizzuto, Grazia Serino, Alberta Terzi, Francesco Dituri, Eugenio Maiorano, Leonardo Vincenti, Mario De Bellis, Francesco Ardito, Diego F Calvisi, Gianluigi Giannelli

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Abstract

Background: Cancer-associated fibroblasts (CAFs), mainly responsible for the desmoplastic reaction hallmark of intrahepatic Cholangiocarcinoma (iCCA), likely have a role in tumor aggressiveness and resistance to therapy, although the molecular mechanisms involved are unknown. Aim of the study is to investigate how targeting hCAF/iCCA cross-talk with a Notch1 inhibitor, namely Crenigacestat, may affect cancer progression.

Methods: We used different in vitro models in 2D and established new 3D hetero-spheroids with iCCA cells and human (h)CAFs. The results were confirmed in a xenograft model, and explanted tumoral tissues underwent transcriptomic and bioinformatic analysis.

Results: hCAFs/iCCA cross-talk sustains increased migration of both KKU-M213 and KKU-M156 cells, while Crenigacestat significantly inhibits only the cross-talk stimulated migration. Hetero-spheroids grew larger than homo-spheroids, formed by only iCCA cells. Crenigacestat significantly reduced the invasion and growth of hetero- but not of homo-spheroids. In xenograft models, hCAFs/KKU-M213 tumors grew significantly larger than KKU-M213 tumors, but were significantly reduced in volume by Crenigacestat treatment, which also significantly decreased the fibrotic reaction. Ingenuity pathway analysis revealed that genes of hCAFs/KKU-M213 but not of KKU-M213 tumors increased tumor lesions, and that Crenigacestat treatment inhibited the modulated canonical pathways. Cell cycle checkpoints were the most notably modulated pathway and Crenigacestat reduced CCNE2 gene expression, consequently inducing cell cycle arrest. In hetero-spheroids, the number of cells increased in the G2/M cell cycle phase, while Crenigacestat significantly decreased cell numbers in the G2/M phase in hetero but not in homo-spheroids.

Conclusions: The hCAFs/iCCA cross-talk is a new target for reducing cancer progression with drugs such as Crenigacestat.

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针对癌症相关成纤维细胞/肿瘤细胞交叉对话，通过细胞周期停滞抑制肝内胆管癌的进展。

背景：癌症相关成纤维细胞（CAFs）主要负责肝内胆管癌（iCCA）标志性的去瘤细胞反应，可能在肿瘤侵袭性和耐药性中发挥作用，但其中涉及的分子机制尚不清楚。本研究的目的是探讨用 Notch1 抑制剂（即 Crenigacestat）靶向 hCAF/iCCA 交叉对话如何影响癌症进展：我们使用了不同的二维体外模型，并用 iCCA 细胞和人（h）CAFs 建立了新的三维异型干细胞。结果：hCAFs/iCCA 交叉配对可维持 KKU-M213 和 KKU-M156 细胞迁移的增加，而 Crenigacestat 仅能显著抑制交叉配对刺激的迁移。仅由 iCCA 细胞形成的异种球形体比同种球形体长得更大。Crenigacestat 能显著降低异型球体的侵袭和生长，但不能降低同型球体的侵袭和生长。在异种移植模型中，hCAFs/KKU-M213肿瘤的体积明显大于KKU-M213肿瘤，但经Crenigacestat处理后体积明显缩小，纤维化反应也明显减轻。Ingenuity通路分析显示，hCAFs/KKU-M213肿瘤的基因增加了肿瘤病变，而KKU-M213肿瘤的基因没有增加，Crenigacestat治疗抑制了被调控的典型通路。细胞周期检查点是最显著的调节途径，Crenigacestat 可降低 CCNE2 基因的表达，从而诱导细胞周期停滞。在异种球形体中，处于G2/M细胞周期阶段的细胞数量增加，而在异种球形体中，Crenigacestat能显著减少处于G2/M阶段的细胞数量，但在同种球形体中却没有：结论：hCAFs/iCCA交叉对话是使用克瑞格司他等药物减少癌症进展的一个新靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Experimental & Clinical Cancer Research 医学-肿瘤学

CiteScore

18.20

自引率

1.80%

发文量

333

审稿时长

1 months

期刊介绍： The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.