Different types of reactions to E7386 among colorectal cancer patient‑derived organoids and corresponding CAFs

Imai,Toshio; Naruse,Mie; Ochiai,Masako; Matsumoto,Kenji; Ikeda,Satsuki; Kani,Manami; Kato,Yuyu; Hirayama,Akiyoshi; Soga,Tomoyoshi; Hori,Yusaku; Yokoi,Akira; Ochiai,Atsushi

doi:10.3892/ol.2022.13342

Different types of reactions to E7386 among colorectal cancer patient‑derived organoids and corresponding CAFs

Authors:
- Toshio Imai
- Mie Naruse
- Masako Ochiai
- Kenji Matsumoto
- Satsuki Ikeda
- Manami Kani
- Yuyu Kato
- Akiyoshi Hirayama
- Tomoyoshi Soga
- Yusaku Hori
- Akira Yokoi
- Atsushi Ochiai
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Affiliations: Central Animal Division, National Cancer Center Research Institute, Tokyo 104‑0045, Japan, Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo 157‑8535, Japan, Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997‑0035, Japan, Oncology Business Group, Eisai Co., Ltd., Tokyo 112‑8088, Japan, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo 104‑0045, Japan
Published online on: May 23, 2022 https://doi.org/10.3892/ol.2022.13342
Article Number: 221
Copyright: © Imai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Colorectal cancer (CRC) harbors genetic alterations in a component of the Wnt signaling pathway in ~90% of cases. In addition, the Wnt signaling pathway has been previously suggested to serve a notable role in the pathophysiology of CRC cells and cancer‑associated fibroblasts (CAFs). In the present study, the possible effects of E7386, a selective inhibitor of the interaction between β‑catenin and the cAMP response element‑binding protein‑binding protein, were evaluated using organoids and the corresponding CAFs derived from patients with CRC. E7386 at 100 nM was revealed to decrease the viability of CRC organoids and CAFs. Analysis of the gene expression profiles revealed marked changes in the expression levels of different types of cancer‑associated genes associated with E7386 concentrations in the organoids and/or CAFs, such as those regulating glucose and amino acid metabolism [phosphoenolpyruvate carboxykinase 2, asparagine synthetase (glutamine‑hydrolyzing), phosphoserine aminotransferase 1 and phosphoglycerate dehydrogenase], stimulation of natural killer cell‑mediated cytotoxicity (UL16‑binding protein 1) and modification of the Wnt/β‑catenin signaling pathway (indicated by very low density lipoprotein receptor). Results of the hydrophilic metabolome analysis in the organoids were consistent with those of the transcriptomic analysis. In vivo experiments used corresponding xenograft models, although changes in volume of tumor tissues could not be observed at 50 mg/kg body weight twice a day for 14 days, results on the protein expression levels partially supported those in the in vitro experiments. In conclusion, different types of reactions, such as alterations in the glucose and amino acid metabolic pathways, stimulation of stress responses and NK‑cell mediated cytotoxicity and components in the Wnt/β‑catenin signaling pathway, to E7386 in the CRC organoids and corresponding CAFs were observed under conditions with decreased cell viability. However, further mechanistic studies to clarify the relationships with Wnt/β‑catenin signaling pathway and these reactions using preclinical models and biomarker studies using clinical human samples are required for verification of the present preclinical biomarkers.

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