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Gastric Cancer
Published in: Gastric Cancer 4/2021

01-07-2021 | Gastric Cancer | Original Article

Drug-exposed cancer-associated fibroblasts facilitate gastric cancer cell progression following chemotherapy

Authors: Takahiro Ishii, Ayako Suzuki, Takeshi Kuwata, Shoshi Hisamitsu, Hiroko Hashimoto, Yuuki Ohara, Kazuyoshi Yanagihara, Shuichi Mitsunaga, Takayuki Yoshino, Takahiro Kinoshita, Atsushi Ochiai, Kohei Shitara, Genichiro Ishii

Published in: Gastric Cancer | Issue 4/2021

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Abstract

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.
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Metadata
Title
Drug-exposed cancer-associated fibroblasts facilitate gastric cancer cell progression following chemotherapy
Authors
Takahiro Ishii
Ayako Suzuki
Takeshi Kuwata
Shoshi Hisamitsu
Hiroko Hashimoto
Yuuki Ohara
Kazuyoshi Yanagihara
Shuichi Mitsunaga
Takayuki Yoshino
Takahiro Kinoshita
Atsushi Ochiai
Kohei Shitara
Genichiro Ishii
Publication date
01-07-2021
Publisher
Springer Singapore
Published in
Gastric Cancer / Issue 4/2021
Print ISSN: 1436-3291
Electronic ISSN: 1436-3305
DOI
https://doi.org/10.1007/s10120-021-01174-9

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