Takahiro Ishii1,2,3,4, Ayako Suzuki5, Takeshi Kuwata4, Shoshi Hisamitsu1, Hiroko Hashimoto1, Yuuki Ohara1, Kazuyoshi Yanagihara6, Shuichi Mitsunaga6,7, Takayuki Yoshino2, Takahiro Kinoshita8, Atsushi Ochiai6, Kohei Shitara2, Genichiro Ishii9,10,11. 1. Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. 2. Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. 3. Courses of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, Japan. 4. Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, National Cancer Center, Kashiwa, Chiba, Japan. 5. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan. 6. Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. 7. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. 8. Department of Gastric Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. 9. Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. gishii@east.ncc.go.jp. 10. Courses of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, Japan. gishii@east.ncc.go.jp. 11. Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, National Cancer Center, Kashiwa, Chiba, Japan. gishii@east.ncc.go.jp.
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.
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.
Entities:
Keywords:
Cancer treatment; Gp130; RNA-sequencing; Tumor microenvironment
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