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Open Access 01-12-2018 | Primary research

Activated gastric cancer-associated fibroblasts contribute to the malignant phenotype and 5-FU resistance via paracrine action in gastric cancer

Authors: Yongchen Ma, Jing Zhu, Shanwen Chen, Tengyu Li, Ju Ma, Shihao Guo, Jianwen Hu, Taohua Yue, Junling Zhang, Pengyuan Wang, Xin Wang, Guowei Chen, Yucun Liu

Published in: Cancer Cell International | Issue 1/2018

Abstract

Background

Cancer-associated fibroblasts (CAFs) play important roles in tumor progression. However, the behaviors of activated CAFs in gastric cancer remain to be determined. The aim of the present study was to investigate the correlations between activated gastric CAFs and the prognosis of patients with gastric cancer, and to determine the effects of activated CAFs on the malignant phenotype and 5-fluorouracil resistance in this cancer.

Methods

Ninety-five patients with primary gastric cancer were enrolled in this study. Activation states of gastric CAFs were evaluated by immunohistochemistry. A modified method for the primary culture of gastric CAFs was employed. Types of CAFs and activation states were identified by immunocytochemical and immunofluorescent staining. Cell co-culture and gastric CAF conditioned medium transfer models were established to investigate the paracrine effects of activated CAFs on the migration and invasion of gastric cell lines. The half maximal inhibitory concentration of 5-fluorouracil and levels of cell apoptosis were examined using cell viability assay and flow cytometry, respectively. Protein expression levels of associated molecules were measured by Western blotting.

Results

Kaplan–Meier survival curves showed that activated gastric CAFs identified via fibroblast activation protein were significantly related to poorer cumulative survival in gastric cancer patients. Five strains of CAFs were successfully cultured via the modified culture method, and three gastric CAFs strains were identified as activated gastric CAFs. The migration and invasion abilities of gastric cells were significantly enhanced in both the co-culture group and the conditioned medium group. The half maximal inhibitory concentration for 5-fluorouracil in BGC-823 cells was elevated after treatment with conditioned medium, and early apoptosis was inhibited. Additionally, an obvious elevation of epithelial–mesenchymal transition level was observed in the conditioned medium group.

Conclusions

Activated gastric CAFs correlate with a poor prognosis of cancer patients and may contribute to the malignant phenotype and the development of resistance to 5-fluorouracil via paracrine action in gastric cancer. Gastric CAFs with a specific activation state might be used as a tumor biomarker within the microenvironment for prognosis and as a new therapeutic target for chemoresistant gastric cancer.

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Title: Activated gastric cancer-associated fibroblasts contribute to the malignant phenotype and 5-FU resistance via paracrine action in gastric cancer
Authors: Yongchen Ma
Jing Zhu
Shanwen Chen
Tengyu Li
Ju Ma
Shihao Guo
Jianwen Hu
Taohua Yue
Junling Zhang
Pengyuan Wang
Xin Wang
Guowei Chen
Yucun Liu
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Cancer Cell International / Issue 1/2018
Electronic ISSN: 1475-2867
DOI: https://doi.org/10.1186/s12935-018-0599-7

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