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Cytokine-driven positive feedback loop organizes fibroblast transformation and facilitates gastric cancer progression

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Abstract

Background

Gastric cancer (GC) is a malignancy that belongs to one of the most common leading causes of cancer death. Cancer-associated fibroblasts (CAFs) promote the GC cells’ malignant behavior. It is still unknown how GC converts normal fibroblasts (NFs) to CAFs.

Methods

GC cells were co-cultured with NFs. Bioinformatics was used to analyze the genes and signaling pathways that were changed in fibroblast. RT-PCR, western blot, and Elisa assays were used to detect the expression of cytokines in fibroblast and condition medium. Western blot and immunofluorescence demonstrated activation of relevant pathways in CAFs-like cells. Transwell, scrape, colony formation, and CCK-8 assays were performed to reveal the feedback effect of CAFs-like cells on GC cells.

Results

GC promoted the conversion of NFs to CAFs by secreting Interleukin 17A (IL-17). It included both morphological and molecular marker changes. This process was achieved by activating the nuclear factor-κB (NF-κB) pathway. On the other hand, CAFs cells could secrete C-X-C Motif Chemokine Ligand 8 (IL-8, IL-8), which promoted the malignant phenotype of GC cells. In this way, a feedback loop of mutual influence was constructed in the GC and tumor microenvironment (TME).

Conclusions

Our research proved a novel model of GC-educated NFs. GC-IL-17-fibroblast-IL-8-GC axis might be a potential pathway of the interaction between GC and TME.

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Data availability

No additional data are available.

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Funding

Liaoning S&T Project (2019-ZD-0592).

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Authors and Affiliations

  1. Department of General Surgery, Liaoning Province Cancer Hospital and Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning, China

    Xian-Kui Cao, Bin Xie, Yang Shao & Jie Lin

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All the authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

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Correspondence to Jie Lin.

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The study protocol was approved by the Faculty of Science Ethics Committee at Liaoning Cancer Hospital and Institute (20191215). All participants provided expressed consent for publication of their details. All personal information have been made anonymous.

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All patients included in the study signed informed consent forms before surgery at the Liaoning Province Cancer Hospital and Institute.

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Cao, XK., Xie, B., Shao, Y. et al. Cytokine-driven positive feedback loop organizes fibroblast transformation and facilitates gastric cancer progression. Clin Transl Oncol 24, 1354–1364 (2022). https://doi.org/10.1007/s12094-022-02777-z

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