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Targeting interleukin-6 as a strategy to overcome stroma-induced resistance to chemotherapy in gastric cancer

Authors
Ham, IH  | Oh, HJ | Jin, H | Bae, CA | Jeon, SM | Choi, KS  | Son, SY  | Han, SU  | Brekken, RA | Lee, D  | Hur, H
Citation
Molecular cancer, 18. : 68-68, 2019
Journal Title
Molecular cancer
ISSN
1476-4598
Abstract
BACKGROUND: Although the tumor stroma in solid tumors like gastric cancer (GC) plays a crucial role in chemo-resistance, specific targets to inhibit the interaction between the stromal and cancer cells have not yet been utilized in clinical practice. The present study aims to determine whether cancer-associated fibroblasts (CAFs), a major component of the tumor stroma, confer chemotherapeutic resistance to GC cells, and to discover potential targets to improve chemo-response in GC.
METHODS: To identify CAF-specific proteins and signal transduction pathways affecting chemo-resistance in GC cells, secretome and transcriptome analyses were performed. We evaluated the inhibiting effect of CAF-specific protein in in vivo and in vitro models and investigated the expression of CAF-specific protein in human GC tissues.
RESULTS: Secretome and transcriptome data revealed that interleukin-6 (IL-6) is a CAF-specific secretory protein that protects GC cells via paracrine signaling. Furthermore, CAF-induced activation of the Janus kinase 1-signal transducer and activator of transcription 3 signal transduction pathway confers chemo-resistance in GC cells. CAF-mediated inhibition of chemotherapy-induced apoptosis was abrogated by the anti-IL-6 receptor monoclonal antibody tocilizumab in various experimental models. Clinical data revealed that IL-6 was prominently expressed in the stromal portion of GC tissues, and IL-6 upregulation in GC tissues was correlated with poor responsiveness to chemotherapy.
CONCLUSIONS: Our data provide plausible evidence for crosstalk between GC cells and CAFs, wherein IL-6 is a key contributor to chemoresistance. These findings suggest the potential therapeutic application of IL-6 inhibitors to enhance the responsiveness to chemotherapy in GC.
Keywords

MeSH

DOI
10.1186/s12943-019-0972-8
PMID
30927911
Appears in Collections:
Journal Papers > Research Organization > Inflamm-aging Translational Research Center
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
Journal Papers > School of Medicine / Graduate School of Medicine > Surgery
Journal Papers > School of Medicine / Graduate School of Medicine > Pathology
Ajou Authors
손, 상용  |  이, 다근  |  최, 경숙  |  한, 상욱  |  함, 인혜  |  허, 훈
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