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

Cited 153 time in Web of Science Cited 155 time in Scopus
Authors

Ham, In-Hye; Oh, Hye Jeong; Jin, Hyejin; Bae, Cheong A.; Jeon, Sang-Min; Choi, Kyeong Sook; Son, Sang-Yong; Han, Sang-Uk; Brekken, Rolf A.; Lee, Dakeun; Hur, Hoon

Issue Date
2019-03
Publisher
BioMed Central
Citation
Molecular Cancer, Vol.18 No.1, p. 68
Abstract
BackgroundAlthough 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.MethodsTo 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.ResultsSecretome 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.ConclusionsOur 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.
ISSN
1476-4598
URI
https://hdl.handle.net/10371/200535
DOI
https://doi.org/10.1186/s12943-019-0972-8
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  • College of Pharmacy
  • Department of Pharmacy
Research Area Cancer Origin, Metabolism, Toxicology

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