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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

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

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. More... »

PAGES

68

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s12943-019-0972-8

DOI

http://dx.doi.org/10.1186/s12943-019-0972-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1113145828

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30927911


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