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

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

Research output: Contribution to journalArticle

14 Scopus citations

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.

Original languageEnglish (US)
Article number68
JournalMolecular Cancer
Volume18
Issue number1
DOIs
StatePublished - Mar 30 2019

Keywords

  • Cancer-associated fibroblasts
  • Chemo-resistance
  • Gastric cancer
  • Interleukin-6
  • Jak1-STAT3
  • Tocilizumab
  • Tumor microenvironment

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

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    Ham, I. H., Oh, H. J., Jin, H., Bae, C. A., Jeon, S. M., Choi, K. S., Son, S. Y., Han, S. U., Brekken, R. A., Lee, D., & Hur, H. (2019). Targeting interleukin-6 as a strategy to overcome stroma-induced resistance to chemotherapy in gastric cancer. Molecular Cancer, 18(1), [68]. https://doi.org/10.1186/s12943-019-0972-8