Abstract
Abstract Introduction Gastric carcinomas (GCs) are known to progress through the interaction between cancer cells and the tumor stroma. Moreover, recent molecular analysis revealed that the expression of stroma-related genes was significantly associated with poor response to chemotherapy in GCs. However, the specific targets to inhibit the interaction between stroma and cancer cells and to reverse stroma-induced chemoresistance have never been suggested in GCs. Experimental procedures The gene expression in the biopsied GCs tissues from 10 patients, who were treated with preoperative chemotherapy, was analyzed using Nanostring analyzer. We compared the expression pattern of genes involved in the cancer progression panel between chemotherapy response and non-response groups. In addition, we investigated the level of serum interleukin-6 (IL-6) in 39 GCs patients, who underwent curative gastrectomy and postoperative adjuvant chemotherapy. GCs patients were subclassified into recurrence and non-recurrence groups, and the level of IL-6 was compared between two groups. We performed cell proliferation assay, qRT-PCR, ELISA and Western blot to investigate the role of cancer-associated fibroblasts(CAFs)-produced IL-6 on the chemoresistance. Summary of the new data For pretreated biopsied tissues of patients with preoperative chemotherapy, the expression of IL-6 gene in non-response group was significantly higher than response group. In addition, for patients with postoperative adjuvant chemotherapy, the serum level of IL-6 in GCs patients with recurrence was higher than patients without recurrence. Moreover, In vitro studies demonstrate that co-culture with CAFs increased chemoresistance of various GCs cell lines to 5-fluouracil (5-FU) and CAFs-derived IL-6 activated the membrane gp130 and the STAT3 signal pathway in GCs cell lines. When anti-IL-6R monoclonal antibody was added to 5-FU for GCs cell lines in co-culture with CAFs, activation of STAT3 was significantly reduced and apoptosis markers efficiently induced. Conclusion Our study showed that the stroma-induced IL-6 is a key player in the resistance to chemotherapy in GCs. We convinced that the interaction between stroma cells and cancer cells could be inhibited by blockade of IL-6 signal pathway. We suggest the use of IL-6 inhibitor as therapeutic agent to enhance the response to chemotherapy in GCs. Citation Format: In-Hye Ham, Dakeun Lee, Hyejin Jin, Sang Yong Son, Yong Bae Kim, Sang-Uk Han, Hoon Hur. Interleukin-6 is a key player in stroma-induced resistance to chemotherapy for gastric carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4334. doi:10.1158/1538-7445.AM2017-4334
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