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인터루킨-6 를 표적으로 하여 위암에서 기질유발 항암제 저항성을 극복하기 위한 연구
- Alternative Title
- Targeting interleukin-6 as a strategy to overcome stroma-induced resistance to chemotherapy in gastric carcinomas
- Author(s)
- 함인혜
- Alternative Author(s)
- In-Hye Ham
- Advisor
- 허훈
- Department
- 일반대학원 의생명과학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2018-02
- Language
- eng
- Alternative Abstract
- In solid tumors such as gastric cancer (GC), the stroma plays a crucial role in decreasing responsiveness to chemotherapy. However, specific targets have not yet been identified to inhibit the interaction between stroma and cancer cells to inhibit stroma-induced chemotherapeutic resistance. The present study aimed to determine whether cancer-associated fibroblasts (CAFs), a major component of tumor stroma, confer chemotherapeutic resistance in GC and what drives this interaction resulting in chemotherapeutic resistance in in vitro and in vivo experimental models. Transcriptome analysis and validation revealed that interleukin-6 (IL-6) is a CAF-specific secretory protein that activates GC cells via paracrine signaling. Furthermore, the IL-6/Jak1/STAT3 signal transduction pathway in CAFs conferred stroma-induced resistance to chemotherapy in GC cells. When monoclonal anti-IL-6R antibody (tocilizumab) was added to chemotherapeutic agents, CAF-induced inhibition of apoptosis was notably abrogated in GC cells. Furthermore, tocilizumab had the same synergistic effects during chemotherapy on GC xenograft tumors in animal models. Clinical data revealed that IL-6 was prominently expressed in the stromal portion in GC tissues; consequently, upregulation of stroma-related genes, including IL-6, in GC tissues was correlated with poor responsiveness to chemotherapy. Our data provide plausible evidence for crosstalk between GC cells and CAFs, wherein IL-6 plays a key role in initiating chemotherapeutic resistance. The present findings suggest the use of IL-6 inhibitor as therapeutic agent to enhance responsiveness to chemotherapy in GCs.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Biomedical Sciences > 4. Theses(Ph.D)
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