Novel treatment strategy targeting interleukin-6 induced by cancer associated fibroblasts for peritoneal metastasis of gastric cancer
Abstract Cancer-associated fibroblasts (CAFs) are a crucial component in the tumor microenvironment (TME) of peritoneal metastasis (PM), where they contribute to tumor progression and metastasis via secretion of interleukin-6 (IL-6). Here, we investigated the role of IL-6 in PM of gastric cancer (GC...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-88033-0 |
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| author | Ema Mitsui Satoru Kikuchi Tomohiro Okura Hiroshi Tazawa Yuta Une Noriyuki Nishiwaki Shinji Kuroda Kazuhiro Noma Shunsuke Kagawa Toshiaki Ohara Junko Ohtsuka Rieko Ohki Toshiyoshi Fujiwara |
| author_facet | Ema Mitsui Satoru Kikuchi Tomohiro Okura Hiroshi Tazawa Yuta Une Noriyuki Nishiwaki Shinji Kuroda Kazuhiro Noma Shunsuke Kagawa Toshiaki Ohara Junko Ohtsuka Rieko Ohki Toshiyoshi Fujiwara |
| author_sort | Ema Mitsui |
| collection | DOAJ |
| description | Abstract Cancer-associated fibroblasts (CAFs) are a crucial component in the tumor microenvironment (TME) of peritoneal metastasis (PM), where they contribute to tumor progression and metastasis via secretion of interleukin-6 (IL-6). Here, we investigated the role of IL-6 in PM of gastric cancer (GC) and assessed whether anti-IL-6 receptor antibody (anti-IL-6R Ab) could inhibit PM of GC. We conducted immunohistochemical analysis of IL-6 and α-smooth muscle (α-SMA) expressions in clinical samples of GC and PM, and investigated the interactions between CAFs and GC cells in vitro. Anti-tumor effects of anti-IL-6R Ab on PM of GC were investigated in an orthotopic murine PM model. IL-6 expression was significantly correlated with α-SMA expression in clinical samples of GC, and higher IL-6 expression in the primary tumor was associated with poor prognosis of GC. Higher IL-6 and α-SMA expressions were also observed in PM of GC. In vitro, differentiation of fibroblasts into CAFs and chemoresistance were observed in GC cells cocultured with fibroblasts. Anti-IL-6R Ab inhibited the progression of PM in GC cells cocultured with fibroblasts in the orthotopic mouse model but could not inhibit the progression of PM consisting of GC cells alone. IL-6 expression in the TME was associated with poor prognosis of GC, and CAFs were associated with establishment and progression of PM via IL-6. Anti-IL-6R Ab could inhibit PM of GC by the blockade of IL-6 secreted by CAFs, which suggests its therapeutic potential for PM of GC. |
| format | Article |
| id | doaj-art-a17c852293e84492ab862790d283f15a |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-a17c852293e84492ab862790d283f15a2025-01-26T12:27:01ZengNature PortfolioScientific Reports2045-23222025-01-0115111110.1038/s41598-025-88033-0Novel treatment strategy targeting interleukin-6 induced by cancer associated fibroblasts for peritoneal metastasis of gastric cancerEma Mitsui0Satoru Kikuchi1Tomohiro Okura2Hiroshi Tazawa3Yuta Une4Noriyuki Nishiwaki5Shinji Kuroda6Kazuhiro Noma7Shunsuke Kagawa8Toshiaki Ohara9Junko Ohtsuka10Rieko Ohki11Toshiyoshi Fujiwara12Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesLaboratory of Fundamental Oncology, National Cancer Center Research InstituteLaboratory of Fundamental Oncology, National Cancer Center Research InstituteDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAbstract Cancer-associated fibroblasts (CAFs) are a crucial component in the tumor microenvironment (TME) of peritoneal metastasis (PM), where they contribute to tumor progression and metastasis via secretion of interleukin-6 (IL-6). Here, we investigated the role of IL-6 in PM of gastric cancer (GC) and assessed whether anti-IL-6 receptor antibody (anti-IL-6R Ab) could inhibit PM of GC. We conducted immunohistochemical analysis of IL-6 and α-smooth muscle (α-SMA) expressions in clinical samples of GC and PM, and investigated the interactions between CAFs and GC cells in vitro. Anti-tumor effects of anti-IL-6R Ab on PM of GC were investigated in an orthotopic murine PM model. IL-6 expression was significantly correlated with α-SMA expression in clinical samples of GC, and higher IL-6 expression in the primary tumor was associated with poor prognosis of GC. Higher IL-6 and α-SMA expressions were also observed in PM of GC. In vitro, differentiation of fibroblasts into CAFs and chemoresistance were observed in GC cells cocultured with fibroblasts. Anti-IL-6R Ab inhibited the progression of PM in GC cells cocultured with fibroblasts in the orthotopic mouse model but could not inhibit the progression of PM consisting of GC cells alone. IL-6 expression in the TME was associated with poor prognosis of GC, and CAFs were associated with establishment and progression of PM via IL-6. Anti-IL-6R Ab could inhibit PM of GC by the blockade of IL-6 secreted by CAFs, which suggests its therapeutic potential for PM of GC.https://doi.org/10.1038/s41598-025-88033-0Peritoneal metastasisGastric cancerInterleukin-6Cancer-associated fibroblastsInterleukin-6 receptor antibody |
| spellingShingle | Ema Mitsui Satoru Kikuchi Tomohiro Okura Hiroshi Tazawa Yuta Une Noriyuki Nishiwaki Shinji Kuroda Kazuhiro Noma Shunsuke Kagawa Toshiaki Ohara Junko Ohtsuka Rieko Ohki Toshiyoshi Fujiwara Novel treatment strategy targeting interleukin-6 induced by cancer associated fibroblasts for peritoneal metastasis of gastric cancer Scientific Reports Peritoneal metastasis Gastric cancer Interleukin-6 Cancer-associated fibroblasts Interleukin-6 receptor antibody |
| title | Novel treatment strategy targeting interleukin-6 induced by cancer associated fibroblasts for peritoneal metastasis of gastric cancer |
| title_full | Novel treatment strategy targeting interleukin-6 induced by cancer associated fibroblasts for peritoneal metastasis of gastric cancer |
| title_fullStr | Novel treatment strategy targeting interleukin-6 induced by cancer associated fibroblasts for peritoneal metastasis of gastric cancer |
| title_full_unstemmed | Novel treatment strategy targeting interleukin-6 induced by cancer associated fibroblasts for peritoneal metastasis of gastric cancer |
| title_short | Novel treatment strategy targeting interleukin-6 induced by cancer associated fibroblasts for peritoneal metastasis of gastric cancer |
| title_sort | novel treatment strategy targeting interleukin 6 induced by cancer associated fibroblasts for peritoneal metastasis of gastric cancer |
| topic | Peritoneal metastasis Gastric cancer Interleukin-6 Cancer-associated fibroblasts Interleukin-6 receptor antibody |
| url | https://doi.org/10.1038/s41598-025-88033-0 |
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