{"title":"肿瘤相关成纤维细胞分泌的白细胞介素-6抑制胆道肿瘤的生长","authors":"Naoki Tani, Shimpei Eguchi, Kenjiro Kimura, Ryota Tanaka, Masahiko Kinoshita, Kohei Nishio, Hiroji Shinkawa, G O Ohira, Shogo Tanaka, Masakazu Yashiro, Takeaki Ishizawa","doi":"10.21873/anticanres.17681","DOIUrl":null,"url":null,"abstract":"<p><strong>Background/aim: </strong>Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and can either promote or suppress tumor growth. This study aimed to identify CAFs that inhibit proliferation in biliary tract cancer (BTC) cell lines and explore the underlying mechanisms.</p><p><strong>Materials and methods: </strong>Three BTC cell lines and one pancreatic cancer cell line were treated with conditioned media (CM) from CAFs isolated from BTC specimens. Cell proliferation was assessed, and cytokine profiles in CM were analyzed using protein arrays. Expression of interleukin-6 (IL-6) pathway proteins was examined via western blot and immunohistochemistry (IHC) in BTC tissues. Survival outcomes were analyzed using Kaplan-Meier curves.</p><p><strong>Results: </strong>Some BTC-derived CAFs suppressed cancer cell growth. IL-6 was identified in the CM as a key inhibitory cytokine. IL-6 treatment significantly reduced BTC cell proliferation, accompanied by increased suppressor of cytokine signaling 3 (SOCS3) and decreased activator of transcription 3 (STAT3) expression. In BTC patient tissues, stromal IL-6 expression correlated with improved relapse-free survival (RFS; 60.8 <i>vs.</i> 18.5 months, <i>p</i>=0.008) and overall survival (OS; 61.6 <i>vs.</i> 33.9 months, <i>p</i>=0.05). Patients with positive expression of IL-6 receptor subunits CD130 and CD126, as well as SOCS3, had significantly longer RFS and/or OS compared to negative cases. For CD130, median RFS and OS were 60.8 <i>vs.</i> 17.4 months (<i>p</i>=0.02) and 60.7 <i>vs.</i> 34.6 months (<i>p</i>=0.05), respectively. For SOCS3, RFS and OS were 60.8 <i>vs.</i> 21.1 months (<i>p</i>=0.05) and 51.6 <i>vs.</i> 34.8 months (<i>p</i>=0.04). CD126 positivity was associated with longer RFS (60.8 <i>vs.</i> 21.1 months, <i>p</i>=0.04), but OS did not differ significantly.</p><p><strong>Conclusion: </strong>A subset of CAFs in BTC has tumor-suppressive activity mediated by IL-6, which inhibits cancer cell proliferation <i>via</i> the SOCS3/STAT3 pathway and correlates with better clinical outcomes.</p>","PeriodicalId":8072,"journal":{"name":"Anticancer research","volume":"45 8","pages":"3183-3196"},"PeriodicalIF":1.7000,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Interleukin-6 Secreted from Cancer-associated Fibroblast Inhibits Cancer Growth in Biliary Tract Cancer.\",\"authors\":\"Naoki Tani, Shimpei Eguchi, Kenjiro Kimura, Ryota Tanaka, Masahiko Kinoshita, Kohei Nishio, Hiroji Shinkawa, G O Ohira, Shogo Tanaka, Masakazu Yashiro, Takeaki Ishizawa\",\"doi\":\"10.21873/anticanres.17681\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background/aim: </strong>Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and can either promote or suppress tumor growth. This study aimed to identify CAFs that inhibit proliferation in biliary tract cancer (BTC) cell lines and explore the underlying mechanisms.</p><p><strong>Materials and methods: </strong>Three BTC cell lines and one pancreatic cancer cell line were treated with conditioned media (CM) from CAFs isolated from BTC specimens. Cell proliferation was assessed, and cytokine profiles in CM were analyzed using protein arrays. Expression of interleukin-6 (IL-6) pathway proteins was examined via western blot and immunohistochemistry (IHC) in BTC tissues. Survival outcomes were analyzed using Kaplan-Meier curves.</p><p><strong>Results: </strong>Some BTC-derived CAFs suppressed cancer cell growth. IL-6 was identified in the CM as a key inhibitory cytokine. IL-6 treatment significantly reduced BTC cell proliferation, accompanied by increased suppressor of cytokine signaling 3 (SOCS3) and decreased activator of transcription 3 (STAT3) expression. In BTC patient tissues, stromal IL-6 expression correlated with improved relapse-free survival (RFS; 60.8 <i>vs.</i> 18.5 months, <i>p</i>=0.008) and overall survival (OS; 61.6 <i>vs.</i> 33.9 months, <i>p</i>=0.05). Patients with positive expression of IL-6 receptor subunits CD130 and CD126, as well as SOCS3, had significantly longer RFS and/or OS compared to negative cases. For CD130, median RFS and OS were 60.8 <i>vs.</i> 17.4 months (<i>p</i>=0.02) and 60.7 <i>vs.</i> 34.6 months (<i>p</i>=0.05), respectively. For SOCS3, RFS and OS were 60.8 <i>vs.</i> 21.1 months (<i>p</i>=0.05) and 51.6 <i>vs.</i> 34.8 months (<i>p</i>=0.04). CD126 positivity was associated with longer RFS (60.8 <i>vs.</i> 21.1 months, <i>p</i>=0.04), but OS did not differ significantly.</p><p><strong>Conclusion: </strong>A subset of CAFs in BTC has tumor-suppressive activity mediated by IL-6, which inhibits cancer cell proliferation <i>via</i> the SOCS3/STAT3 pathway and correlates with better clinical outcomes.</p>\",\"PeriodicalId\":8072,\"journal\":{\"name\":\"Anticancer research\",\"volume\":\"45 8\",\"pages\":\"3183-3196\"},\"PeriodicalIF\":1.7000,\"publicationDate\":\"2025-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Anticancer research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.21873/anticanres.17681\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Anticancer research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.21873/anticanres.17681","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景/目的：癌症相关成纤维细胞（Cancer-associated fibroblasts, CAFs）是肿瘤微环境的关键组成部分，可以促进或抑制肿瘤生长。本研究旨在鉴定抑制胆道癌（BTC）细胞系增殖的CAFs，并探讨其潜在机制。材料和方法：将3株BTC细胞株和1株胰腺癌细胞株用条件培养基（CM）处理。评估细胞增殖，并使用蛋白质阵列分析CM中的细胞因子谱。western blot和免疫组化（IHC）检测BTC组织中白细胞介素-6 （IL-6）通路蛋白的表达。生存结果采用Kaplan-Meier曲线分析。结果：一些btc衍生的CAFs抑制了癌细胞的生长。IL-6在CM中被鉴定为关键的抑制细胞因子。IL-6处理显著降低BTC细胞增殖，同时细胞因子信号传导抑制因子3 （SOCS3）表达增加，转录激活因子3 （STAT3）表达降低。在BTC患者组织中，间质IL-6表达与改善无复发生存期(RFS；60.8 vs 18.5个月，p=0.008)和总生存期(OS；61.6个月vs 33.9个月，p=0.05)。IL-6受体亚单位CD130和CD126以及SOCS3阳性表达的患者与阴性患者相比，RFS和/或OS明显更长。对于CD130，中位RFS和OS分别为60.8 vs 17.4个月（p=0.02）和60.7 vs 34.6个月（p=0.05）。SOCS3的RFS和OS分别为60.8 vs. 21.1个月（p=0.05）和51.6 vs. 34.8个月（p=0.04）。CD126阳性与较长的RFS相关（60.8 vs 21.1个月，p=0.04），但OS无显著差异。结论：BTC中一部分CAFs具有IL-6介导的肿瘤抑制活性，通过SOCS3/STAT3通路抑制肿瘤细胞增殖，与较好的临床预后相关。
Interleukin-6 Secreted from Cancer-associated Fibroblast Inhibits Cancer Growth in Biliary Tract Cancer.
Background/aim: Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and can either promote or suppress tumor growth. This study aimed to identify CAFs that inhibit proliferation in biliary tract cancer (BTC) cell lines and explore the underlying mechanisms.
Materials and methods: Three BTC cell lines and one pancreatic cancer cell line were treated with conditioned media (CM) from CAFs isolated from BTC specimens. Cell proliferation was assessed, and cytokine profiles in CM were analyzed using protein arrays. Expression of interleukin-6 (IL-6) pathway proteins was examined via western blot and immunohistochemistry (IHC) in BTC tissues. Survival outcomes were analyzed using Kaplan-Meier curves.
Results: Some BTC-derived CAFs suppressed cancer cell growth. IL-6 was identified in the CM as a key inhibitory cytokine. IL-6 treatment significantly reduced BTC cell proliferation, accompanied by increased suppressor of cytokine signaling 3 (SOCS3) and decreased activator of transcription 3 (STAT3) expression. In BTC patient tissues, stromal IL-6 expression correlated with improved relapse-free survival (RFS; 60.8 vs. 18.5 months, p=0.008) and overall survival (OS; 61.6 vs. 33.9 months, p=0.05). Patients with positive expression of IL-6 receptor subunits CD130 and CD126, as well as SOCS3, had significantly longer RFS and/or OS compared to negative cases. For CD130, median RFS and OS were 60.8 vs. 17.4 months (p=0.02) and 60.7 vs. 34.6 months (p=0.05), respectively. For SOCS3, RFS and OS were 60.8 vs. 21.1 months (p=0.05) and 51.6 vs. 34.8 months (p=0.04). CD126 positivity was associated with longer RFS (60.8 vs. 21.1 months, p=0.04), but OS did not differ significantly.
Conclusion: A subset of CAFs in BTC has tumor-suppressive activity mediated by IL-6, which inhibits cancer cell proliferation via the SOCS3/STAT3 pathway and correlates with better clinical outcomes.
期刊介绍：
ANTICANCER RESEARCH is an independent international peer-reviewed journal devoted to the rapid publication of high quality original articles and reviews on all aspects of experimental and clinical oncology. Prompt evaluation of all submitted articles in confidence and rapid publication within 1-2 months of acceptance are guaranteed.
ANTICANCER RESEARCH was established in 1981 and is published monthly (bimonthly until the end of 2008). Each annual volume contains twelve issues and index. Each issue may be divided into three parts (A: Reviews, B: Experimental studies, and C: Clinical and Epidemiological studies).
Special issues, presenting the proceedings of meetings or groups of papers on topics of significant progress, will also be included in each volume. There is no limitation to the number of pages per issue.
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