[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-345762-105":3,"detail-sidebar-cat-0-en-105":80,"doc-detail-345762-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":73,"head_meta":75,"extra_data":77,"updated_unix":79},105,"en","super-enhancer-formation-in-scirrhous-gastric-cafs-and-the-presence-of-a-stromal-field-in-non-cancerous-tissues-original-article","Super-Enhancer Formation in Scirrhous Gastric CAFs, and the Presence of a Stromal Field in Non-Cancerous Tissues - Original Article","","Scirrhous gastric cancer features aggressive clinical behavior and is dominated by cancer-associated fibroblasts (CAFs), yet the origin and epigenetic basis of scirrhous CAFs remain unclear. Conditioned medium from scirrhous CAFs increases migration of gastric cancer cells by 2–4-fold compared with non-scirrhous CAFs. This phenotype links to TGFβ1 and NF-κB activation and downstream gene upregulation, with heavily acetylated super-enhancers as a therapeutic vulnerability.",{"@graph":14,"@context":72},[15,34,55],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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distinguishes scirrhous gastric CAFs from non-scirrhous CAFs in this study?","Question",{"text":62,"@type":63},"Conditioned medium from scirrhous CAFs markedly increases gastric cancer cell migration (2–4-fold) versus conditioned medium from non-scirrhous CAFs.","Answer",{"name":65,"@type":60,"acceptedAnswer":66},"Which signaling pathways and gene expression changes are associated with the aggressive CAF phenotype?",{"text":67,"@type":63},"The aggressive phenotype is associated with activation of TGFβ1 and NF-κB and increased expression of their downstream genes.",{"name":69,"@type":60,"acceptedAnswer":70},"How do super-enhancers and BET inhibitors relate to CAF-driven migration?",{"text":71,"@type":63},"Scirrhous CAFs contain heavily acetylated super-enhancers, and targeting super-enhancers using BET bromodomain inhibitors (mivebresib and JQ-1) significantly decreases migration-promoting 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Scirrhous Gastric CAFs, and the Presence of a Stromal Field in Non-Cancerous Tissues  \nYoshimi Yasukawa1 | Naoko Hattori1,2  | Yu-Yu Liu1 | Masayuki Tobo2 | Genki Yamagishi2 | Takahiro Irie1 |  \nShigeki Sekine3 | Tohru Kiyono4  | Satoshi Yamashita5  | Yukinori Yamagata6 | Takaki Yoshikawa6 | Yasuyuki Seto7 | Toshikazu Ushijima1   \n1Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan | 2Laboratory of Integrative Metabolic Regulation, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan | 3Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan | 4Project for Prevention of HPV-Related Cancer, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Chiba, Japan | 5Division of Biotechnology, Graduate School of Engineering, Maebashi Institute of Technology, Maebashi, Gunma, Japan | 6Division of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan | 7Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan  \nCorrespondence: Naoko Hattori ([naoko.hattori@gunma-u.ac.jp](naoko.hattori@gunma-u.ac.jp)) | Toshikazu Ushijima ([tushijima142@hoshi.ac.jp](tushijima142@hoshi.ac.jp))  \nReceived: 21 September 2025 | Revised: 18 April 2026 | Accepted: 23 April 2026  \nKeywords: BET inhibitor | enhancer | epigenetics | epigenome | gastric cancer | histone acetylation  \nABSTRACT  \nScirrhous gastric cancer has aggressive clinical courses and is characterized by dominating cancer-associated fibroblasts (CAFs) . However, the origin of scirrhous CAFs remains unclear, and we here aimed to explore the epigenetic basis for scirrhous CAFsand their origin. Conditioned medium (CM) from scirrhous CAFs was shown to have a marked effect (2–4 folds) on the migration of gastric cancer cells compared to that from non-scirrhous CAFs. The aggressive phenotype of scirrhous CAFs was associated with activation of TGFβ1 and NF-κB, along with increased expression of their downstream genes. Scirrhous CAFs had heavily acetylated super-enhancers, and therapeutic targeting of super-enhancers by a BET bromodomain inhibitor, mivebresib and JQ-1, markedly decreased their migration-promoting activity. Notably, in scirrhous gastric cancer patients, normal fibroblasts in non-cancerous tissues also had a strong migration-promoting effect. It was suggested that fibroblasts in the non-cancerous tissue of scirrhous gastric patients have already acquired tumor-promoting capacity, forming a stromal field for scirrhous gastric cancer although its spatial extent remains to be solved.  \n1 | Introduction  \nThe tissue ecosystem plays important roles in cancer development and progression [1], and cancer-associated fibroblasts (CAFs) are a major component. Although many studies have shown that CAFs can support growth, infiltration, and migration of cancer cells [2, 3] via secretion of multiple factors into the stroma, fibroblasts have heterogeneity both in normal and cancer tissues [4], and some CAFs even show an anti-tumoral effect [5] . Such factors, including IGF2, WNT, IL6, and other  \nchemokines or growth factors, have recently attracted attention as therapeutic targets [6–8] . CAFs have been considered to be produced from local normal fibroblasts or mesenchymal stem cells by “education” from cancer cells [9, 10], and classified into three subtypes, myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs) [11–13] . myCAFs are generated by activating the canonical TGFβ pathway, iCAFs are induced by inflammatory pathways including JAK–STAT and NF-κB signaling, and apCAFs are characterized by high expression of MHC class II. CAFs maintain their  \n\n| Abbreviations: CAF, cancer-associated fibroblast; ChIP, chromatin immunoprecipitation; CM, conditioned","cbCaihFXrxSMFTyM","https://ap.wps.com/l/cbCaihFXrxSMFTyM","pdf",13135731,13,"English","# Abstract\n## Key Findings\n## Mechanistic Links\n## Therapeutic Implications\n## Stromal Field Concept\n# Introduction\n## CAF Role in Cancer Progression\n## CAF Heterogeneity and Subtypes\n## Epigenetic and Enhancer Alterations\n## Scirrhous Gastric Cancer Context\n## Study Focus","[{\"question\":\"What distinguishes scirrhous gastric CAFs from non-scirrhous CAFs in this study?\",\"answer\":\"Conditioned medium from scirrhous CAFs markedly increases gastric cancer cell migration (2–4-fold) versus conditioned medium from non-scirrhous CAFs.\"},{\"question\":\"Which signaling pathways and gene expression changes are associated with the aggressive CAF phenotype?\",\"answer\":\"The aggressive phenotype is associated with activation of TGFβ1 and NF-κB and increased expression of their downstream genes.\"},{\"question\":\"How do super-enhancers and BET inhibitors relate to CAF-driven migration?\",\"answer\":\"Scirrhous CAFs contain heavily acetylated super-enhancers, and targeting super-enhancers using BET bromodomain inhibitors (mivebresib and JQ-1) significantly decreases migration-promoting activity.\"}]","Super-Enhancer Formation in Scirrhous Gastric CAFs, and the Presence of a Stromal Field in Non-Cancerous Tissues - Original Article | PDF",1790058812,33]