来自肿瘤相关巨噬细胞的骨桥蛋白通过活性氧的产生调节口腔鳞状细胞癌的放射敏感性

IF 0.4 Q4 DENTISTRY, ORAL SURGERY & MEDICINE

Journal of Oral and Maxillofacial Surgery Medicine and Pathology Pub Date : 2025-05-15 DOI:10.1016/j.ajoms.2025.05.008

Hikaru Nakashima , Keisuke Yamana , Ryoji Yoshida , Yuichiro Matsuoka , Hidetaka Arita , Shunsuke Gohara , Masatoshi Hirayama , Kenta Kawahara , Akiyuki Hirosue , Yoshikazu Kuwahara , Tomohiko Wakayama , Hideki Nakayama

{"title":"来自肿瘤相关巨噬细胞的骨桥蛋白通过活性氧的产生调节口腔鳞状细胞癌的放射敏感性","authors":"Hikaru Nakashima , Keisuke Yamana , Ryoji Yoshida , Yuichiro Matsuoka , Hidetaka Arita , Shunsuke Gohara , Masatoshi Hirayama , Kenta Kawahara , Akiyuki Hirosue , Yoshikazu Kuwahara , Tomohiko Wakayama , Hideki Nakayama","doi":"10.1016/j.ajoms.2025.05.008","DOIUrl":null,"url":null,"abstract":"<div><h3>Objective</h3><div>This study investigated the role of osteopontin (OPN), a secreted phosphoglycoprotein, in radioresistance in oral squamous cell carcinoma (OSCC).</div></div><div><h3>Methods</h3><div>Samples were collected from 66 patients with OSCC. Immunohistochemistry and double staining were performed on tissue sections to assess OPN levels in stromal and tumor cells and OPN and CD163 colocalization, respectively. Cell lines were treated to simulate cancer-associated environments. Macrophage and fibroblast differentiation were induced; enzyme-linked immunosorbent assays, in situ hybridization, and western blotting were performed; and reactive oxygen species (ROS) were detected to evaluate protein levels and cell responses. Cells were also irradiated for survival analysis.</div></div><div><h3>Results</h3><div>Immunohistochemical analysis of OSCC tissue samples revealed OPN localization predominantly in the tumor stroma, particularly in tumor-associated macrophages (TAMs). In vitro experiments demonstrated that TAM-like cells differentiated from THP-1 monocytes secreted higher OPN levels compared with cancer-associated fibroblast-like cells. Clinicopathological analysis revealed a significant correlation between high OPN expression and poor chemoradiotherapy response. The addition of recombinant OPN to OSCC cell lines decreased radiosensitivity, which was reversed by blocking OPN signaling using anti-CD44 and anti-integrin αVβ3 antibodies. Furthermore, OPN treatment reduced radiation-induced DNA double-strand breaks and ROS production and increased glutathione levels, which were inhibited by blocking OPN-CD44 and OPN-integrin αVβ3 pathways.</div></div><div><h3>Conclusions</h3><div>OPN secreted by the tumor stroma, particularly TAMs, contributes to OSCC radioresistance by regulating ROS and GSH levels via the OPN-CD44 and OPN-integrin αVβ3 axes. Therefore, targeting OPN signaling may represent a novel therapeutic strategy for overcoming radioresistance in OSCC.</div></div>","PeriodicalId":45034,"journal":{"name":"Journal of Oral and Maxillofacial Surgery Medicine and Pathology","volume":"37 6","pages":"Pages 1186-1195"},"PeriodicalIF":0.4000,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Osteopontin derived from tumor-associated macrophages modulates radiosensitivity of oral squamous cell carcinoma via reactive oxygen species production\",\"authors\":\"Hikaru Nakashima , Keisuke Yamana , Ryoji Yoshida , Yuichiro Matsuoka , Hidetaka Arita , Shunsuke Gohara , Masatoshi Hirayama , Kenta Kawahara , Akiyuki Hirosue , Yoshikazu Kuwahara , Tomohiko Wakayama , Hideki Nakayama\",\"doi\":\"10.1016/j.ajoms.2025.05.008\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Objective</h3><div>This study investigated the role of osteopontin (OPN), a secreted phosphoglycoprotein, in radioresistance in oral squamous cell carcinoma (OSCC).</div></div><div><h3>Methods</h3><div>Samples were collected from 66 patients with OSCC. Immunohistochemistry and double staining were performed on tissue sections to assess OPN levels in stromal and tumor cells and OPN and CD163 colocalization, respectively. Cell lines were treated to simulate cancer-associated environments. Macrophage and fibroblast differentiation were induced; enzyme-linked immunosorbent assays, in situ hybridization, and western blotting were performed; and reactive oxygen species (ROS) were detected to evaluate protein levels and cell responses. Cells were also irradiated for survival analysis.</div></div><div><h3>Results</h3><div>Immunohistochemical analysis of OSCC tissue samples revealed OPN localization predominantly in the tumor stroma, particularly in tumor-associated macrophages (TAMs). In vitro experiments demonstrated that TAM-like cells differentiated from THP-1 monocytes secreted higher OPN levels compared with cancer-associated fibroblast-like cells. Clinicopathological analysis revealed a significant correlation between high OPN expression and poor chemoradiotherapy response. The addition of recombinant OPN to OSCC cell lines decreased radiosensitivity, which was reversed by blocking OPN signaling using anti-CD44 and anti-integrin αVβ3 antibodies. Furthermore, OPN treatment reduced radiation-induced DNA double-strand breaks and ROS production and increased glutathione levels, which were inhibited by blocking OPN-CD44 and OPN-integrin αVβ3 pathways.</div></div><div><h3>Conclusions</h3><div>OPN secreted by the tumor stroma, particularly TAMs, contributes to OSCC radioresistance by regulating ROS and GSH levels via the OPN-CD44 and OPN-integrin αVβ3 axes. Therefore, targeting OPN signaling may represent a novel therapeutic strategy for overcoming radioresistance in OSCC.</div></div>\",\"PeriodicalId\":45034,\"journal\":{\"name\":\"Journal of Oral and Maxillofacial Surgery Medicine and Pathology\",\"volume\":\"37 6\",\"pages\":\"Pages 1186-1195\"},\"PeriodicalIF\":0.4000,\"publicationDate\":\"2025-05-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Oral and Maxillofacial Surgery Medicine and Pathology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S221255582500095X\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"DENTISTRY, ORAL SURGERY & MEDICINE\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Oral and Maxillofacial Surgery Medicine and Pathology","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S221255582500095X","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"DENTISTRY, ORAL SURGERY & MEDICINE","Score":null,"Total":0}

引用次数: 0

摘要

目的探讨骨桥蛋白（OPN）在口腔鳞状细胞癌（OSCC）放射耐药中的作用。方法对66例OSCC患者进行标本采集。对组织切片进行免疫组化和双染色，分别评估间质细胞和肿瘤细胞中的OPN水平以及OPN和CD163的共定位。细胞系被处理以模拟癌症相关的环境。诱导巨噬细胞和成纤维细胞分化；进行酶联免疫吸附试验、原位杂交和western blotting；并检测活性氧（ROS）来评估蛋白水平和细胞反应。细胞也被照射以进行存活分析。结果OSCC组织样本的免疫组化分析显示，OPN主要定位于肿瘤间质，特别是肿瘤相关巨噬细胞（tam）。体外实验表明，与癌症相关的成纤维细胞样细胞相比，THP-1单核细胞分化的tam样细胞分泌更高的OPN水平。临床病理分析显示高OPN表达与放化疗反应差有显著相关性。在OSCC细胞系中添加重组OPN可降低放射敏感性，而使用抗cd44和抗整合素αVβ3抗体阻断OPN信号传导可逆转这一现象。此外，通过阻断OPN- cd44和OPN-整合素α v - β3通路，OPN处理降低了辐射诱导的DNA双链断裂和ROS产生，并增加了谷胱甘肽水平。结论肿瘤基质分泌的sopn，特别是tam，通过OPN-CD44和OPN-integrin α v - β3轴调控ROS和GSH水平，参与OSCC的耐辐射作用。因此，靶向OPN信号可能是克服OSCC放射耐药的一种新的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Osteopontin derived from tumor-associated macrophages modulates radiosensitivity of oral squamous cell carcinoma via reactive oxygen species production

Objective

This study investigated the role of osteopontin (OPN), a secreted phosphoglycoprotein, in radioresistance in oral squamous cell carcinoma (OSCC).

Methods

Samples were collected from 66 patients with OSCC. Immunohistochemistry and double staining were performed on tissue sections to assess OPN levels in stromal and tumor cells and OPN and CD163 colocalization, respectively. Cell lines were treated to simulate cancer-associated environments. Macrophage and fibroblast differentiation were induced; enzyme-linked immunosorbent assays, in situ hybridization, and western blotting were performed; and reactive oxygen species (ROS) were detected to evaluate protein levels and cell responses. Cells were also irradiated for survival analysis.

Results

Immunohistochemical analysis of OSCC tissue samples revealed OPN localization predominantly in the tumor stroma, particularly in tumor-associated macrophages (TAMs). In vitro experiments demonstrated that TAM-like cells differentiated from THP-1 monocytes secreted higher OPN levels compared with cancer-associated fibroblast-like cells. Clinicopathological analysis revealed a significant correlation between high OPN expression and poor chemoradiotherapy response. The addition of recombinant OPN to OSCC cell lines decreased radiosensitivity, which was reversed by blocking OPN signaling using anti-CD44 and anti-integrin αVβ3 antibodies. Furthermore, OPN treatment reduced radiation-induced DNA double-strand breaks and ROS production and increased glutathione levels, which were inhibited by blocking OPN-CD44 and OPN-integrin αVβ3 pathways.

Conclusions

OPN secreted by the tumor stroma, particularly TAMs, contributes to OSCC radioresistance by regulating ROS and GSH levels via the OPN-CD44 and OPN-integrin αVβ3 axes. Therefore, targeting OPN signaling may represent a novel therapeutic strategy for overcoming radioresistance in OSCC.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊