塑造肿瘤进展的机械线索及其与化学致癌途径的相关性

IF 2.9 3区 医学 Q2 TOXICOLOGY
G. Del Favero
{"title":"塑造肿瘤进展的机械线索及其与化学致癌途径的相关性","authors":"G. Del Favero","doi":"10.1016/j.toxlet.2025.07.058","DOIUrl":null,"url":null,"abstract":"<div><div>Mechanical cues can be seen as an essential part of the tumor microenvironment: these include changes in tissue architecture upon tumor growth, shear stress experienced by the metastatic cells in the bloodstream or the interaction with the extracellular matrix (ECM) and its physiological stiffness. To support the necessary plasticity, cells can efficiently convert physical stimuli into biochemical signals via mechanotransduction. On these premises, the integration of physical cues into cell culture models (e.g. for the development of organ-on-chip platforms or microfluidic devices) not only contributes to the recreation of <em>in vitro</em> models that more faithfully reproduce cellular environment, but also opens up the possibility of novel signaling crossroads. Hypothesizing that physical forces could lever the same molecular targets as those modulated by the xenobiotics, it is possible to postulate that the final cellular response could reflect both contributions, similarly to chemical-mixture toxicology. Pursuing these ambitious questions, ovarian cancer cell models were chosen here to explore these delicate interactions. In addition to being prone to chemoresistance and sensitive to the activity of endocrine disrupting chemicals (EDCs), ovarian cancer cells are exposed to a complex biophysical microenvironment in the abdominal cavity <span><span><sup>[1–3]</sup></span></span>. Retracing molecular events that accompany cancer development and spread, cells were exposed to fluid shear stress, or cultivated on modified ECM stiffness. Exploring signaling pathways inwards and outwards, targeted (microscopy-based) and untargeted (omics-based) analyses were harmonized to investigate whether chemical-driven cascades can affect cell capacity to withstand mechanical stimulation and, in turn, how physical preconditioning can possibly tune cellular response to xenobiotics. Considering molecular effectors that play an acknowledged role in carcinogenesis and might sustain pathway interaction with xenobiotics, a special focus was given to mechanosensitive transcription factors (TFs), including Krüppel-like factors (KLFs), the Nuclear factor erythroid 2-related factor 2 (Nrf2), Sterol regulatory element-binding proteins (SREBPs) or the Yes1 associated transcriptional regulator (YAP1) <span><span>4</span></span>, <span><span>5</span></span>, <span><span>6</span></span>, <span><span>7</span></span>. Tailored physical and chemical manipulation of the TFs translocation patterns enabled the definition of cell-line specific functional performances, such as the regulation of cancer cell proliferation and metabolism, ROS management or the response to cytotoxic insults. Taken together, these data contribute to elucidating molecular mechanisms of toxicity that can be tuned by chemical and physical cues. These promise to be of relevance when extending the use and application of organ-on-chip platforms and support the identification of synergistic or antagonistic interactions in the evaluation of xenobiotics with complex cell culture systems.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Pages S18-S19"},"PeriodicalIF":2.9000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"S05-01 Mechanical cues shaping tumor progression and their relevance for pathways of chemical carcinogenesis\",\"authors\":\"G. Del Favero\",\"doi\":\"10.1016/j.toxlet.2025.07.058\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Mechanical cues can be seen as an essential part of the tumor microenvironment: these include changes in tissue architecture upon tumor growth, shear stress experienced by the metastatic cells in the bloodstream or the interaction with the extracellular matrix (ECM) and its physiological stiffness. To support the necessary plasticity, cells can efficiently convert physical stimuli into biochemical signals via mechanotransduction. On these premises, the integration of physical cues into cell culture models (e.g. for the development of organ-on-chip platforms or microfluidic devices) not only contributes to the recreation of <em>in vitro</em> models that more faithfully reproduce cellular environment, but also opens up the possibility of novel signaling crossroads. Hypothesizing that physical forces could lever the same molecular targets as those modulated by the xenobiotics, it is possible to postulate that the final cellular response could reflect both contributions, similarly to chemical-mixture toxicology. Pursuing these ambitious questions, ovarian cancer cell models were chosen here to explore these delicate interactions. In addition to being prone to chemoresistance and sensitive to the activity of endocrine disrupting chemicals (EDCs), ovarian cancer cells are exposed to a complex biophysical microenvironment in the abdominal cavity <span><span><sup>[1–3]</sup></span></span>. Retracing molecular events that accompany cancer development and spread, cells were exposed to fluid shear stress, or cultivated on modified ECM stiffness. Exploring signaling pathways inwards and outwards, targeted (microscopy-based) and untargeted (omics-based) analyses were harmonized to investigate whether chemical-driven cascades can affect cell capacity to withstand mechanical stimulation and, in turn, how physical preconditioning can possibly tune cellular response to xenobiotics. Considering molecular effectors that play an acknowledged role in carcinogenesis and might sustain pathway interaction with xenobiotics, a special focus was given to mechanosensitive transcription factors (TFs), including Krüppel-like factors (KLFs), the Nuclear factor erythroid 2-related factor 2 (Nrf2), Sterol regulatory element-binding proteins (SREBPs) or the Yes1 associated transcriptional regulator (YAP1) <span><span>4</span></span>, <span><span>5</span></span>, <span><span>6</span></span>, <span><span>7</span></span>. Tailored physical and chemical manipulation of the TFs translocation patterns enabled the definition of cell-line specific functional performances, such as the regulation of cancer cell proliferation and metabolism, ROS management or the response to cytotoxic insults. Taken together, these data contribute to elucidating molecular mechanisms of toxicity that can be tuned by chemical and physical cues. These promise to be of relevance when extending the use and application of organ-on-chip platforms and support the identification of synergistic or antagonistic interactions in the evaluation of xenobiotics with complex cell culture systems.</div></div>\",\"PeriodicalId\":23206,\"journal\":{\"name\":\"Toxicology letters\",\"volume\":\"411 \",\"pages\":\"Pages S18-S19\"},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2025-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Toxicology letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0378427425016418\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"TOXICOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Toxicology letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0378427425016418","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"TOXICOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

机械信号可以被视为肿瘤微环境的重要组成部分:包括肿瘤生长时组织结构的变化、血液中转移细胞所经历的剪切应力或与细胞外基质(ECM)及其生理刚度的相互作用。为了支持必要的可塑性,细胞可以通过机械转导有效地将物理刺激转化为生化信号。在这些前提下,将物理线索整合到细胞培养模型中(例如用于开发器官芯片平台或微流体装置)不仅有助于重建更忠实地再现细胞环境的体外模型,而且还开辟了新的信号交叉路口的可能性。假设物理力量可以影响与外源药物调节的相同的分子目标,就有可能假设最终的细胞反应可以反映这两种作用,类似于化学混合物毒理学。为了追求这些雄心勃勃的问题,我们选择了卵巢癌细胞模型来探索这些微妙的相互作用。卵巢癌细胞除了容易产生化疗耐药和对内分泌干扰物(EDCs)的活性敏感外,还暴露于腹腔内复杂的生物物理微环境中[1-3]。追溯伴随癌症发展和扩散的分子事件,细胞暴露在流体剪切应力下,或在改良的ECM刚度下培养。探索向内和向外的信号通路,靶向(基于显微镜的)和非靶向(基于组学的)分析被协调起来,以研究化学驱动的级联是否会影响细胞承受机械刺激的能力,进而,物理预处理如何可能调节细胞对外源性药物的反应。考虑到在致癌过程中发挥公认作用的分子效应物,并可能维持与外源药物的通路相互作用,我们特别关注了机械敏感转录因子(TFs),包括kr ppel样因子(KLFs)、核因子红系2相关因子2 (Nrf2)、固醇调节元件结合蛋白(SREBPs)或Yes1相关转录调节剂(YAP1) 4,5,6,7。对tf易位模式进行量身定制的物理和化学操作,可以定义细胞系特定的功能性能,如癌细胞增殖和代谢的调节、ROS管理或对细胞毒性损伤的反应。综上所述,这些数据有助于阐明可通过化学和物理线索调节的毒性分子机制。这些有望在扩展器官芯片平台的使用和应用时具有相关性,并支持在评估复杂细胞培养系统的外源性药物时识别协同或拮抗相互作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
S05-01 Mechanical cues shaping tumor progression and their relevance for pathways of chemical carcinogenesis
Mechanical cues can be seen as an essential part of the tumor microenvironment: these include changes in tissue architecture upon tumor growth, shear stress experienced by the metastatic cells in the bloodstream or the interaction with the extracellular matrix (ECM) and its physiological stiffness. To support the necessary plasticity, cells can efficiently convert physical stimuli into biochemical signals via mechanotransduction. On these premises, the integration of physical cues into cell culture models (e.g. for the development of organ-on-chip platforms or microfluidic devices) not only contributes to the recreation of in vitro models that more faithfully reproduce cellular environment, but also opens up the possibility of novel signaling crossroads. Hypothesizing that physical forces could lever the same molecular targets as those modulated by the xenobiotics, it is possible to postulate that the final cellular response could reflect both contributions, similarly to chemical-mixture toxicology. Pursuing these ambitious questions, ovarian cancer cell models were chosen here to explore these delicate interactions. In addition to being prone to chemoresistance and sensitive to the activity of endocrine disrupting chemicals (EDCs), ovarian cancer cells are exposed to a complex biophysical microenvironment in the abdominal cavity [1–3]. Retracing molecular events that accompany cancer development and spread, cells were exposed to fluid shear stress, or cultivated on modified ECM stiffness. Exploring signaling pathways inwards and outwards, targeted (microscopy-based) and untargeted (omics-based) analyses were harmonized to investigate whether chemical-driven cascades can affect cell capacity to withstand mechanical stimulation and, in turn, how physical preconditioning can possibly tune cellular response to xenobiotics. Considering molecular effectors that play an acknowledged role in carcinogenesis and might sustain pathway interaction with xenobiotics, a special focus was given to mechanosensitive transcription factors (TFs), including Krüppel-like factors (KLFs), the Nuclear factor erythroid 2-related factor 2 (Nrf2), Sterol regulatory element-binding proteins (SREBPs) or the Yes1 associated transcriptional regulator (YAP1) 4, 5, 6, 7. Tailored physical and chemical manipulation of the TFs translocation patterns enabled the definition of cell-line specific functional performances, such as the regulation of cancer cell proliferation and metabolism, ROS management or the response to cytotoxic insults. Taken together, these data contribute to elucidating molecular mechanisms of toxicity that can be tuned by chemical and physical cues. These promise to be of relevance when extending the use and application of organ-on-chip platforms and support the identification of synergistic or antagonistic interactions in the evaluation of xenobiotics with complex cell culture systems.
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
Toxicology letters
Toxicology letters 医学-毒理学
CiteScore
7.10
自引率
2.90%
发文量
897
审稿时长
33 days
期刊介绍: An international journal for the rapid publication of novel reports on a range of aspects of toxicology, especially mechanisms of toxicity.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信