Mass spectrometry imaging of endogenous metabolites in response to doxorubicin in a novel 3D osteosarcoma cell culture model

Palubeckait? Ieva; Crooks Lucy; Smith David P.; Cole Laura M.; Bram Heijs; Le Maitre Christine; Clench Malcolm R.; Cross Neil A.

摘要

Abstract > Three‐dimensional (3D) cell culture is a rapidly emerging field, which mimics some of the physiological conditions of human tissues. In cancer biology, it is considered a useful tool in predicting <fi>in vivo</fi> chemotherapy responses, compared with conventional two‐dimensional (2D) cell culture. We have developed a novel 3D cell culture model of osteosarcoma composed of aggregated proliferative tumour spheroids, which shows regions of tumour heterogeneity formed by aggregated spheroids of polyclonal tumour cells. Aggregated spheroids show local necrotic and apoptotic regions and have sizes suitable for the study of spatial distribution of metabolites by mass spectrometry imaging (MSI). We have used this model to perform a proof‐of‐principle study showing a heterogeneous distribution of endogenous metabolites that colocalise with the necrotic core and apoptotic regions in this model. Cytotoxic chemotherapy (doxorubicin) responses were significantly attenuated in our 3D cell culture model compared with those of standard cell culture, as determined by resazurin assay, despite sufficient doxorubicin diffusion demonstrated by localisation throughout the 3D constructs. Finally, changes to the distribution of endogenous metabolites in response to doxorubicin were readily detected by MSI. Principal component analysis identified 50 metabolites which differed most in their abundance between treatment groups, and of these, 10 were identified by both in‐software t test and mixed‐effects analysis of variance (ANOVA). Subsequent independent MSIs of identified species were consistent with principle component analysis findings. This proof‐of‐principle study shows for the first time that chemotherapy‐induced changes in metabolite abundance and distribution may be determined in 3D cell culture by MSI, highlighting this method as a potentially useful tool in the elucidation of chemotherapy responses as an alternative to <fi>in vivo</fi> testing. </abstract> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> <div class="translation abstracttxt"> <span class="zhankaihshouqi fivelineshidden" id="abstract"> <span>机译：</span><Abstract Type =“Main”XML：Lang =“en”> <标题类型=“main”>抽象</ title> > 三维（3D）细胞培养是一种快速的新兴领域，模仿一些人体组织的生理条件。在癌症生物学中，它被认为是预测的有用工具 <fi>在体内</ fi> 与常规二维（2D）细胞培养相比化疗反应。我们开发了由聚集的增殖性肿瘤球状体组成的骨肉瘤的新型3D细胞培养模型，其表示通过多克隆肿瘤细胞的聚集球体形成的肿瘤异质性区域。聚集的球体显示局部坏死和凋亡区域，并且具有适合于通过质谱成像（MSI）的代谢物的空间分布研究的尺寸。我们使用该模型来执行原则上的证据，显示内源性代谢物的异质分布，即该模型中的坏死核心和凋亡区域。与标准细胞培养的3D细胞培养模型相比，通过转基脲测定确定的三种细胞培养模型中的细胞毒性化疗（多柔比星）反应显着衰减，尽管通过在整个3D构建体中定位证明了足够的多柔比星扩散。最后，通过MSI容易地检测到响应于多柔比星的内源代谢物分布的变化。主成分分析确定了50种代谢物，其在治疗组之间最丰富的差异，其中10个由软件鉴定出来 t </ i> 方差（ANOVA）的测试和混合效应分析。所识别物种的后续独立MSIS与原理成分分析结果一致。该原则上的研究表明，MSI的3D细胞培养中首次在3D细胞培养中测定化疗诱导的变化，突出了该方法作为阐明化疗响应的潜在工具作为替代方案 <fi>在体内</ fi> 测试。 </ p> </摘要> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> </div> <div class="record"> <h2 class="all_title" id="enpatent33" > 著录项</h2> <ul> <li> <span class="lefttit">来源</span> <div style="width: 86%;vertical-align: text-top;display: inline-block;"> <a href='/journal-foreign-34906/'>《Journal of mass spectrometry: JMS 》</a> <b style="margin: 0 2px;">|</b><span>2020年第4期</span><b style="margin: 0 2px;">|</b> <span>共11页</span> </div> </li> <li> <div class="author"> <span class="lefttit">作者</span> <p id="fAuthorthree" class="threelineshidden zhankaihshouqi"> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Palubeckait? Ieva&option=202" target="_blank" rel="nofollow">Palubeckait? Ieva;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Crooks Lucy&option=202" target="_blank" rel="nofollow">Crooks Lucy;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Smith David P.&option=202" target="_blank" rel="nofollow">Smith David P.;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Cole Laura M.&option=202" target="_blank" rel="nofollow">Cole Laura M.;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Bram Heijs&option=202" target="_blank" rel="nofollow">Bram Heijs;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Le Maitre Christine&option=202" target="_blank" rel="nofollow">Le Maitre Christine;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Clench Malcolm R.&option=202" target="_blank" rel="nofollow">Clench Malcolm R.;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Cross Neil A.&option=202" target="_blank" rel="nofollow">Cross Neil A.;</a> </p> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zkzz" style="display: none;">展开▼</span> </div> </li> <li> <div style="display: flex;"> <span class="lefttit">作者单位</span> <div style="position: relative;margin-left: 3px;max-width: 639px;"> <div class="threelineshidden zhankaihshouqi" id="fOrgthree"> <p>Department of PathologyLeiden University Medical CenterPO Box 9600 2300 RC Leiden The Netherlands;</p> <p>Centre for Mass Spectrometry Imaging Biomolecular Sciences Research CentreSheffield Hallam UniversityHoward Street Sheffield S1 1WB UK;</p> <p>Centre for Mass Spectrometry Imaging Biomolecular Sciences Research CentreSheffield Hallam UniversityHoward Street Sheffield S1 1WB UK;</p> <p>Centre for Mass Spectrometry Imaging Biomolecular Sciences Research CentreSheffield Hallam UniversityHoward Street Sheffield S1 1WB UK;</p> <p>Center for Proteomics and MetabolomicsLeiden University Medical CenterPO Box 9600 2300 RC Leiden The Netherlands;</p> <p>Centre for Mass Spectrometry Imaging Biomolecular Sciences Research CentreSheffield Hallam UniversityHoward Street Sheffield S1 1WB UK;</p> <p>Centre for Mass Spectrometry Imaging Biomolecular Sciences Research CentreSheffield Hallam UniversityHoward Street Sheffield S1 1WB UK;</p> <p>Centre for Mass Spectrometry Imaging Biomolecular Sciences Research CentreSheffield Hallam UniversityHoward Street Sheffield S1 1WB UK;</p> </div> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zhdw" style="display: none;">展开▼</span> </div> </div> </li> <li> <span class="lefttit">收录信息</span> <span style="width: 86%;vertical-align: text-top;display: inline-block;"></span> </li> <li> <span class="lefttit">原文格式</span> <span>PDF</span> </li> <li> <span class="lefttit">正文语种</span> <span>eng</span> </li> <li> <span class="lefttit">中图分类</span> <span> <a href="https://www.zhangqiaokeyan.com/clc/1187.html" title="分析化学">分析化学 ;</a></span> </li> <li class="antistop"> <span class="lefttit">关键词</span> <p style="width: 86%;vertical-align: text-top;"> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=3D cell culture&option=203" rel="nofollow">3D cell culture;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=doxorubicin&option=203" rel="nofollow">doxorubicin;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=mass spectrometry imaging&option=203" rel="nofollow">mass spectrometry imaging;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=multivariate analysis&option=203" rel="nofollow">multivariate analysis;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=osteosarcoma&option=203" rel="nofollow">osteosarcoma;</a> </p> <div class="translation"> 机译：3D细胞培养;多柔比星;质谱成像;多变量分析;骨肉瘤; </div> </li> </ul> </div> </div> <div class="literature cardcommon"> <div class="similarity "> <h3 class="all_title" id="enpatent66">相似文献</h3> <div class="similaritytab clearfix"> <ul> <li class="active" >外文文献</li> <li >中文文献</li> <li >专利</li> </ul> </div> <div class="similarity_details"> <ul > <li> <div> <b>1. </b><a class="enjiyixqcontent" href="/journal-foreign-detail/0704025633109.html">Mass spectrometry imaging of endogenous metabolites in response to doxorubicin in a novel 3D osteosarcoma cell culture model</a> <b>[J]</b> . <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Palubeckait? 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through syncronized plant cell cultures</a> <b>[P]</b> . <span> 外国专利：  EP2386626B1 </span> <span> . 2016-10-26</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：通过同步化植物细胞培养的次级代谢产物大量生产的稳定性 </span> </p> </li> <li> <div> <b>4. </b><a class="enjiyixqcontent" href="/patent-detail/06130412041943.html">STABILITY OF SECONDARY METABOLITE MASS PRODUCTION THROUGH SYNCRONIZED PLANT CELL CULTURES</a> <b>[P]</b> . <span> 外国专利：  PL1951863T3 </span> <span> . 2015-12-31</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：通过同步植物细胞培养进行次生代谢产物生产的稳定性 </span> </p> </li> <li> <div> <b>5. </b><a class="enjiyixqcontent" href="/patent-detail/06130414750228.html">STABILITY OF SECONDARY METABOLITE MASS PRODUCTION THROUGH SYNCRONIZED PLANT CELL CULTURES</a> 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