This work was supported by grant 1R01CA152303-01.

伦理声明:在按照科罗拉多州的多机构审查委员会（08-0439）批准了一项协议，在科罗拉多大学医院同意患者获得来自患者的大肠腺癌肿瘤标本。所有的动物工作在科罗拉多州丹佛机构动物护理和使用委员会的批准大学动物方案执行（IACUC，协议＃51412（06）1E和96813（04）1E）。 1.接收和准备患者血<ol><li>收集1 - 在含有柠檬酸钠血液/细胞分离管2毫升血液（管相包括的是血浆，淋巴细胞和单核细胞带，密度梯度液，凝胶屏障，和红细胞和嗜中性粒细胞）。注意，请遵守血液或组织血源性病原体的指导方针。 注意:PBMC和血浆可用于未来的研究，其可以包括:比较与肿瘤的突变种系遗传变异，隔离circula婷肿瘤细胞，细胞评价游离DNA（cfDNA），研究蛋白质和小分子RNA 等 。 </li><li>离心血液/细胞分离管在2,500 xg离心与RT没有刹车15分钟。 </li><li>采集外周血单个核细胞（淋巴细胞和管单核细胞带外周血单个核细胞），并放入1.5 ml离心管（透明，高温高压消毒，酶，RNA酶和无热原），并填写用无菌磷酸盐缓冲管的顶部盐水（PBS）。 <ol><li>离心机2,300 xg离心在RT 3分钟以在管的底部形成的PBMC的粒料。其次，小心地取出上清。加入1ml无菌PBS洗涤沉淀和离心以3000×g离心30秒，然后除去上清液。 </li></ol></li><li>在1.5毫升无菌低温小瓶用吸移管从血液/细胞分离管收集血浆（在管的血浆相）（DNA酶和RNA酶，无人类DNA，不含内毒素）和放PMBC的血浆和沉淀成-80°缩略词reezer贮存。 </li></ol> 2.接收和准备患者的肿瘤样本<ol><li>制备要么RPMI或DMEM培养基以1:青霉素 - 链霉素和非必需氨基酸的100（10％），1:1000（1％）Plasmocin和10％灭活的胎牛血清（完全培养基），并添加20 - 25毫升到无菌收集杯的肿瘤样品。 </li><li>检索肿瘤样品在含有冰的完全培养基中的无菌杯或保持在4℃。 注意:肿瘤样品是一块过量患者肿瘤组织由外科医生移除，由病理学家进行处理，并置于无菌收集杯与完整的媒体。注意，请遵守血液或组织血源性病原体的指导方针。另外，理想地注入五只小鼠中，肿瘤应大约1立方厘米。 </li><li>使肿瘤样品的动物设施用于注射入免疫缺陷的小鼠。 注意:最好是尽快处理肿瘤样品。 <ol><li>在层流罩，将肿瘤样品到从肿瘤杯的无菌塑料切割盘。使用高压灭菌小剪刀和镊子要切成10 - 12约3×3×3mm的片，并放置到装有300微升胶状蛋白质混合物溶液的高压灭菌1.5 ml离心管。管保持在冰上。 </li><li>作为优先注入肿瘤到小鼠，但如果有遗留任何肿瘤，收集快速冷冻小瓶（FF），福尔马林固定的石蜡包埋（FFPE）杯，和一个可行的肿瘤小瓶中。 </li><li>为FF，收集小块肿瘤组织从无菌低温小瓶用于进一步分析，例如蛋白质，RNA或DNA分离。立即将FF成液氮杜瓦和长期-80存储在一个℃冰箱。 </li><li>对FFPE，如果有足够的肿瘤，代替3-小块到10ml 10％福尔马林杯和工艺成石蜡包埋块一旦肿瘤已经在福尔马林中至少24小时。 注意:24小时是基于从我们的组织学的核心建议11。 </li><li>最后，将剩余的肿瘤成低温管中。通过加入10％二甲亚砜（DMSO）中来完成媒体使可行介质。接下来，加入1毫升低温管，并储存在冰。注意:不要让冰上很长一段时间。 <ol><li>切断的任何剩余肿瘤小块理想地将是足够的10个肿瘤被注入在未来5只小鼠。然后，放置在冰上的活肿瘤管，直到它可被放入异丙醇冷冻容器（在一个时间缓慢冻结肿瘤1℃）并放入-80℃的冰箱中，以确保肿瘤不期间死冷冻过程。 注意:对于长期储存的肿瘤被删除（后2 - 3天），并置于一个大液氮杜瓦。请注意，可行的管不应允许解冻除非正在取出它注入到小鼠体内。 </li></ol></li></ol></li></ol> 3。患者来源肿瘤异种移植物的注射<ol><li>用五年6 - 8周大的雄性和/或雌性无胸腺裸鼠（T细胞缺陷型）为每个单独的患者来源的肿瘤。注射共有10个肿瘤（每只小鼠2次注射）皮下（SQ）。 注:原人类肿瘤被指定为F0，然后一次注射到小鼠下一代为F1。此外，使用镊子蒸压，剪刀和套管的每一个独特的外植体。 </li><li>肿瘤的负荷件从胶状蛋白质混合物溶液注入高压灭菌12g的套管，并确保该肿瘤被完全推入套管针。 <ol><li>在无菌层流罩，将5只小鼠成被连接到异氟烷麻醉机的麻醉箱（在5％异氟醚的初始速度开始，3 - 4％的氧，和2 - 3％异氟烷维持麻醉的）和木炭过滤器（吸收多余的气体）。 注意:有经验的技师应该能够上执行的整个程序5只小鼠在大约5分钟总（每只小鼠大约30秒）一笼。因此额外的热支持和眼睛的润滑一般不使用。对于缺乏经验的个人或训练时，强烈建议个人无论是在同一时间就少动物执行程序和/或过程中使用暖垫/眼润滑，如果动物会超过5分钟被麻醉更长。程序是基于我们大学IACUC标准。 </li></ol></li><li>捏老鼠的脚趾，以确保鼠标不再响应，然后拿鼠标移出异氟醚盒。鼠标放置到一个干净的领域，直到与蒸压12g的套管达到侧翼区中等偏上的背颈部和滑动套管针皮下向下注入肿瘤。 <ol><li>传送一个肿瘤皮下给小鼠的侧面的每一侧。捏肿瘤时套管针被拉出时，确保该肿瘤停留在所需的侧翼区域。葛latinous蛋白质混合物变硬用鼠标的体温和封装肿瘤为大约一周来帮助肿瘤生长，将它固定到SQ结缔组织。由套管针取得的病变是不大于4mm大，就没有必要关闭与订书钉皮肤。 注意:我们的兽医确定没有闭合是根据病灶的非常小的尺寸需要，快速愈合时间（中间背颈部区域减少任何皮肤张力或病变的修饰）在这一段时间内，没有感染所指出的，与动物的密切监测。 </li></ol></li><li>之前鼠标完全清醒美洛昔康注射2毫克/公斤SQ（止痛药）从肿瘤注射部位了。下一步，将鼠标放到笼子和监控，直到鼠标清醒动人。 注意:不要让动物恢复到无人看管完全清醒。美洛昔康的剂量是根据我校IACUC标准。 <ol><li>接着，重复相同的过程与4剩下的老鼠和监控他们的呼吸。 注:请注意，这是一个非常快的过程和小鼠注射美洛昔康后很快醒过来，但根据需要调整异氟醚。每个鼠标取出来的时候，调低异氟醚。美洛昔康将持续24小时，从套管病变会在一周内完全愈合。 </li></ol></li></ol> 4.维护患者来源的肿瘤异种移植的银行<ol><li>监测小鼠的生长和健康，每周至少一次。使用电子表格（或其它跟踪系统）来跟踪肿瘤的大小，肿瘤生成，肿瘤注射的日期，和小鼠的健康状况。 注意:如果小鼠失去了原有的体重的15％，低体况评分（≥2），有肿瘤溃疡，肿瘤2 000名立方毫米或总肿瘤3000毫米3，或是病弱的（驼背，冷，嗜睡等以任何方式。），将小鼠通过二氧化碳安乐死或麻醉颈椎脱位一样econdary方法。通过麻醉和颈椎脱位安乐死，如果收集肿瘤，否则小鼠通过CO 2和颈椎脱位安乐死。 </li><li>当肿瘤约为1,500-2,000毫米3麻醉如上所述，然后执行颈椎脱位安乐死的小鼠。 <ol><li>检查鼠标有没有心跳。消费与蒸压剪刀和镊子的SQ肿瘤。 注:允许肿瘤生长长达1年，如果没有肿瘤看出然后安乐死经由CO 2的小鼠，随后通过颈椎脱位作为次要方法。 </li><li>通道最好生长的肿瘤到下一代（ 又名新组5只小鼠）。上面的使用说明，收集10 - 12肿瘤的传球，然后收集剩余的肿瘤也如上所述。 注:收集众多可行的管子是初代（F1 - F8）非常重要;因此，收集几个可行的管，管FF，并且每个发电机密封1 FFPE离子。 </li><li>保持其余小鼠，直到新的一代小鼠具有约300mm 3肿瘤的生长。当剩余的小鼠具有肿瘤的大，继续如上所述收集。 </li></ol></li><li>继续道肿瘤，并在每个阶段收集到F15。在这一点上，以最早的一代可能出液氮的一个可行的管，让冰融化，并按照上述肿瘤注射程序。 注意:从可行的管长肿瘤需要更长的时间在小鼠相比增长从一代传给一代，所以当规划记住这一点。如果特定PDTX模型不再需要在任何通道，安乐死并收集肿瘤，以确保许多可行的管被收集以供将来使用。 </li></ol> 5.发展治疗与患者来源的肿瘤异种移植注意:大多数肿瘤在F3代有良好的生长动力学（成长得更快，更合作nsistent），因此，继续PDTX药物疗效研究。 <ol><li>当所需的肿瘤是非常大的（1500 - 2000 立方毫米），按照上述程序收集肿瘤扩展到小鼠需要的金额。 <ol><li>根据这一假设被测试确定每个处理组所需的肿瘤的数目。 注意:1毫升胶状蛋白质混合物溶液可以近似拟合30小肿瘤片（取决于肿瘤形态学）用于注射到小鼠中。 </li></ol></li><li>检查小鼠的肿瘤每周和当大多数肿瘤明显小（大约50之间 - 300立方毫米）测量用卡尺肿瘤，以确定肿瘤体积。肿瘤体积= [width²（最小测量）x长（最大测量）]×0.52。 注意:胶状蛋白质混合物溶液围绕注入肿瘤片一周，在此之后一周的肿瘤生长将是准确的。 </li><li>使用50之间的肿瘤体积 - 300立方毫米和Ñ平均左侧和右侧的肿瘤。然后随机分为治疗组，每组和一组平均10个肿瘤彼此的几个数字中。接下来，排序的老鼠分成组，并开始所需的治疗研究。 </li><li>剂量与药物（时间表取决于药物），每周两次称重和测量（肿瘤）的小鼠。在研究结束时，通过安乐死麻醉和颈椎脱位的小鼠并收集肿瘤在实验室未来的药效学分析。 注:本研究持续取决于车辆肿瘤大小和小鼠的健康30天。 </li></ol> 6. PDTX银行组织<ol><li>保持一个良好的记录形式预防研究和适当使用动物的重复。 注意:这是成功的关键PDTX银行。 <ol><li>使用电子表格来跟踪肿瘤的从人类患者在诊所，在PDTX银行小鼠，治疗，数据，和什么被收集。注:包括冷冻机，液态氮杜瓦和FFPE存储。 </li></ol></li></ol>

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J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Identification+of+predictive+markers+of+response+to+the+MEK1/2+inhibitor+selumetinib+(AZD6244)+in+K-ras-mutated+colorectal+cancer.">Identification of predictive markers of response to the MEK1/2 inhibitor selumetinib (AZD6244) in K-ras-mutated colorectal cancer.</a> Mol Cancer Ther. 9 (12), 3351-3362 (2010).</li><li>Bardelli, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Amplification+of+the+MET+receptor+drives+resistance+to+anti-EGFR+therapies+in+colorectal+cancer.">Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer.</a> Cancer Discov. 3 (6), 658-673 (2013).</li><li>Bertotti, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+molecularly+annotated+platform+of+patient-derived+xenografts+("xenopatients")+identifies+HER2+as+an+effective+therapeutic+target+in+cetuximab-resistant+colorectal+cancer.">A molecularly annotated platform of patient-derived xenografts ("xenopatients") identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer.</a> Cancer Discov. 1 (6), 508-523 (2011).</li><li>Davis, S. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Combined+inhibition+of+MEK+and+Aurora+A+kinase+in+KRAS/PIK3CA+double-mutant+colorectal+cancer+models.">Combined inhibition of MEK and Aurora A kinase in KRAS/PIK3CA double-mutant colorectal cancer models.</a> Front Pharmacol. 6, 120 (2015).</li><li>Morelli, M. P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Preclinical+activity+of+the+rational+combination+of+selumetinib+(AZD6244)+in+combination+with+vorinostat+in+KRAS-mutant+colorectal+cancer+models.">Preclinical activity of the rational combination of selumetinib (AZD6244) in combination with vorinostat in KRAS-mutant colorectal cancer models.</a> Clin Cancer Res. 18 (4), 1051-1062 (2012).</li><li>Pitts, T. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Dual+pharmacological+targeting+of+the+MAP+kinase+and+PI3K/mTOR+pathway+in+preclinical+models+of+colorectal+cancer.">Dual pharmacological targeting of the MAP kinase and PI3K/mTOR pathway in preclinical models of colorectal cancer.</a> PLoS One. 9 (11), e113037 (2014).</li><li>Spreafico, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rational+combination+of+a+MEK+inhibitor,+selumetinib,+and+the+Wnt/calcium+pathway+modulator,+cyclosporin+A,+in+preclinical+models+of+colorectal+cancer.">Rational combination of a MEK inhibitor, selumetinib, and the Wnt/calcium pathway modulator, cyclosporin A, in preclinical models of colorectal cancer.</a> Clin Cancer Res. 19 (15), 4149-4162 (2013).</li><li>Arcaroli, J. 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The authors have nothing to disclose.

该PDTX药物发现平台提供了一个改进的模型，以用于预测新化合物的临床活动不可靠等临床前模型的缺点。重要的是，在此模型中的肿瘤在生物学上稳定的，保留转移潜能，并从代显示出到代类似药物的响应。在这种模式下，患者来源的肿瘤被注入无胸腺裸鼠，传代，随后在治疗评价中使用。有一个成功的PDTX银行，其中包括几个关键步骤:1）一个有凝聚力的临床小组，以查明/同意病人和切除和肿?...

结直肠癌（CRC）是一个显著贡献在美国癌症死亡。 2015年，有CRC估计有132 700新病例有49700人死亡1。虽然患者的预后与局部的疾病是优秀的，晚期患者有不良后果，以新颖的疗法的发展使这是一个主要的优先事项。尽管护理化疗方案和部署防治这一疾病新型生物制剂的标准，出现了只在总生存期的增量增加。因此，存在对于理解参与促进在这种疾病的肿瘤生长的驱动通路一个显著努力。癌症基因组图谱网络最近发现了有牵连的CRC失调，包括众多的主要途径:WNT，磷酸肌醇3-激酶（PI3K），RAS，转化生长因子β（TGF-β）和TP53 2。总之，与调查描述OT她的途径，在CRC使可能的增长已经点燃了旨在改善显著的生存在这个病人的人口3-5新疗法的发展。在肿瘤学药物开发利用临床前模型已在此过程中预测这些新化合物的临床活性是必不可少的。 各种临床前模型已被用于在药物开发过程。考虑到临床前的转基因动物模型和永生细胞系已经确定的新型抗肿瘤药治疗的临床活动不成功，主要是由于其无法反映人类肿瘤的复杂性，患者来源的肿瘤异种移植（PDTX）模型已经建立。这种模式的最大好处是，肿瘤异质性保持不变，并密切反映了原始病人肿瘤6-9的分子特征和克隆。 PDTX模型提供的体内极好临床前研究平台，研究新型药物，耐药性的途径，组合策略，和癌症干细胞生物学10。 该PDTX过程的一般概述在图1中示出，它开始在临床上，同意患者以允许他们的一些过量的肿瘤组织用于本研究。接着，在外科手术，一块肿瘤是由一个病理学家票房并放入介质被运送到研究人员。紧接在此之后，将肿瘤的部分被切成小块并移植到免疫缺陷小鼠皮下。一旦肿瘤生长，这是传代到小鼠的不同世代以维持肿瘤10。典型地，F3代后的肿瘤可以扩展为一个治疗研究，其中被评估的新化合物和/或组合疗法。利用下一代序列（外显子组序列，RNA测序和SNP阵列）潜在的预测生物标志物发现编了协助的可从特定治疗中获益的患者的选择。 使用PDTX模型的总体目标是:1）评估新疗法作为单一药剂或组合的有效性和2）确定前临床研究敏感性或抗性的预测生物标记。在这个手稿，我们提供一个CRC PDTX银行的启动和维护的方法和提供该模型在药物开发发现的优点和局限性。 <img alt="图1" src="/files/ftp_upload/54393/54393fig1.jpg" /> 图 1. CRC PDTX示范协议概述。患者来源的肿瘤手术收到并立即注入无胸腺裸鼠皮下。一旦肿瘤生长被扩大到后代，并最终扩大了治疗研究。治疗respo国家科学教育标准进行评估和预测生物标志物被确定可在病人的选择提供帮助。 <a href="https://www.jove.com/files/ftp_upload/54393/54393fig1large.jpg" target="_blank">请点击此处查看该图的放大版本。</a>

<table><tbody><tr><td>RPMI or DMEM</td><td>Corning</td><td>10-040-CV</td><td></td></tr><tr><td>Penicillin-Streptomycin</td><td>Corning</td><td>30-002-CI</td><td></td></tr><tr><td>Non-essential Amino Acids</td><td>Corning</td><td>25-025-CI</td><td></td></tr><tr><td>Fetal Bovine Serum</td><td>Corning</td><td>35-010-CV</td><td>Thaw in -4 &amp;deg;C, then activate for 30 min at 60 &amp;deg;C water bath</td></tr><tr><td>CPT blood tube</td><td>BD vacutainer</td><td>362761</td><td></td></tr><tr><td>Microcentrifuge tube</td><td>Surelock</td><td>A-7002</td><td></td></tr><tr><td>Phosphate-Buffered Saline</td><td>Corning</td><td>21-040-CV</td><td></td></tr><tr><td>Cyrogenic vials</td><td>Cyroking</td><td>C0732901</td><td></td></tr><tr><td>Plastic tumor cutting dish</td><td>Trueline</td><td>TR4001</td><td></td></tr><tr><td>Scissors</td><td>Roboz</td><td>RS-5881</td><td></td></tr><tr><td>Forceps</td><td>Roboz</td><td>RS-5135</td><td></td></tr><tr><td>Matrigel (gelatinous protein mixture)</td><td>Corning</td><td>354234</td><td>Store at -20 or -80 &amp;deg;C, then thaw on ice, do not leave at RT</td></tr><tr><td>10% Formalin cups</td><td>Protocol</td><td>032-059</td><td></td></tr><tr><td>Liquid Nitrogen Dewar Storage</td><td>Thermolyne</td><td>CY50900</td><td></td></tr><tr><td>Portable liquid nitrogen dewar</td><td>Nalgene</td><td>4150-2000</td><td></td></tr><tr><td>Dimethyl Sulfoxide</td><td>Fischer</td><td>67-68-5</td><td></td></tr><tr><td>Freezing container: Mr Frosty</td><td>Nalgene</td><td>5100-0001</td><td></td></tr><tr><td>Isopropyl Alcohol</td><td>Decon</td><td>64-17-5</td><td></td></tr><tr><td>Trocars</td><td>Innovative Research of America</td><td>MP-182</td><td></td></tr><tr><td>Anesthesia machine</td><td>Patterson Veterinary</td><td></td><td></td></tr><tr><td>Anesthesia box</td><td>Patterson Veterinary</td><td></td><td></td></tr><tr><td>Isoflurane</td><td>Vet one</td><td>1038005</td><td></td></tr><tr><td>F-Air Canister</td><td>Bickford Omnicon</td><td>80120</td><td></td></tr><tr><td>Meloxicam</td><td>Vet one</td><td>5182-90C</td><td></td></tr><tr><td>Calipers</td><td>Fowler</td><td>54-100-167</td><td></td></tr><tr><td>Weight scale</td><td>Ohaus</td><td>Scout Pro SP601</td><td></td></tr></tbody></table>

development and maintenance of a preclinical patient derived tumor xenograft model for the investigation of novel anti-cancer therapies

Patient derived tumor xenograft (PDTX) models provide a necessary platform in facilitating anti-cancer drug development prior to human trials. Human tumor pieces are injected subcutaneously into athymic nude mice (immunocompromised, T cell deficient) to create a bank of tumors and subsequently are passaged into different generations of mice in order to maintain these tumors from patients. Importantly, cellular heterogeneity of the original tumor is closely emulated in this model, which provides a more clinically relevant model for evaluation of drug efficacy studies (single agent and combination), biomarker analysis, resistant pathways and cancer stem cell biology. Some limitations of the PDTX model include the replacement of the human stroma with mouse stroma after the first generation in mice, inability to investigate treatment effects on metastasis due to the subcutaneous injections of the tumors, and the lack of evaluation of immunotherapies due to the use of immunocompromised mice. However, even with these limitations, the PDTX model provides a powerful preclinical platform in the drug discovery process.

在CRC PDTX模型和TCGA常见突变的异同 我们研究在CRC PDTX银行常见的突变基因（KRAS，NRAS，BRAF，PIK3CA，APC，CTNNB1和TP53）的百分比是否代表在CRC患者群体看到的突变频率。如在图2A（TCGA）和B（CRC PDTX银行）所示，在这些基因突变的频率是所述TCGA（N = 276名患者）和CRC PDTX银行（N = 59的CRC患...

Watch this Scientific Journal Video about Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies at JoVE.com

Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies

在皮下临床前模型利用患者来源的肿瘤是研究新的治疗方法，预测生物标志物的发现，以及耐药性途径的有效性的好方法。这种模式，在药物开发过程中，在事先确定了许多新的抗癌疗法的命运临床研究至关重要。

开发和维护的临床前患者来源的肿瘤异种移植模型为新的抗癌疗法的调查

Patient derived tumor xenograft (PDTX) models provide a necessary platform in facilitating anti-cancer drug development prior to human trials. Human tumor ...

development-maintenance-preclinical-patient-derived-tumor-xenograft

Research

JoVE Journal

Cancer Research

13.6K 次观看.  University of Colorado Denver Anschutz Medical Campus. 在皮下临床前模型利用患者来源的肿瘤是研究新的治疗方法，预测生物标志物的发现，以及耐药性途径的有效性的好方法。这种模式，在药物开发过程中，在事先确定了许多新的抗癌疗法的命运临床研究至关重要。 

视频: Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies

Labeling of Breast Cancer Patient-derived Xenografts with Traceable Reporters for Tumor Growth and Metastasis Studies

The use of preclinical models to study tumor biology and response to treatment is central to cancer research. Long-established human cell lines, and many transgenic mouse models, often fail to recapitulate the key aspects of human malignancies. Thus, alternative models that better represent the heterogeneity of patients' tumors and their metastases are being developed. Patient-derived xenograft (PDX) models in which surgically resected tumor samples are engrafted into immunocompromised mice have become an attractive alternative as they can be transplanted through multiple generations,and more efficiently reflect tumor heterogeneity than xenografts derived from human cancer cell lines. A limitation to the use of PDXs is that they are difficult to transfect or transduce to introduce traceable reporters or to manipulate gene expression. The current protocol describes methods to transduce dissociated tumor cells from PDXs with high transduction efficiency, and the use of labeled PDXs for experimental models of breast cancer metastases. The protocol also demonstrates the use of labeled PDXs in experimental metastasis models to study the organ-colonization process of the metastatic cascade. Metastases to different organs can be easily visualized and quantified using bioluminescent imaging in live animals, or GFP expression during dissection and in excised organs. These methods provide a powerful tool to extend the use of multiple types of PDXs to metastasis research.

We describe a method for stable labeling of patient-derived xenografts (PDXs) with lentiviral particles expressing green-fluorescent protein and luciferase reporters. This method allows for tracking the growth of PDXs at the primary site, as well as detecting spontaneous and experimental metastases using in vivo imaging systems.

可追踪记者乳腺癌患者来源的移植瘤贴标肿瘤生长和转移的研究

The use of preclinical models to study tumor biology and response to treatment is central to cancer research. Long-established human cell lines, and many ...

科研

癌症研究

Transplantation of Zebrafish Pediatric Brain Tumors into Immune-competent Hosts for Long-term Study of Tumor Cell Behavior and Drug Response

Tumor cell transplantation is an important technique to define the mechanisms controlling cancer cell growth, migration, and host response, as well as to assess potential patient response to therapy. Current methods largely depend on using syngeneic or immune-compromised animals to avoid rejection of the tumor graft. Such methods require the use of specific genetic strains that often prevent the analysis of immune-tumor cell interactions and/or are limited to specific genetic backgrounds. An alternative method in zebrafish takes advantage of an incompletely developed immune system in the embryonic brain before 3 days, where tumor cells are transplanted for use in short-term assays (i.e., 3 to 10 days). However, these methods cause host lethality, which prevents the long-term study of tumor cell behavior and drug response. This protocol describes a simple and efficient method for the long-term orthotopic transplantation of zebrafish brain tumor tissue into the fourth ventricle of a 2-day-old immune-competent zebrafish. This method allows: 1) long-term study of tumor cell behaviors, such as invasion and dissemination; 2) durable tumor response to drugs; and 3) re-transplantation of tumors for the study of tumor evolution and/or the impact of different host genetic backgrounds. In summary, this technique allows cancer researchers to assess engraftment, invasion, and growth at distant sites, as well as to perform chemical screens and cell competition assays over many months. This protocol can be extended to studies of other tumor types and can be used to elucidate mechanisms of chemoresistance and metastasis.

The transplantation of cancer cells is an important tool for the identification of cancer mechanisms and therapeutic responses. Current techniques depend on immune-incompetent animals. Here, we describe a method to transplant zebrafish tumor cells into immune-competent embryos for the long-term analysis of tumor cell behavior and in vivo drug responses.

将斑马鱼小儿脑肿瘤移植入免疫能力的宿主，用于长期研究肿瘤细胞行为和药物反应

Tumor cell transplantation is an important technique to define the mechanisms controlling cancer cell growth, migration, and host response, as well as to ...

Utilization of Ultrasound Guided Tissue-directed Cellular Implantation for the Establishment of Biologically Relevant Metastatic Tumor Xenografts

Preclinical testing of anticancer therapies relies on relevant xenograft models that mimic the innate tendencies of cancer. Advantages of standard subcutaneous flank models include procedural ease and the ability to monitor tumor progression and response without invasive imaging. Such models are often inconsistent in translational clinical trials and have limited biologically relevant characteristics with low proclivity to produce metastasis, as there is a lack of a native microenvironment. In comparison, orthotopic xenograft models at native tumor sites have been shown to mimic the tumor microenvironment and replicate important disease characteristics such as distant metastatic spread. These models often require tedious surgical procedures with prolonged anesthetic time and recovery periods. To address this, cancer researchers have recently utilized ultrasound-guided injection techniques to establish cancer xenograft models for preclinical experiments, which allows for rapid and reliable establishment of tissue-directed murine models. Ultrasound visualization also provides a noninvasive method for longitudinal assessment of tumor engraftment and growth. Here, we describe the method for ultrasound-guided injection of cancer cells, utilizing the adrenal gland for NB and renal sub capsule for ES. This minimally invasive approach overcomes tedious open surgery implantation of cancer cells in tissue-specific locations for growth and metastasis, and abates morbid recovery periods. We describe the utilization of both established cell lines and patient derived cell lines for orthotopic injection. Pre-made commercial kits are available for tumor dissociation and luciferase tagging of cells. Injection of cell suspension using image-guidance provides a minimally invasive and reproducible platform for the creation of preclinical models. This method is utilized to create reliable preclinical models for other cancers such as bladder, liver and pancreas exemplifying its untapped potential for numerous cancer models.

Here, we present a protocol to utilize ultrasound-guided injection of neuroblastoma (NB) and Ewing's sarcoma (ES) cells (established cell lines and patient-derived tumor cells) at biologically relevant sites to create reliable preclinical models for cancer research.

超声引导组织定向细胞植入术在生物学相关转移性肿瘤移植中的应用

Preclinical testing of anticancer therapies relies on relevant xenograft models that mimic the innate tendencies of cancer. Advantages of standard ...

A Melanoma Patient-Derived Xenograft Model

Accumulating evidence suggests that molecular and biological properties differ in melanoma cells grown in traditional two-dimensional tissue culture vessels versus in vivo in human patients. This is due to the bottleneck selection of clonal populations of melanoma cells that can robustly grow in vitro in the absence of physiological conditions. Further, responses to therapy in two-dimensional tissue cultures overall do not faithfully reflect responses to therapy in melanoma patients, with the majority of clinical trials failing to show the efficacy of therapeutic combinations shown to be effective in vitro. Although xenografting of melanoma cells into mice provides the physiological in vivo context absent from two-dimensional tissue culture assays, the melanoma cells used for engraftment have already undergone bottleneck selection for cells that could grow under two-dimensional conditions when the cell line was established. The irreversible alterations that occur as a consequence of the bottleneck include changes in growth and invasion properties, as well as the loss of specific subpopulations. Therefore, models that better recapitulate the human condition in vivo may better predict therapeutic strategies that effectively increase the overall survival of patients with metastatic melanoma. The patient-derived xenograft (PDX) technique involves the direct implantation of tumor cells from the human patient to a mouse recipient. In this manner, tumor cells are consistently grown under physiological stresses in vivo and never undergo the two-dimensional bottleneck, which preserves the molecular and biological properties present when the tumor was in the human patient. Notable, PDX models derived from organ sites of metastases (i.e., brain) display similar metastatic capacity, while PDX models derived from therapy naive patients and patients with acquired resistance to therapy (i.e., BRAF/MEK inhibitor therapy) display similar sensitivity to therapy.

Patient-derived xenograft (PDX) models more robustly recapitulate melanoma molecular and biological features and are more predictive of therapy response compared to traditional plastic tissue culture-based assays. Here we describe our standard operating protocol for the establishment of new PDX models and the characterization/experimentation of existing PDX models.

黑色素瘤患者衍生异种移植模型

Accumulating evidence suggests that molecular and biological properties differ in melanoma cells grown in traditional two-dimensional tissue culture ...

Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts

We present here an integrative approach for testing efficacy of targeted therapies that combines the next generation sequencing technolo-gies, therapeutic target analyses and drug response monitoring using patient derived xenografts (PDX). This strategy was validated using ovarian tumors as an example. The mate-pair next generation sequencing (MPseq) protocol was used to identify structural alterations and followed by analysis of potentially targetable alterations. Human tumors grown in immunocompromised mice were treated with drugs selected based on the genomic analyses. Results demonstrated a good correlation between the predicted and the observed responses in the PDX model. The presented approach can be used to test the efficacy of combination treatments and aid personalized treatment for patients with recurrent cancer, specifically in cases when standard therapy fails and there is a need to use drugs off label.

Here we present a protocol to test the efficacy of targeted therapies selected based on the genomic makeup of a tumor. The protocol describes identification and validation of structural DNA rearrangements, engraftment of patients&#8217; tumors into mice and testing responses to corresponding drugs.

使用结构DNA改变分析和患者衍生异种移植测试癌症的靶向疗法

We present here an integrative approach for testing efficacy of targeted therapies that combines the next generation sequencing technolo-gies, therapeutic ...

Creation and Maintenance of a Living Biobank - How We Do It

In light of the growing knowledge about the inter-individual properties and heterogeneity of cancers, the emerging field of personalized medicine requires a platform for preclinical research. Over recent years, we have established a biobank of colorectal and pancreatic cancers comprising of primary tumor tissue, normal tissue, sera, isolated peripheral blood lymphocytes (PBL), patient-derived xenografts (PDX), as well as primary and secondary cancer cell lines. Since original tumor tissue is limited and the establishment rate of primary cancer cell lines is still relatively low, PDX allow not only the preservation and extension of the biobank but also the generation of secondary cancer cell lines. Moreover, PDX-models have been proven to be the ideal in vivo model for preclinical drug testing. However, biobanking requires careful preparation, strict guidelines and a well attuned infrastructure. Colectomy, duodenopancreatectomy or resected metastases specimens are collected immediately after resection and transferred to the pathology department. Respecting priority of an unbiased histopathological report, at the discretion of the attending pathologist who carries out the dissections, small tumor pieces and non-tumor tissue are harvested. 
Necrotic parts are discarded and the remaining tumor tissue is cut into small, identical cubes and cryopreserved for later use. Additionally, a small portion of the tumor is minced and strained for primary cancer cell culture. Additionally, blood samples drawn from the patient pre- and postoperatively, are processed to obtain serum and PBLs. For PDX engraftment, the cryopreserved specimens are defrosted and implanted subcutaneously into the flanks of immunodeficient mice. The resulting PDX closely recapitulate the histology of the "donor" tumors and can be either used for subsequent xenografting or cryopreserved for later use. In the following work, we describe the individual steps of creation, maintenance and administration of a large biobank of colorectal and pancreatic cancer. Moreover, we highlight the crucial details and caveats associated with biobanking.

In the following work, we describe the consecutive steps necessary for the establishment of a large biobank of colorectal and pancreatic cancer.

活生物库的创建和维护 - 我们如何做到这一点

In light of the growing knowledge about the inter-individual properties and heterogeneity of cancers, the emerging field of personalized medicine requires ...

Establishment and Characterization of Patient-Derived Xenograft Models of Anaplastic Thyroid Carcinoma and Head and Neck Squamous Cell Carcinoma

Patient-derived xenograft (PDX) models faithfully preserve the histological and genetic characteristics of the primary tumor and maintain its heterogeneity. Pharmacodynamic results based on PDX models are highly correlated with clinical practice. Anaplastic thyroid carcinoma (ATC) is the most malignant subtype of thyroid cancer, with strong invasiveness, poor prognosis, and limited treatment. Although the incidence rate of ATC accounts for only 2%-5% of thyroid cancer, its mortality rate is as high as 15%-50%. Head and neck squamous cell carcinoma (HNSCC) is one of the most common head and neck malignancies, with over 600,000 new cases worldwide each year. Herein, detailed protocols are presented to establish PDX models of ATC and HNSCC. In this work, the key factors influencing the success rate of model construction were analyzed, and the histopathological features were compared between the PDX model and the primary tumor. Furthermore, the clinical relevance of the model was validated by evaluating the in vivo therapeutic efficacy of representative clinically used drugs in the successfully constructed PDX models.

The present protocol establishes and characterizes a patient-derived xenograft (PDX) model of anaplastic thyroid carcinoma (ATC) and head and neck squamous cell carcinoma (HNSCC), as PDX models are rapidly becoming the standard in the field of translational oncology.

间变性甲状腺癌和头颈部鳞状细胞癌患者来源异种移植模型的建立与表征

Patient-derived xenograft (PDX) models faithfully preserve the histological and genetic characteristics of the primary tumor and maintain its ...

<meta charset="utf8"></head><body>患者来源的黑色素瘤类器官：癌症免疫治疗的前沿

Unveiling Therapeutic Opportunities with Melanoma Patient-derived Organoid Models

With the development of immunotherapy, there is an ongoing need to develop models that can recapitulate the tumor microenvironment of native tumors. While traditional two- and three-dimensional models can offer insights into cancer development and progression, these lack crucial aspects that hinder a faithful mimic of native tumors. An alternative model that has gained a lot of attention is the patient-derived organoid. The development of these organoids recapitulates the complex intercellular communication, tumor microenvironment, and histoarchitecture of tumors. This paper describes the protocol for establishing melanoma patient-derived organoid (MPDO) models. To validate these models, we assessed the immune cell composition, including the expression levels of T-cell activation markers, to confirm the cellular heterogeneity of the organoids. Additionally, to describe the potential utility of MPDOs in cellular therapies, we evaluated the cytotoxic capabilities of treating the organoids with &#947;&#948; T-cells. In conclusion, the MPDO models offer promising avenues for understanding tumor complexity, validating therapeutic strategies, and potentially advancing personalized treatment.

<meta charset="utf8"></head><body>作者聚焦：使用患者来源的类器官重建黑色素瘤复杂性以进行免疫治疗评估

Here, we present a protocol to generate melanoma patient-derived organoids by culturing disassociated cell suspensions from fresh melanoma tissues. These organoids faithfully recapitulate patient-specific tumors in vitro, offering an innovative approach to exploring tumor immunosuppressive mechanisms, drug screening, drug resistance mechanisms, and cancer surveillance approaches.

揭示黑色素瘤患者来源的类器官模型的治疗机会

With the development of immunotherapy, there is an ongoing need to develop models that can recapitulate the tumor microenvironment of native tumors. While ...

开发和维护的临床前患者来源的肿瘤异种移植模型为新的抗癌疗法的调查

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活生物库的创建和维护 - 我们如何做到这一点

间变性甲状腺癌和头颈部鳞状细胞癌患者来源异种移植模型的建立与表征

揭示黑色素瘤患者来源的类器官模型的治疗机会

揭示黑色素瘤患者来源的类器官模型的治疗机会

揭示黑色素瘤患者来源的类器官模型的治疗机会