Name: dynamic contrast enhanced magnetic resonance imaging of an orthotopic pancreatic cancer mouse model
Uploaded: 2015-04-18T15:00:00.000+00:00
Duration: 6 min 24 s
Description: Watch this Scientific Journal Video about Dynamic Contrast Enhanced Magnetic Resonance Imaging of an Orthotopic Pancreatic Cancer Mouse Model at JoVE.com

Authors thank Jeffrey Sellers to assist orthotopic pancreatic cancer mouse modeling. This work was supported by Research Initiative Pilot Awards from the Department of Radiology at UAB and NIH grants 2P30CA013148 and P50CA101955.

所有的程序批准的机构动物护理和使用委员会在阿拉巴马大学伯明翰分校。 1.原位胰腺肿瘤的老鼠模型<ol><li>在Dulbecco改良的Eagle培养基（DMEM）中培养的标准人胰腺癌肿瘤细胞系在补充有10％胎牛血清。保持所有培养物在37℃下在湿润的气氛中，用5％的CO 2。 </li><li>使用8-10周龄雌性重症联合免疫缺陷小鼠。放置动物笼子在12小时光照和12小时黑暗周期在RT（21±2℃）和60％的湿度。 </li><li>麻醉用通风所有动物用异氟烷与氧气（2L /分钟）在整个手术混合的2％。确认麻醉通过脚趾捏反射性的深度。上的加热垫（37℃）处的动物，以保持体温。取适量涂抹于眼睛兽医眼药膏，以防止干燥，而在麻醉下。 ＆＃160; </li><li>除去毛在各小鼠的腹部的左上象限，并给予止痛药（carpofen，5毫克/公斤体重皮下​​）进入该区。应用优碘解决暴露的皮肤。制备蒸压手术器械。 </li><li>使1cm的切口，在皮肤和腹膜使用虹膜直剪刀。轻轻地取出使用手术镊子腹部的胰腺。 </li><li>插入0.5 ml胰岛素注射器28克针入胰尾，然后慢慢注入2500000人胰腺癌细胞的溶液在30微升DMEM中。确认的小疱在胰头通过溶液创建。 </li><li>轻轻将胰腺回用手术镊子腹部。关闭腹膜和皮肤中1层2间断5-0普理灵缝线，然后终止麻醉。不返回已经历手术给其他动物的公司，直到完全恢复的动物。60; 7〜10日手术后取出缝合。 </li><li>给予止痛药（carpofen，5毫克/公斤体重皮下​​）的另一剂量在手术后24小时。 </li><li>检查肿瘤大小通过触诊用两个手指手术区域。肿瘤通常感觉比周围组织器官密度和颠簸。通常需要1〜 - 2周开始感觉肿瘤。 </li><li>每天监控动物疾病的迹象。当动物出现不适（缺乏正常的疏导和回避行为），我们终止它们使用颈椎脱位，而在麻醉下。 </li></ol> 2.磁共振成像<ol><li>适用的MRI当肿瘤大小为约5 - 7毫米直径通常在2〜4周后，细胞植入。使用磁共振扫描仪专门用于小动物成像或临床磁共振扫描仪配备了专门的线圈小动物成像。 注意:我们使用了9.4T小动物磁共振扫描仪有1小时容量谐振器的组合/发射机和表面线圈接收器（30毫米直径）（布鲁克BIOSPIN股份有限公司，比尔里卡，MA）中。表面线圈提供更好的信噪比（SNR），14。 </li><li>制备钆基MRI对比剂注入〜0.1 - 0.2毫摩尔/千克，以每只动物在〜0.1 - 0.2毫升的PBS（磷酸盐缓冲盐水）。 注意:我们使用钆特醇，并在一段持续15秒（0.1毫升/秒）注入0.2毫摩尔/千克0.15毫升的PBS。 </li><li>制备微聚乙烯管（长度:7.62毫米，内径:0.45毫米，外径0.64毫米）。插入地下30针（12.7毫米长）插入管的一端，和一个地下30的钝头针头（9.5毫米长）到另一端。连接1ml注射器含有MR造影剂的钝头针头，并慢慢地推注射器填满整个管与MR造影剂。 </li><li>在整个制备和成像异氟烷与氧气（2L /分钟）混合的2％ - 麻醉用通气〜1动物。确认ANEST的深度hesia由脚趾捏反射。取适量涂抹于眼睛兽医眼药膏，以防止干燥，而在麻醉下。扩张尾静脉用烤灯针头插入前。抢用凯利镊子地下30针的中间，并且将其插入到尾静脉。胶带二者的尾管上的一块塑料或纸板纸（10毫米宽×100毫米长），以保持尾直。 </li><li>放置在仰卧位的动物在装有循环热水（或暖空气）成像期间调节体温的动物床。设置在床的温度至37℃。插入直肠温度探头监控成像期间的体温。 </li><li>应用的垂直弯曲的塑料板到腹部。确保肿瘤位于板的上端身后，然后拉下板略（〜2毫米），确保肿瘤被捉住由董事会。大盘董事会动物睡觉坚决。 </li><li>大盘呼吸垫转导R（SA仪器公司，石溪，NY）的胸部成像过程中监测动物的呼吸。放置在肿瘤区域的顶部表面线圈，并将其用胶带动物床牢牢。推动物床进入MR扫描仪放置肿瘤区域中心处的体积线圈（内径72毫米）。 </li><li>为接收器和发射器进行匹配和调整，其次是垫补。 </li><li>开头的解剖磁共振序列来定位肿瘤。使用T2加权（T2W）快速自旋回波序列，以获得轴向图像与下列采集参数。重复时间（TR）/回波时间（TE）= 3000/34毫秒，128×128矩阵，图30×30mm的场，平均值的数= 1，回波串长度= 4，和20个连续1mm厚的片在隔行模式，以覆盖整个肿瘤区域（总扫描时间:1.6分钟）。 注意:由于原位胰腺肿瘤更难位于比皮下的人，常规locali具有较低分辨率图像ZER未必有用。 </li><li>获得T1加权（T1W）与各种翻转角度的图像检索T1的地图。为了这个目的，可使用回波使用以下参数multiflip角的方法的梯度:重复时间（TR）/回波时间（TE）=三分之一百一十五毫秒，128×128矩阵，来看一个30×30mm的场，数平均值= 4，〜5 - 7个连续1mm厚的片在交错模式以覆盖肿瘤区域，和10个7翻转角，20，30，40，50，60，和每翻转角70（总扫描时间:1分钟）。 注意:不过，multiflip角度的方法是有效的，只有当B1场均匀性是很高的。如果没有，T1的地图可以与多个TR方法，而不是15获得。 </li><li>之前基于钆磁共振造影剂注射后，即可获得T1W图像。使用相同的采集参数和几何形状为T1的映射，但与30使用线性编码的固定的翻转角，以确保获得的k空间的中心时稳定状态下，尤ecially当短TR和低度翻转角被使用。收购注射造影剂前5的基准图像。那么收购后注射造影剂40张图片（共扫描时间:45分钟）。使用注射泵以恒定速率（0.01毫升/秒）注入造影剂。 </li><li>持续监测动物的呼吸，并调整异氟醚浓度，保持呼吸频率50 - 每分钟100次呼吸。监控整个成像动物体温。 </li><li>完成DCE-MRI之后，脱下针和其他探测器，并把动物层状用纸巾空笼子。轻轻按摩下腹部区域。笼应放置在热灯下一半，以允许动物进出，因为它恢复移动的热量梯度。不要让动物无人看管，直到它恢复足够的意识，保持胸骨斜卧。 </li></ol> 3.图像处理与分析<ol><li>段肿瘤REGI<html>在T2W图像。在T2W成像，在肿瘤区域中的信号强度比周围组织更亮，所以肿瘤边界可以手动圈定。 注:如全局阈值或活性轮廓半自动分割技术可以用来16,17，但不均匀背景强度应当纠正特别是当一个表面线圈被使用。 </li><li>创建T1和质子密度图。在用梯度回波序列获得T1W图像，假定回波时间（TE）比T2 *值，像素值由下式确定要少得多 <img alt="式（1）" fo:content-width="3in" src="/files/ftp_upload/52641/52641eq1.jpg" /> 其中S 0是质子密度，T 1为T 1弛豫时间常数，TR为重复时间，θ是一翻转角。公式（1）可重写为 641eq2.jpg"/&gt; 当S（θ）/SINθ替换为Y，和S（θ）/tanθ被替换的X.等式（2）是线性方程，其斜率和截距可用于检索的T1和S 0的值，分别为。 </li><li>计算DCE-MR图像的磁共振造影剂浓度。当基于钆MR对比剂注射，T 1弛豫时间常数随时间变化。所以，方程（1）可重写为 <img alt="公式3" fo:content-width="3in" src="/files/ftp_upload/52641/52641eq3.jpg" /> Ť1（t）的相关与MR对比浓度C（T），如下， <img alt="公式4" fo:content-width="3in" src="/files/ftp_upload/52641/52641eq4.jpg" /> 其中 ，r 1是磁共振造影剂的纵向弛豫。这样，通过结合方程式（3）和（4），MR造影浓度由下式确定 <img aLT ="式5"FO:内容宽度="3英寸"SRC ="/文件/ ftp_upload / 52641 / 52641eq5.jpg"/&gt; </li><li>发起对比度注射后定量的MR造影剂。 中c p（t）的呈现在血浆MR造影浓度的药代动力学参数在时间 t。 中c p（t）被所谓的动脉输入功能（AIF）。如果AIF是可用的，MR造影剂的药代动力学参数可通过计算 <img alt="方程6" fo:content-width="4in" src="/files/ftp_upload/52641/52641eq6.jpg" /> 其中，C T（t）是MR造影剂浓度在靶组织，V p是小数血浆容量，V e是分数血管外细胞外液容量， 和 K 跨量是转移常数。通量速率常数，k EP，等于 k TRANs除以V 即如果AIF不可用，则参考区模型可以用来代替18,19。基准区域模型是基于所述流限制凯蒂模型20，并且使用对比度浓度在基准区域如下来除去的必要性AIF中， <img alt="公式7" fo:content-width="5in" src="/files/ftp_upload/52641/52641eq7.jpg" /> 其中，C T，投资回报率 （T），K 反，投资回报率 ，以及v E，ROI是造影剂浓度，体积转移常数和分数血管外，细胞外液容量，分别在感兴趣区域（ROI）的区域，而C T，RR （吨），K 反式，RR和 v 即，RR是那些在该基准区域。椎旁肌常被选择为基准区域， 和 v 即，RR小鼠巴ravertebral肌肉被假定为恒定在0.08 21。我们使用的参考区域模型。 </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=Experimentally-derived+functional+form+for+a+population-averaged+high-temporal-resolution+arterial+input+function+for+dynamic+contrast-enhanced+MRI.">Experimentally-derived functional form for a population-averaged high-temporal-resolution arterial input function for dynamic contrast-enhanced MRI.</a> Magn Reson Med. 56 (5), 993-1000 (2006).</li><li>Tseng, W., Leong, X., Engleman, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Orthotopic+mouse+model+of+colorectal+cancer.">Orthotopic mouse model of colorectal cancer.</a> J Vis Exp. (10), 484 (2007).</li><li>Bhullar, J. S., 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+true+orthotopic+gastric+cancer+murine+model+using+electrocoagulation.">A true orthotopic gastric cancer murine model using electrocoagulation.</a> J Am Coll Surg. 217 (1), 64-70 (2013).</li></ol>

Authors do not have any conflicts of interest to declare.

我们已经介绍了原位胰腺肿瘤模型使用免疫缺陷小鼠，小鼠的DCE-MRI腹部肿瘤，以及其动力学参数量化的具体方法。在原位胰腺肿瘤模型中，必须将针插入胰尾时服用。如果成功的话，将细胞将被转移到胰头创建一个小疱。当施加一个垂直弯曲的塑料板，关键是要确认肿瘤位于下方板的上端。由于胰腺肿瘤附近至该膜片，所述基板也可以是不能够牢固地保持它，特别是当肿瘤大小小于5毫米的直径。成像后，腹部区域应轻轻按摩直到动物是有意识的。它建议不要超过总成像和准备时间为每个动物长于90分钟，以防止腹痛。 塑料的尺寸板可能需要根据肿瘤或动物的大小来调整。如果肿瘤的大小是小于5毫米，肿瘤可能不能牢固地抓住由具有4mm的深度和由此运动伪影，可能会发生在MR图像的垂直弯曲板。此外，如果在动物的大小是大于20克，4毫米深度可能不足以容纳肿瘤。但是，过高的压力为腹部会损坏腹部神经系统瘫痪动物的下半身。 在使用标准的人胰腺癌细胞系的小鼠原位胰腺肿瘤模型已被用于研究胰腺肿瘤的治疗反应。然而，肿瘤取率和生长率分别为高度依赖于肿瘤细胞的特性（的该动物将具有在植入后可触及的肿瘤的百分比），所以建议以启动具有两倍的动物和它们的选择半轴承类似尺寸肿瘤。肿瘤的形态不规则，应排除在外，因为他们可能对治疗反应不同;形状不规则可以通过常规触诊来检测，但是超声成像将提供更好的评估9。某些细胞系可以在肝脏通常发展转移。肝转移（耗氧量）可以检测一般使用时，荧光素酶阳性细胞被植入或生物发光成像肝脏解剖的动物抢救无效死亡。肝脏代谢当量缩短动物的寿命，所以学习计划应相应建立。 定量DCE-MRI已成功实施了原位胰腺肿瘤的小鼠模型。定量基于所述流量限制凯蒂模型20 MR造影剂的药代动力学参数，动脉输入功能（AIF）必须可用。在本申请中，腹主动脉是视场之内，所以，AIF可以通过直接测量的MR造影剂浓度的在腹主动脉的变化而获得。然而，T鼠标腹主动脉他内径小于1毫米（0.5 - 0.7mm）的22，并且凭经验像素尺寸应比直径（0.125毫米），以防止严重的部分容积效应小至少4倍。此外，AIF的理想采样率是1 - 2秒23。在MRI，时空分辨率妥协SNR。因此它是具有挑战性，得到可靠的AIF中的小鼠的DCE-MRI。可替代地，基准区域（RR）模型可以使用。 RR模型采用在参考区域的对比度增强（通常肌肉组织）的数据以去除AIF中的药代动力学参数量化的需要。然而，在基准区域分数血管外胞外体积必须假设，这在一项研究中（N = 9）21造成约35％的误差。然而，肿瘤微血管以下治疗的变化可以精确地测量，如果相同的参考区域中选择在每一个时间。 24,25的其它原位小鼠模型。

该方法的总的目标是要应用动态对比增强磁共振成像（DCE-MRI）对小鼠原位胰腺肿瘤异种移植物。 DCE-MRI是一种非侵入性的方法，通过监测MR对比的变化超过一定时间内注射后，以评估微脉管的目标组织。 DCE-MRI已经被用于诊断恶性肿瘤，并评估肿瘤对各种疗法1-4。定量DCE-MRI已经呈现高重复性5。定量的靶组织的磁共振造影剂的药代动力学参数，在注射造影剂前获得不同的时间点和T1地图获得的所有DCE-MR图像必须配准6。然而，由于在腹部呼吸和蠕动运动，定量的DCE-MRI已经具备了胃肠道肿瘤应用有限。 原位胰腺肿瘤模型已被用于评估胰腺肿瘤反应下的生物治疗和化疗7,8。原位肿瘤模型被认为是优于传统的皮下模型中，由于在原来的肿瘤部位的微环境被反射并由此人肿瘤对治疗的反应，可以更准确地预测。然而，小鼠胰腺位于腹部的左上象限，在小鼠中，以便定量的DCE-MRI的原位胰腺肿瘤异种移植物还未容易地实现。 我们已经建立了小鼠腹部肿瘤中的DCE-MRI的协议通过使用正交弯曲的塑料板，以防止从胸部区域9运动传递定影的肿瘤。通过这款主板所施加的压力是局部的腹部，并没有导致呼吸困难。一种自动化图像配准技术已经被验证为在自由呼吸模式腹部器官的DCE-MRI，但它执行effectivelY仅在目标地区缓慢移动，并定期10。动物的呼吸速率成像期间可变的，在腹部区域，以便物理约束将是必要的，以检索在原位胰腺肿瘤小鼠模型可靠的药物动力学参数。我们已经使用正交弯曲的塑料板DCE-MRI中11-13成功定量在原位胰腺肿瘤异种移植物的MR造影剂的药动学参数。在这里，我们提出了原位胰腺肿瘤模型的详细过程，对移植瘤小鼠和药代动力学参数量化的DCE-MRI。

<table><tbody><tr><td>DMEM</td><td>Invitrogen</td><td>11965-118</td><td></td></tr><tr><td>Fetal bovine serum</td><td>Harlan Laboratories</td><td>BT-9501</td><td></td></tr><tr><td>Betadine</td><td>Purdue products</td><td>67618-153-01</td><td></td></tr><tr><td>5-0 Prolene sutures</td><td>Ethicon</td><td>8720H</td><td></td></tr><tr><td>9.4T MR scanner</td><td>Bruker Biospin Corporation</td><td>BioSpec 94/20 USR</td><td></td></tr><tr><td>Gadoteridol</td><td>Bracco Diagnostics Inc</td><td>NDC 0270-1111-03</td><td></td></tr><tr><td>Micro-polyethelene tube</td><td>Strategic Applications, Inc</td><td>#PE-10-25</td><td></td></tr><tr><td>30 G blunt tip needle</td><td>Strategic Applications, Inc</td><td>89134-194</td><td></td></tr><tr><td>Monitoring and gating system</td><td>SA instruments, Inc</td><td>Model 1030</td><td>This is an MR compatiable system to measure resiratory rating and body temperature of small animals at the same time.</td></tr><tr><td>Syringe pump</td><td>New Era Pump Systems, Inc.</td><td>NE-1600</td><td></td></tr></tbody></table>

dynamic contrast enhanced magnetic resonance imaging of an orthotopic pancreatic cancer mouse model

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been limitedly used for orthotopic pancreatic tumor xenografts due to severe respiratory motion artifact in the abdominal area. Orthotopic tumor models offer advantages over subcutaneous ones, because those can reflect the primary tumor microenvironment affecting blood supply, neovascularization, and tumor cell invasion. We have recently established a protocol of DCE-MRI of orthotopic pancreatic tumor xenografts in mouse models by securing tumors with an orthogonally bent plastic board to prevent motion transfer from the chest region during imaging. The pressure by this board was localized on the abdominal area, and has not resulted in respiratory difficulty of the animals. This article demonstrates the detailed procedure of orthotopic pancreatic tumor modeling using small animals and DCE-MRI of the tumor xenografts. Quantification method of pharmacokinetic parameters in DCE-MRI is also introduced. The procedure described in this article will assist investigators to apply DCE-MRI for orthotopic gastrointestinal cancer mouse models.

人类胰腺肿瘤细胞在小鼠胰腺创建实体瘤成功生长。 图1显示（A）的正常的胰腺，其中肿瘤细胞溶液被注入，和（B）的照片的代表性小鼠附有是胰腺肿瘤异种移植物原位（MIA PACA -2- ）。肿瘤位于腹部的左上腹，旁边的脾脏。它通常需要2 - 4周的肿瘤长到5 - 后细胞植入直径7毫米。 原位胰腺肿瘤异种移植的议案被大幅抑制，尽管运动伪影存在于MR图像有一定幅度。在T2W MR图像，MR信号在肿瘤区域上方的空气中的标准偏差为当胰腺肿瘤细胞原位移植相比的是，当皮下肿瘤模型，采用约2.5倍大。 图2A示出了用于DCE一个设置的示意原位pancreati的-MRIÇ肿瘤异种移植。橙色圆圈表示肿瘤，捕获由一个正交弯曲的塑料板的上端。 图2B示出了塑料板与尺寸的示意图。电路板的宽度（30毫米）的设计是相同的动物床的小鼠的宽度。该板的长度被设计成足够长，牢牢贴上胶带。板尖端（4mm）所的深度被设计为20克小鼠。 图2C示出了一个代表性的小鼠的T2W MR图像（矢状视图）轴承原位胰腺肿瘤异种移植物（MIA PACA-2）。肿瘤显示在虚线红圈，并诱导塑料板压痕表示用白色箭头。 定量的DCE-MRI被成功地应用于使用参考区域（RR）的模型原位胰腺肿瘤异种移植物，如在等式（7）所述。 图3A示出了在肿瘤区域（色标）的对比映射在MRÇ前1分钟<html> ontrast（钆特醇）注射，并在5至40分钟，在注射后，分别重叠T2W MR图像（灰度）。将小鼠轴承MIA PACA-2肿瘤异种移植物原位。 图3B示出均在肿瘤区域（3×3窗口）和椎旁肌区域（9×9窗口）具有两个白色方块分别表示对比度增强的曲线，在图图3A。图3C和3D示出ķ 反式和k EP地图，分别。 <img alt="图1" src="/files/ftp_upload/52641/52641fig1highres.jpg" width="600" /> 图1的照片（A）的注射肿瘤细胞溶液和（B）一种胰腺肿瘤异种移植物在免疫缺陷小鼠原位正常胰腺。肿瘤位于腹部的左上象限，用白色虚线圆表示。ES / ftp_upload / 52641 / 52641fig1highres.jpg"目标="_空白"&gt;点击此处查看该图的放大版本。 <img alt="图2" src="/files/ftp_upload/52641/52641fig2highres.jpg" width="600" /> 图中的胰腺肿瘤异种移植原位2示意图在DCE-MRI。 （A）的示意图DCE-MRI的胰腺肿瘤异种移植原位的（橙色圆形区域）一个安装的。的导管插入到尾静脉注入MR造影剂。一个正交弯曲的塑料板的尺寸（B）的示意图。（C）的小鼠T2W MR图像（矢状视图）附有是胰腺肿瘤异种移植物orthothopic用虚线表示红色圆圈，当垂直弯曲的塑料板被应用（用白色箭头指示）。 <a href="https://www.jove.com/files/ftp_upload/52641/52641fig2highres.jpg" target="_blank">请点击此处查看大图VERSI</a>在这个数字的。 <img alt="图3" src="/files/ftp_upload/52641/52641fig3highres.jpg" width="700" /> 图3. DCE-MR图像和胰腺肿瘤异种移植原位的paramatric地图。 （A）中 ，在之前或在5 1分钟和MR对比（钆特醇）注射后40分钟，对比图。（B）的对比度增强曲线平均化，在肿瘤区域（3×3窗口）和椎旁肌区域（9×9窗口）有2个白色方块，分别表示在图3A。（C）K 跨地图。（D）K EP地图。 <a href="https://www.jove.com/files/ftp_upload/52641/52641fig3highres.jpg" target="_blank">请点击此处查看该图的放大版本。</a>

Watch this Scientific Journal Video about Dynamic Contrast Enhanced Magnetic Resonance Imaging of an Orthotopic Pancreatic Cancer Mouse Model at JoVE.com

Dynamic Contrast Enhanced Magnetic Resonance Imaging of an Orthotopic Pancreatic Cancer Mouse Model

The goal of this protocol is to apply dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for orthotopic pancreatic tumor xenografts in mice. DCE-MRI is a non-invasive method to analyze microvasculature in a target tissue, and useful to assess vascular response in a tumor following a novel therapy.

原位胰腺癌小鼠模型的动态对比增强磁共振成像

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been limitedly used for orthotopic pancreatic tumor xenografts due to severe ...

dynamic-contrast-enhanced-magnetic-resonance-imaging-an-orthotopic

Nanyang Technological University

Research

JoVE Journal

Medicine

15.1K 次观看.  University of Alabama at Birmingham. The goal of this protocol is to apply dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for orthotopic pancreatic tumor xenografts in mice. DCE-MRI is a non-invasive method to analyze microvasculature in a target tissue, and useful to assess vascular response in a tumor following a novel therapy. 

视频: Dynamic Contrast Enhanced Magnetic Resonance Imaging of an Orthotopic Pancreatic Cancer Mouse Model

Fluorescent Orthotopic Mouse Model of Pancreatic Cancer

Pancreatic cancer remains one of the cancers for which survival has not improved substantially in the last few decades. Only 7% of diagnosed patients will survive longer than five years. In order to understand and mimic the microenvironment of pancreatic tumors, we utilized a murine orthotopic model of pancreatic cancer that allows non-invasive imaging of tumor progression in real time. Pancreatic cancer cells expressing green fluorescent protein (PANC-1 GFP) were suspended in basement membrane matrix, high concentration, (e.g., Matrigel HC) with serum-free media and then injected into the tail of the pancreas via laparotomy. The cell suspension in the high concentration basement membrane matrix becomes a gel-like substance once it reaches room temperature; therefore, it gels when it comes in contact with the pancreas, creating a seal at the injection site and preventing any cell leakage. Tumor growth and metastasis to other organs are monitored in live animals by using fluorescence. It is critical to use the appropriate filters for excitation and emission of GFP. The steps for the orthotopic implantation are detailed in this article so researchers can easily replicate the procedure in nude mice. The main steps of this protocol are preparation of the cell suspension, surgical implantation, and whole body fluorescent in vivo imaging. This orthotopic model is designed to investigate the efficacy of novel therapeutics on primary and metastatic tumors.

A procedure to implant green fluorescent protein-expressing pancreatic cancer cells (PANC-1 GFP) orthotopically into the pancreas of Balb-c Ola Hsd-Fox1nu mice to assess tumor progression and metastasis is presented here.

胰腺癌的荧光原位小鼠模型

Pancreatic cancer remains one of the cancers for which survival has not improved substantially in the last few decades. Only 7% of diagnosed patients will ...

科研

癌症研究

Utilizing High Resolution Ultrasound to Monitor Tumor Onset and Growth in Genetically Engineered Pancreatic Cancer Models

The LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mouse model represents an established and frequently used transgenic model to evaluate novel therapies in pancreatic cancer. Tumor onset is variable in the KPC model between 8 weeks and several months. Therefore, non-invasive imaging tools are required to screen for tumor onset and monitor for response to treatment. To address this issue, different approaches have emerged over the last years. High resolution ultrasound has major advantages such as non-invasiveness, fast session times and a high image resolution without radiation exposure. However, ultrasound in mice is not trivial and sufficient anatomical knowledge and practical skills are required to successfully perform high resolution ultrasound in preclinical pancreatic cancer models. With the following article, a detailed hands-on guide for abdominal ultrasound in murine models with a particular focus on endogenous pancreatic cancer models is presented. Furthermore, a summary of common mistakes and how to avoid them is provided.

This article describes the utilization of high-resolution ultrasound in genetically engineered pancreatic cancer mice. The primary aim is to provide a detailed instruction for detection and evaluation of endogenous pancreatic tumors.

应用高分辨率超声监测基因工程胰腺癌的肿瘤发病和生长

The LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mouse model represents an established and frequently used transgenic model to evaluate novel ...

Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma

The recent success of immune checkpoint blockade in melanoma and lung adenocarcinoma has galvanized the field of immuno-oncology as well as revealed the limitations of current treatments, as the majority of patients do not respond to immunotherapy. Development of accurate preclinical models to quickly identify novel and effective therapeutic combinations are critical to address this unmet clinical need. Pancreatic ductal adenocarcinoma (PDA) is a canonical example of an immune checkpoint blockade resistant tumor with only 2% of patients responding to immunotherapy. The genetically engineered KrasG12D+/-;Trp53R172H+/-;Pdx-1 Cre (KPC) mouse model of PDA recapitulates human disease and is a valuable tool for assessing therapies for immunotherapy resistant in the preclinical setting, but time to tumor onset is highly variable. Surgical orthotopic tumor implantation models of PDA maintain the immunobiological hallmarks of the KPC tissue-specific tumor microenvironment (TME) but require a time-intensive procedure and introduce aberrant inflammation. Here, we use an ultrasound-guided orthotopic tumor implantation model (UG-OTIM) to non-invasively inject KPC-derived PDA cell lines directly into the mouse pancreas. UG-OTIM tumors grow in the endogenous tissue site, faithfully recapitulate histological features of the PDA TME, and reach enrollment-sized tumors for preclinical studies by four weeks after injection with minimal seeding on the peritoneal wall. The UG-OTIM system described here is a rapid and reproducible tumor model that may allow for high throughput analysis of novel therapeutic combinations in the murine PDA TME.

We describe a protocol for the ultrasound guided implantation of murine-derived pancreatic ductal adenocarcinoma cell lines directly into the native tumor site. This approach resulted in pancreatic tumors detectable by ultrasound scanning within 2-4 weeks of injection, and significantly reduced the proportion tumor cell seeding on the peritoneal wall as compared to surgical orthotopic implantation.

毛尿胰腺腺腺腺癌超声引导正射植入

The recent success of immune checkpoint blockade in melanoma and lung adenocarcinoma has galvanized the field of immuno-oncology as well as revealed the ...

An Orthotopic Resectional Mouse Model of Pancreatic Cancer

There is a lack of satisfactory animal models to study adjuvant and/or neoadjuvant therapy in patients being considered for surgery of pancreatic cancer (PC). To address this deficiency, we describe a mouse model involving orthotopic implantation of PC followed by distal pancreatectomy and splenectomy. The model has been demonstrated to be safe and suitably flexible for the study of various therapeutic approaches in adjuvant and neo adjuvant settings.
In this model, a pancreatic tumor is first generated by implanting a mixture of human pancreatic cancer cells (luciferase-tagged AsPC-1) and human cancer associated pancreatic stellate cells into the distal pancreas of Balb/c athymic nude mice. After three weeks, the cancer is resected by re-laparotomy, distal pancreatectomy and splenectomy. In this model, bioluminescence imaging can be used to follow the progress of cancer development and effects of resection/treatments. Following resection, adjuvant therapy can be given. Alternatively, neoadjuvant treatment can be given prior to resection.
Representative data from 45 mice are presented. All mice underwent successful distal pancreatectomy/splenectomy with no issues of hemostasis. A macroscopic proximal pancreatic margin greater than 5 mm was achieved in 43 (96%) mice. The technical success rate of pancreatic resection was 100%, with 0% early mortality and morbidity. None of the animals died during the week after resection.
In summary, we describe a robust and reproducible technique for a surgical resection model of pancreatic cancer in mice which mimics the clinical scenario. The model may be useful for the testing of both adjuvant and neoadjuvant treatments.

In the clinical context, patients with localized pancreatic cancer will undergo pancreatectomy followed by adjuvant treatment. This protocol reported here aims to establish a safe and effective method of modelling this clinical scenario in nude mice, through orthotopic implantation of pancreatic cancer followed by distal pancreatectomy and splenectomy.

胰腺癌矫形小鼠模型

There is a lack of satisfactory animal models to study adjuvant and/or neoadjuvant therapy in patients being considered for surgery of pancreatic cancer ...

Bioluminescent Orthotopic Model of Pancreatic Cancer Progression

Pancreatic cancer has an extremely poor five-year survival rate of 4-6%. New therapeutic options are critically needed and depend on improved understanding of pancreatic cancer biology. To better understand the interaction of cancer cells with the pancreatic microenvironment, we demonstrate an orthotopic model of pancreatic cancer that permits non-invasive monitoring of cancer progression. Luciferase-tagged pancreatic cancer cells are resuspended in Matrigel and delivered into the pancreatic tail during laparotomy. Matrigel solidifies at body temperature to prevent leakage of cancer cells during injection. Primary tumor growth and metastasis to distant organs are monitored following injection of the luciferase substrate luciferin, using in vivo imaging of bioluminescence emission from the cancer cells. In vivo imaging also may be used to track primary tumor recurrence after resection. This orthotopic model is suited to both syngeneic and xenograft models and may be used in pre-clinical trials to investigate the impact of novel anti-cancer therapeutics on the growth of the primary pancreatic tumor and metastasis.

Improved understanding of pancreatic cancer biology is critically needed to enable the development of better therapeutic options to treat pancreatic cancer. To address this need, we demonstrate an orthotopic model of pancreatic cancer that permits non-invasive monitoring of cancer progression using in vivo bioluminescence imaging.

生物荧光原位模型胰腺癌进展

Pancreatic cancer has an extremely poor five-year survival rate of 4-6%.  New therapeutic options are critically needed and depend on improved ...

医学

Generation of an Orthotopic Xenograft of Pancreatic Cancer Cells by Ultrasound-Guided Injection

Pancreatic cancer (PCa) represents one of the deadliest cancer types worldwide. The reasons for PCa malignancy mainly rely on its intrinsic malignant behavior and high resistance to therapeutic treatments. Indeed, despite many efforts, both standard chemotherapy and innovative target therapies have substantially failed when moved from preclinical evaluation to the clinical setting. In this scenario, the development of preclinical mouse models better mimicking in vivo characteristics of PCa is urgently needed to test newly developed drugs. The present protocol describes a method to generate a mouse model of PCa, represented by an orthotopic xenograft obtained by ultrasound-guided injection of human pancreatic tumor cells. Using such a reliable and minimally invasive protocol, we also provide evidence of in vivo engraftment and development of tumor masses, which can be monitored by ultrasound (US) imaging. A noteworthy aspect of the PCa model described here is the slow development of the tumor masses over time, which allows precise identification of the starting point for pharmacological treatments and better monitoring of the effects of therapeutic interventions. Moreover, the technique described here is an example of implementation of the 3Rs principles since it minimizes pain and suffering and directly improves the welfare of animals in research.

We present a protocol to generate a minimally invasive orthotopic pancreatic cancer model by ultrasound-guided injection of human pancreatic cancer cells and the subsequent monitoring of tumor growth in vivo by ultrasound imaging.

通过超声引导注射产生胰腺癌细胞的原位异种移植物

Pancreatic cancer (PCa) represents one of the deadliest cancer types worldwide. The reasons for PCa malignancy mainly rely on its intrinsic malignant ...

Syngeneic Mouse Orthotopic Allografts to Model Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is a very complex disease characterized by a heterogeneous tumor microenvironment made up of a diverse stroma, immune cells, vessels, nerves, and extracellular matrix components. Over the years, different mouse models of PDAC have been developed to address the challenges posed by its progression, metastatic potential, and phenotypic heterogeneity. Immunocompetent mouse orthotopic allografts of PDAC have shown good promise owing to their fast and reproducible tumor progression in comparison to genetically engineered mouse models. Moreover, combined with their ability to mimic the biological features observed in autochthonous PDAC, cell line-based orthotopic allograft mouse models enable large-scale in vivo experiments. Thus, these models are widely used in preclinical studies for rapid genotype-phenotype and drug-response analyses. The aim of this protocol is to provide a reproducible and robust approach to successfully inject primary mouse PDAC cell cultures into the pancreas of syngeneic recipient mice. In addition to the technical details, important information is given that must be considered before performing these experiments.

Syngeneic mouse orthotopic allografts of pancreatic ductal adenocarcinoma (PDAC) recapitulate the biology, phenotypes, and therapeutic responses of disease subtypes. Owing to their fast, reproducible tumor progression, they are widely used in preclinical studies. Here, we show common practices to generate these models, injecting syngeneic murine PDAC cultures into the pancreas.

同系小鼠原位同种异体移植物模拟胰腺癌

Pancreatic ductal adenocarcinoma (PDAC) is a very complex disease characterized by a heterogeneous tumor microenvironment made up of a diverse stroma, ...

DCE-MRI of Orthotopic Pancreatic Tumor Xenografts: A Method to Assess Microvasculature in a Target Tumor Tissue

Source: Kim, H. et al.&#160;<a href="https://www.jove.com/v/52641/" target="_blank">Dynamic Contrast Enhanced Magnetic Resonance Imaging of an Orthotopic Pancreatic Cancer Mouse Model</a>. J. Vis. Exp. (2015).
This video describes the technique of DCE-MRI for orthotropic pancreatic tumor xenografts in mice.&#160;DCE-MRI is a non-invasive method to analyze microvasculature in a target tissue, and useful to assess vascular response in a tumor following a novel therapy. This method will assist investigators to apply DCE-MRI for orthotopic gastrointestinal cancer mouse models.

原位胰腺肿瘤异种移植物的 DCE-MRI:一种评估目标肿瘤组织中微血管系统的方法

Source: Kim, H. et al.&#160;Dynamic Contrast Enhanced Magnetic Resonance Imaging of an Orthotopic Pancreatic Cancer Mouse Model. J. Vis. Exp. (2015).
This ...

JoVE Encyclopedia of Experiments

胰腺癌

Assays & techniques

Bioluminescent Orthotopic Pancreatic Cancer Mouse Model: A Non-invasive Technique to Monitor Cancer Progression in Mice

Source: Chai, M. G., et al. <a href="https://www.jove.com/v/50395/" target="_blank">Bioluminescent Orthotopic Model of Pancreatic Cancer Progression</a>.&#160;J. Vis. Exp.&#160;(2013).
This video demonstrates an orthotopic model of pancreatic cancer that utilizes Matrigel for localized cell delivery and&#160;in vivo&#160;bioluminescence imaging for non-invasive monitoring of tumor progression. The orthotopic model is suited to both syngeneic and xenograft models and could be used in pre-clinical trials to investigate the impact of novel anti-cancer therapeutics on the growth of the primary pancreatic tumor and metastasis.

生物发光原位胰腺癌小鼠模型:一种监测小鼠癌症进展的非侵入性技术

Source: Chai, M. G., et al. Bioluminescent Orthotopic Model of Pancreatic Cancer Progression.&#160;J. Vis. Exp.&#160;(2013).
This video demonstrates an ...

Orthotopic Homograft Tumor Transplantation: A Technique to Generate Pancreatic Tumor Mouse Models

Source: An, X. et al.&#160;<a href="https://www.jove.com/v/57460/" target="_blank">Immunophenotyping of Orthotopic Homograft (Syngeneic) of Murine Primary KPC Pancreatic Ductal Adenocarcinoma by Flow Cytometry</a>. J. Vis. Exp. (2018)
The video explains a stepwise surgical method for orthotopic implantation of a tumor fragment from a cancerous donor to the pancreas of a non-cancerous recipient mice for development of pancreatic cancer. Orthotopically implanted PDAC could recapture the tissue microenvironment of human pancreatic cancers than conventional subcutaneous (SC) models more accurately.

原位同种移植物肿瘤移植:一种生成胰腺肿瘤小鼠模型的技术

Source: An, X. et al.&#160;Immunophenotyping of Orthotopic Homograft (Syngeneic) of Murine Primary KPC Pancreatic Ductal Adenocarcinoma by Flow Cytometry. ...