小鼠中人类胸膜皮质瘤的PET/CT的植入与监测
Summary
本文介绍了通过将H2052/484中皮瘤细胞植入免疫功能性贫血小鼠胸腔，生成人类胸膜中皮瘤的正交小鼠模型。通过非侵入性多式联运 =18F_-2-fluo-2-脱氧-D-葡萄糖正电子发射断层扫描和计算机断层成像，对胸腔内肿瘤的发展进行了纵向监测。
Abstract
恶性胸膜内皮瘤（MPM）是一种罕见的、具有攻击性的肿瘤，在覆盖肺部、心脏和胸腔的中皮内出现。MPM 开发主要与石棉相关。治疗只能提供适量的存活率，因为中位平均存活率从诊断时起为9-18个月。因此，必须确定更有效的治疗方法。描述新治疗靶点的大多数数据都是从体外实验中获得的，需要在可靠的体内临床前模型中进行验证。本文介绍了一种在将人类MPM细胞系H2052/484注射到免疫缺陷贫血小鼠胸腔后获得的这种可靠的MPM正位模型。在正交位位移植允许研究肿瘤在自然体内环境的进展。正电子发射断层扫描/计算机断层扫描（PET/CT）分子成像使用临床[18F+-2-氟-2-脱氧-D-葡萄糖（=18F_FDG）放射跟踪器是检查MPM患者的首选诊断方法。因此，使用18F_FDG-PET/CT 纵向监测 H2052/484 正射模型的疾病进展。这种技术具有很高的3R潜力（Reuce动物的数量，Refine以减轻疼痛和不适，和Replace动物实验与替代品），因为肿瘤的发展可以监测非侵入性和动物的数量可以大大减少。
该模型显示高开发率，快速肿瘤生长，是成本效益，并允许快速临床翻译。通过使用这个正交异种性异种性MPM模型，研究人员可以评估治疗干预后可靠MPM模型的生物反应。
Introduction
恶性胸膜内皮瘤（MPM）是一种癌症，最常见的是与接触石棉纤维1，2，3。虽然石棉在大多数西方国家已被禁用4，5，6，MPM的发病率仍然增加7，8。最近，老鼠接触碳纳米管表明，它们可能导致人类健康风险很大。数据表明，接触这些产品可能导致慢性炎症和分子变化（例如，肿瘤抑制途径的丧失），从而导致恶性间皮瘤的恶化。目前，多壁碳纳米管是纳米技术最重要的产品之一，并越来越多地被纳入各种产品，如复合材料、储能材料、医药、电子和环境修复材料。
MPM是一种预后不佳的癌症，大多数患者在诊断后两年内死亡，因为目前治疗方式11的疗效有限。MPM治疗的选择取决于癌症阶段。对于大多数早期MPM（阶段1，可能一些阶段2或3肿瘤），临床方法是一种多模态疗法，包括肿瘤的手术切除，与放疗和化疗12相关。结合顺铂和pemxed联合化疗，用于治疗大多数被诊断为晚期局部侵入性疾病的患者，即不适合手术切除，或否则不适合治疗手术13，14。因此，迫切需要为MPM患者开发更有效的治疗方法。然而，很少有经过验证的体内动物模型能够反映MPM的临床相关性。几个小鼠MPM模型已经开发，但其中大多数没有忠实地重述MPM肿瘤微环境15，16，17，18的复杂方面。在小鼠、基因工程MPM小鼠模型或鼠MPM细胞系协同移植模型中使用石棉诱导的MPM受到基本表型和功能差异的限制，因此，将新发现转化为临床效果不佳。其他临床前小鼠MPM模型主要依靠免疫缺陷小鼠的人类细胞系的皮下或围肠异种移植物。虽然这些模型很容易监测和提供基本数据，但这些异种移植物的微观环境并不与人类肿瘤相媲美，损害大多数这些临床前研究的转化能力17，19。相反，正交异种移植更好地反映患者的肿瘤行为和治疗反应，因为他们被一个类似的微环境包围，在原始肿瘤部位16发现。
分子成像由+18F_FDG-PET/CT是纵向监测MPM20，21患者疾病进展的首选方法。因此，采用这种非侵入性成像方法，极大地促进了临床前研究转化为临床试验16，22。此外，它有助于减少所需的动物数量，因为每只动物代表自己的控制随着时间的推移。
在本文中，我们提出了一个可靠的正交异种异种移植MPM模型后，获得的人MPM细胞系H2052/484注射到胸腔的贫血小鼠。结合18F_FDG-PET/CT成像，该模型是研究新的诊断策略和治疗人体MPM的功能和机械效应的宝贵和可重复的方法。
Protocol
Representative Results
Discussion
本文介绍了注射在贫血小鼠胸腔中的MPM H2052/484细胞的原始正交模型，以及一种通过小动物PET/CT成像进行监测的方法。该模型可以实施与适度的动物处理和手术技能，并显示一个非常好的发展速度。它允许在未治疗的小鼠中，在未治疗的小鼠中留出约10周的大实验窗口，并在注射后2周内对肿瘤进行非侵入性纵向检测。
正交模型依赖于将活细胞或组织直接植入肿瘤的初始环境中?…
Offenlegungen
The authors have nothing to disclose.
Acknowledgements
这项研究由利格·吉纳沃塞癌症（V.S.-B.）和日内瓦和洛桑大学和医院的生物医学成像中心（CIBM）资助（到D.J.C.、O.B.和S.G.）。
Materials
| 3-mice bed | Minerve | bed for mice imaging | |
| Athymic Nude-Foxn1n nu/nu | Envigo, Huntingdon, UK | 6907F | immunodeficient mouse |
| Betadine | Mundipharma Medical Company, CH | 111131 | polyvidone iodine solution |
| Dulbecco's Phosphate-Buffered Saline (DPBS) | ThermoFisher Scientific, Waltham, MA, USA | 14190094 | Buffer for cell culture |
| Fetal bovine serum (FBS) | PAA Laboratories, Pasching, Austria | A15-101 | cell culture medium supplement |
| Insulin syringes | BD Biosciences, San Jose, CA, USA | 324826 | syringe for cell injection |
| Penicillin/Streptomycin | ThermoFisher Scientific, Waltham, MA, USA | 15140122 | antibiotics for cell culture medium |
| RPMI 1640 | ThermoFisher Scientific, Waltham, MA, USA | 61870010 | basal cell culture medium |
| Temgesic (Buprenorphin 0.3 mg/mL) | Alloga SA, CH | 700320 | opioid analgesic product |
| Triumph PET/SPECT/CT | Trifoil, Chatsworth, CA, USA | imaging equipment | |
| Trypsin | ThermoFisher Scientific, Waltham, MA, USA | 25050014 | enzymatic cell dissociation buffer |
| Virkon S 2% | Milian, Vernier, CH | 972472 | disinfectant |
| Vivoquant | Invicro, Boston, MA, USA |
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