Preclinical models for neuroblastoma: establishing a baseline for treatment.
Preclinical models for neuroblastoma: establishing a baseline for treatment.
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DOI：
10.1371/journal.pone.0019133
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发表时间：
2011-04-29
期刊：
影响因子：
3.7
通讯作者：
Lahti JM
中科院分区：
文献类型：
--
作者：
Teitz T;Stanke JJ;Federico S;Bradley CL;Brennan R;Zhang J;Johnson MD;Sedlacik J;Inoue M;Zhang ZM;Frase S;Rehg JE;Hillenbrand CM;Finkelstein D;Calabrese C;Dyer MA;Lahti JM
儿科癌症的临床前模型对于临床试验测试新的化疗组合是必不可少的。神经母细胞瘤临床前试验最广泛使用的遗传模型是TH-MYCN小鼠。这只易患神经母细胞瘤的小鼠概括了人类神经母细胞瘤的许多特征。该模型的局限性包括骨髓转移频率低，缺乏关于该系统中的基因表达模式是否与人类神经母细胞瘤相似的信息，肿瘤形成速度相对较慢，以及不同遗传背景下肿瘤外显率的差异性。作为另一种选择，临床前研究经常使用人类细胞系异种移植到免疫低下的小鼠体内，作为侧翼植入或原位移植。该系统的缺点包括使用已培养多年的细胞系、侧翼微环境不适当或困难、原位移植手术耗时以及缺乏完整的免疫系统。在这里，我们对这两个系统进行了表征和优化，以增加它们在临床前研究中的实用性。我们发现TH-MYCN小鼠在脊柱旁神经节发生肿瘤，但在肾上腺不发生肿瘤，其细胞和基因表达模式类似于人类NB。此外，我们还提出了一种新的超声引导、微创原位异种移植方法。这种注射技术快速、准确地靶向注射的细胞，并导致有效的植入。我们还证明，肿瘤可以在可视化之前使用超声、MRI和生物发光进行检测、监测和量化。最后，我们开发并测试了一种“标准护理”化疗方案。该方案基于神经母细胞瘤的当前治疗方法，为新的治疗药物的比较提供了基准。研究表明，使用神经母细胞瘤的TH-NMYC模型和原位异种移植模型为测试这种毁灭性的儿童癌症的新化疗方法提供了最佳组合。
Preclinical models of pediatric cancers are essential for testing new chemotherapeutic combinations for clinical trials. The most widely used genetic model for preclinical testing of neuroblastoma is the TH-MYCN mouse. This neuroblastoma-prone mouse recapitulates many of the features of human neuroblastoma. Limitations of this model include the low frequency of bone marrow metastasis, the lack of information on whether the gene expression patterns in this system parallels human neuroblastomas, the relatively slow rate of tumor formation and variability in tumor penetrance on different genetic backgrounds. As an alternative, preclinical studies are frequently performed using human cell lines xenografted into immunocompromised mice, either as flank implant or orthtotopically. Drawbacks of this system include the use of cell lines that have been in culture for years, the inappropriate microenvironment of the flank or difficult, time consuming surgery for orthotopic transplants and the absence of an intact immune system. Here we characterize and optimize both systems to increase their utility for preclinical studies. We show that TH-MYCN mice develop tumors in the paraspinal ganglia, but not in the adrenal, with cellular and gene expression patterns similar to human NB. In addition, we present a new ultrasound guided, minimally invasive orthotopic xenograft method. This injection technique is rapid, provides accurate targeting of the injected cells and leads to efficient engraftment. We also demonstrate that tumors can be detected, monitored and quantified prior to visualization using ultrasound, MRI and bioluminescence. Finally we develop and test a “standard of care” chemotherapy regimen. This protocol, which is based on current treatments for neuroblastoma, provides a baseline for comparison of new therapeutic agents. The studies suggest that use of both the TH-NMYC model of neuroblastoma and the orthotopic xenograft model provide the optimal combination for testing new chemotherapies for this devastating childhood cancer.
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