Orthotopic mouse models for the preclinical and translational study of targeted therapies against metastatic human thyroid carcinoma with BRAF(V600E) or wild-type BRAF.
Orthotopic mouse models for the preclinical and translational study of targeted therapies against metastatic human thyroid carcinoma with BRAF(V600E) or wild-type BRAF.
复制标题
DOI：
10.1038/onc.2013.544
复制
发表时间：
2014-11-20
期刊：
影响因子：
8
通讯作者：
Nucera C
中科院分区：
文献类型：
--
作者：
Antonello ZA;Nucera C
晚期和转移性甲状腺癌的分子特征涉及肿瘤微环境中激活的多个基本途径的失调。它们包括影响肿瘤发生、进展和转移的 BRAFV600E 和 AKT。人类甲状腺癌原位小鼠模型基于人类细胞系，这些细胞系通常含有人类甲状腺癌中发现的遗传改变。它们可以在体内和原位（进入甲状腺）复制侵袭性和难治性人类晚期甲状腺癌的许多特征，包括局部侵袭和转移。人源化原位小鼠模型似乎是理想的，通常用于化合物和疗法的临床前和转化研究，不仅因为它们可以模仿人类疾病的关键方面（例如转移），而且还因为它们的可重复性。此外，它们还可能提供评估治疗的系统效应的可能性。迄今为止，人甲状腺癌体内模型主要用于测试单一化合物、非选择性和选择性。尽管与非选择性药物相比，不同选择性药物具有更高的抗肿瘤活性和更低的毒性，但大多数药物只能延缓疾病进展，最终可能会以类似的攻击行为重新开始。侵袭性甲状腺肿瘤（例如，未分化或低分化甲状腺癌）携带多种复杂的基因改变，这些改变可能共同促进疾病进展，并可能赋予对单一化合物治疗的耐药性。人类甲状腺癌的原位模型也有可能成为测试新型组合疗法的良好模型。在本文中，我们将总结在原位小鼠模型中选择性和非选择性单一化合物的临床前测试结果，该模型基于经过验证的携带 BRAFV600E 突变或野生型 BRAF 的人类甲状腺癌细胞系。此外，我们将讨论该模型在组合方法中的潜在用途，预计将在即将到来的人类甲状腺癌基础和临床研究中进行。
Molecular signature of advanced and metastatic thyroid carcinoma involves deregulation of multiple fundamental pathways activated in the tumor microenvironment. They include BRAFV600E and AKT that affect tumor initiation, progression and metastasis. Human thyroid cancer orthotopic mouse models are based on human cell lines that generally harbor genetic alterations found in human thyroid cancers. They can reproduce in vivo and in situ (into the thyroid) many features of aggressive and refractory human advanced thyroid carcinomas, including local invasion and metastasis. Humanized orthotopic mouse models seem to be ideal and commonly used for preclinical and translational studies of compounds and therapies not only because they may mimic key aspects of human diseases (e.g. metastasis), but also for their reproducibility. In addition, they might provide the possibility to evaluate systemic effects of treatments. So far, human thyroid cancer in vivo models were mainly used to test single compounds, non selective and selective. Despite the greater antitumor activity and lower toxicity obtained with different selective drugs in respect to non-selective ones, most of them are only able to delay disease progression, which ultimately could restart with similar aggressive behavior. Aggressive thyroid tumors (for example, anaplastic or poorly differentiated thyroid carcinoma) carry several complex genetic alterations that are likely cooperating to promote disease progression and might confer resistance to single-compound approaches. Orthotopic models of human thyroid cancer also hold the potential to be good models for testing novel combinatorial therapies. In this article, we will summarize results on preclinical testing of selective and nonselective single compounds in orthotopic mouse models based on validated human thyroid cancer cell lines harboring the BRAFV600E mutation or with wild-type BRAF. Furthermore, we will discuss the potential use of this model also for combinatorial approaches, which are expected to take place in the upcoming human thyroid cancer basic and clinical research.