Modeling metastasis by controlled inactivation of Rb

描述（由申请人提供）：癌症研究的持续进展在很大程度上取决于有效动物模型的开发。然而，只有少数转基因小鼠存在，其中转移阶段的癌发生可以准确地再现。对这种模型的需求非常高，因为转移进展是晚期癌症最致命的特征。建模和靶向转移是PI的长期目标最近，我们已经描述了在具有视网膜母细胞瘤易感基因（Rb）的单个野生型拷贝的小鼠中发展的甲状腺C细胞癌的自发转移。在该模型中，转移性疾病的初始阶段可以通过重建Rb功能来减轻。这些结果是在一个很好的一致性与其他研究表明，Rb可能有助于这种转移相关的细胞特性，如运动，粘附和侵袭。具有临床重要性的是，Rb或Rb介导的通路中的畸变经常在晚期人类癌症（包括肺的小细胞癌）中观察到。不幸的是，与Rb失活相关的转移模型的仔细表征是不可能的，因为大多数Rb+/-小鼠在发展广泛的C细胞转移之前死于垂体中叶肿瘤。最近，已经描述了几种小鼠遗传系统，其允许以时间、空间和细胞类型特异性方式对基因进行条件失活。通过应用这些系统，我们建议（1）制备小鼠模型，允许选择性灭活Rb在甲状腺C-细胞，（2）测试的假设，Rb的C-细胞特异性灭活的结果在甲状腺C-细胞癌变过程中的发展明显的转移，和（3）测试的假设，Rb表达的重建将减弱转移进展。预计这些研究的成功将导致新的、准确的动物模型的开发，使人们能够更好地了解Rb在转移过程中的作用，并提供RB介导的体内转移抑制的最严格证据。因此，将提供一个坚实的基础，设计和测试治疗相关的方法，以合理的基因靶向与Rb缺陷相关的晚期癌症。

DESCRIPTION (provided by applicant): Continuous advances in cancer research greatly depend on development of valid animal models. However, only few genetically modified mice exist in which metastatic stage of carcinogenesis can be accurately reproduced. A need for such models is extremely high, because metastatic progression is the most lethal feature of advanced cancer. Modeling and targeting metastasis are long-term goals of the Pl Recently, we have described spontaneous metastasis of thyroid C-cell carcinomas developing in mice with a single wild-type copy of the retinoblastoma susceptibility gene (Rb). In that model initial stages of metastatic disease can be alleviated by reconstituting Rb function. These results are in a good concordance with other studies indicating that Rb might contribute to such metastasis-relevant cell properties as motility, adhesion, and invasion. Of clinical importance, aberrations in Rb or Rb-mediated pathways are often observed in advanced human cancers, including small cell carcinoma of the lung. Unfortunately, careful characterization of the metastatic model associated with Rb inactivation has been impossible because majority of Rb+/- mice succumb to tumors of the pituitary intermediate lobe before development of extensive C-cell metastasis. Recently, several mouse genetic systems have been described, which allow for conditional inactivation of genes in temporal, spatial and cell type-specific fashion. By applying these systems we propose to (1) prepare mouse models allowing selective inactivation of Rb in thyroid C-cells, (2) test the hypothesis that C-cell specific inactivation of Rb results in development of overt metastasis during thyroid C-cell carcinogenesis, and (3) test the hypothesis that reconstitution of Rb expression will attenuate metastatic progression. It is expected that success of these studies will result in development of new and accurate animal models, allow for better understanding of Rb roles in metastatic process, and provide the most rigorous proof of RB-mediated suppression of metastasis in vivo. Thus, a solid foundation will be provided for design and testing therapeutically relevant approaches to rational gene targeting of advanced cancer associated with Rb deficiency.