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发展。然而，只有少数转基因小鼠能够准确复制癌变的转移阶段。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Pl的长期目标。最近，我们用视网膜母细胞瘤易感基因(Rb)的单个野生型拷贝描述了小鼠甲状腺C细胞癌的自发转移。在该模型中，通过重建Rb功能可以缓解转移性疾病的初始阶段。这些结果与其他研究结果很好地一致，表明Rb可能有助于转移相关的细胞特性，如运动性、粘附性和侵袭性。具有重要临床意义的是，在晚期人类癌症中经常观察到Rb或Rb介导的通路的异常，包括肺小细胞癌。不幸的是，与Rb失活相关的转移模型的仔细描述是不可能的，因为大多数Rb+/-小鼠在发生广泛的C细胞转移之前死于垂体中间叶肿瘤。最近，已经描述了几种小鼠遗传系统，这些系统允许以时间、空间和细胞类型特定的方式有条件地使基因失活。通过应用这些系统，我们建议(1)准备允许选择性灭活Rb在甲状腺C细胞中的小鼠模型，(2)检验C细胞特异性失活Rb导致在甲状腺C细胞癌变过程中发生显性转移的假说，以及(3)检验Rb表达重建将减缓转移进展的假说。预计这些研究的成功将导致新的准确的动物模型的发展，允许更好地了解Rb在转移过程中的作用，并为Rb介导的体内转移抑制提供最严格的证据。因此，将为设计和测试与Rb缺乏症相关的晚期癌症的合理基因靶向的治疗相关方法提供坚实的基础。

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.