文章：

最大化小鼠癌症模型

Maximizing mouse cancer models

原文发布日期：2007-09-01

DOI: 10.1038/nrc2192

类型: Review Article

开放获取: 否

要点：

1. The laboratory mouse (Mus musculus) is one of the best model systems for investigations of cancer biology in vivo, ranging from basic models such as xenograft tumours derived from tumour cell lines or explants, to highly complex genetically engineered mice (GEM).
2. We suggest that xenografts should no longer be referred to as mouse cancer models. Xenografts represent an intermediate step between cell culture and mouse cancer models, and could be more accurately termed 'animal culture'.
3. GEM can be classified as either transgenic or endogenous. This distinction is not merely semantic but is highly relevant, because the type of GEM can determine the experimental outcome in certain situations.
4. Transgenic GEM are mutant mice that express oncogenes or dominant-negative tumour-suppressor genes (TSGs) in a non-physiological manner owing to ectopic promoter and enhancer elements. Advantages of transgenic GEM include the ability to reversibly control target-gene expression with exogenous ligands. One disadvantage is that it might be difficult to elicit the exquisite control necessary to express oncogenes at physiological levels.
5. Endogenous GEM represent mutant mice that lose the expression of TSGs or express dominant-negative TSGs or oncogenes from their native promoters through the use of knockout and knockin technology. Conditional GEM models rely on the use of site-specific recombinases, such as Cre, to control the spatiotemporal mutation of the mouse genome. The use of these conditional models will prove to be key in addressing important molecular and therapeutic questions.
6. Modern GEM are poised to explore facets of cancer biology and medicine that are difficult or impossible to pursue clinically. However, all GEM described so far have certain shortcomings in mimicking human malignancy. Several issues (such as humanizing mice) and practical considerations concerning GEM will need to be addressed in order to meet our objectives.

要点翻译：

1. 实验室小鼠（Mus musculus）是体内癌症生物学研究的最佳模型系统之一，其范围涵盖从肿瘤细胞系或组织块衍生的异种移植瘤等基础模型，到高度复杂的基因工程小鼠（GEM）。
2. 我们建议不应再将异种移植称为小鼠癌症模型。异种移植代表了细胞培养与小鼠癌症模型之间的中间步骤，更准确地应称为“动物培养”。
3. GEM可分为转基因型和内源型。这种区分不仅具有语义学意义，而且高度相关，因为在某些情况下GEM的类型可能决定实验结果。
4. 转基因GEM是通过异位启动子和增强子元件以非生理学方式表达癌基因或显性负性肿瘤抑制基因（TSG）的突变小鼠。其优势包括能够通过外源配体可逆地控制靶基因表达。缺点之一是实现精确调控以使癌基因在生理水平表达可能存在困难。
5. 内源型GEM则是通过基因敲除和敲入技术，使突变小鼠从其天然启动子失去TSG表达或表达显性负性TSG或癌基因。条件性GEM模型依赖位点特异性重组酶（如Cre）来控制小鼠基因组的时空突变。这些条件性模型的应用将成为解决重要分子和治疗学问题的关键。
6. 现代GEM旨在探索临床难以或无法实现的癌症生物学和医学领域。然而迄今为止描述的所有GEM在模拟人类恶性肿瘤方面都存在某些缺陷。为实现我们的目标，需要解决关于GEM的若干问题（如人源化小鼠）及实际考量。

英文摘要：

Animal models of cancer provide an alternative means to determine the causes of and treatments for malignancy, thus representing a resource of immense potential for cancer medicine. The sophistication of modelling cancer in mice has increased to the extent that investigators can both observe and manipulate a complex disease process in a manner impossible to perform in patients. However, owing to limitations in model design and technology development, and the surprising underuse of existing models, only now are we realising the full potential of mouse models of cancer and what new approaches are needed to derive the maximum value for cancer patients from this investment.

摘要翻译： 

癌症动物模型为探究恶性肿瘤的病因与治疗提供了另一种途径，是癌症医学极具潜力的资源。随着小鼠癌症建模技术的日益精进，研究人员已能在体内观察并干预这一复杂疾病过程，而这种方式在患者身上根本无法实现。然而，受限于模型设计和技术发展，加之现有模型竟被惊人地闲置，我们直到最近才意识到小鼠癌症模型的全部潜力，并思考需采取哪些新策略，才能让这一投入为癌症患者带来最大收益。

原文链接：

Maximizing mouse cancer models