文章：

细胞在其原生栖息地的追踪：上皮肿瘤的谱系追踪

Tracking cells in their native habitat: lineage tracing in epithelial neoplasia

原文发布日期：2013-02-07

DOI: 10.1038/nrc3460

类型: Review Article

开放获取: 否

要点：

1. Lineage tracing in transgenic mice allows the study of stem, progenitor and cancer cells in their native environment and can give quantitative insight into cell behaviour. Experiments have two essential components: an inducible genetic switch, such as Cre recombinase, that activates the expression of the second essential component, the reporter gene, which allows the behaviour of cells to be followed.
2. Each lineage tracing system requires characterization to define the properties of the cell subpopulation being followed. Quantifying cell behaviour requires stringent controls and large-scale data sets.
3. Quantitative single cell lineage tracing has revealed cell behaviour in homeostatic epithelial tissues, such as the skin, oesophagus and intestine.
4. The squamous epithelia of the skin and oesophagus are maintained by a single progenitor cell population that generates progenitor and differentiated cells to achieve homeostasis. The epidermis contains quiescent stem cells but the oesophageal epithelium does not.
5. Intestinal epithelium is maintained by cycling stem cells expressing Lgr5 that reside in their niche at the base of the crypt. The restricted size of the niche is key in maintaining homeostasis.
6. Oncogenes disrupt the balance between proliferation and differentiation in epithelial progenitors. For example, TP53-mutant cells in ultraviolet (UV)-exposed epidermis generate an excess of proliferating daughter cells, resulting in exponential expansion of mutant clones.
7. Preliminary studies in benign tumours reveal that intestinal adenomas are sustained by a population of Lgr5-expressing cells that have escaped the niche, and in epidermal papillomas stem and progenitor cells proliferate in a manner that is reminiscent of wound healing.
8. Lineage tracing in malignant lesions is more challenging owing to heterogeneity within and between tumours, but has already revealed unexpected early invasion and metastasis in pancreatic cancer models.

要点翻译：

1. 转基因小鼠的谱系追踪技术能够在原生环境中研究干细胞、祖细胞及癌细胞，从而定量揭示细胞行为。该实验包含两个核心要素：一是可诱导的遗传开关（如Cre重组酶），用于激活第二要素——报告基因的表达，从而实现对细胞行为的追踪。
2. 每个谱系追踪系统都需要明确被追踪细胞亚群的特征属性。量化细胞行为需设置严格对照并获取大规模数据集。
3. 定量单细胞谱系追踪已揭示稳态上皮组织（如皮肤、食管和肠道）中的细胞行为。
4. 皮肤和食管的鳞状上皮由单一祖细胞群体维持，这些祖细胞通过产生新的祖细胞和分化细胞维持稳态。表皮中存在静息干细胞，而食管上皮则不具备此类细胞。
5. 肠上皮由表达Lgr5的循环干细胞维持，这些干细胞定位于隐窝底部的微环境中。微环境的有限空间是维持稳态的关键。
6. 癌基因会破坏上皮祖细胞增殖与分化间的平衡。例如，紫外线暴露表皮中的TP53突变细胞会产生过量增殖子代细胞，导致突变克隆呈指数级扩张。
7. 对良性肿瘤的初步研究表明，肠腺瘤由一群脱离微环境的Lgr5阳性细胞维持；而在表皮乳头状瘤中，干细胞和祖细胞以类似伤口愈合的方式持续增殖。
8. 恶性肿瘤的谱系追踪因肿瘤内及肿瘤间异质性而更具挑战性，但该技术已在胰腺癌模型中意外发现早期侵袭和转移现象。

英文摘要：

For tumours to develop, mutations must disrupt tissue homeostasis in favour of deregulated proliferation. Genetic lineage tracing has uncovered the behaviour of proliferating cells that underpins the maintenance of epithelial tissues and the barriers that are broken in neoplastic transformation. In this Review, we focus on new insights revealed by quantifying the behaviour of normal, preneoplastic and tumour cells in epithelia in transgenic mice and consider their potential importance in humans.

摘要翻译： 

肿瘤的发生需要突变破坏组织稳态，使细胞失控性增殖。遗传谱系追踪揭示了增殖细胞的行为，这些行为是维持上皮组织稳态的基础，而在肿瘤转化过程中被破坏。本综述聚焦于通过转基因小鼠模型定量分析正常、癌前及肿瘤细胞在上皮组织中的行为所带来的新见解，并探讨其在人类中的潜在意义。

原文链接：

Tracking cells in their native habitat: lineage tracing in epithelial neoplasia