文章：

模拟癌症的分子电路

Modelling the molecular circuitry of cancer

原文发布日期：2002-05-01

DOI: 10.1038/nrc795

类型: Review Article

开放获取: 否

要点：

1. The process of malignant transformation occurs in discrete histopathological steps, many of which correlate with specific genetic alterations. Several lines of evidence implicate a limited number of molecular pathways, the disruption of which contributes to most, if not all, cancers.
2. Rodent and human experimental models of cancer have contributed to our understanding of specific cancer-associated mutations. Although these cancer models share many essential components, several important signalling pathways seem to function differently in human and rodent models of transformation.
3. Immortalization is an essential prerequisite for the formation of a tumour cell. Human cells must circumvent two barriers — replicative senescence and cellular crisis — that limit cell lifespan to achieve immortalization. These barriers are regulated by telomere shortening and by the RB and p53 tumour-suppressor pathways.
4. Ablation of the ARF–p53 pathway suffices to immortalize many mouse cells. Telomere shortening does not seem to limit the lifespan of cells that are derived from inbred mice.
5. In parallel with these differences in immortalization, pairs of introduced oncogenes will transform mouse cells, whereas the transformation of human cells requires additional introduced genes.
6. Identifying and characterizing these species-specific differences will allow the construction of human and rodent models of cancer that increasingly phenocopy human cancer. Such models will revolutionize the screening and testing of candidate chemical and biological anticancer therapies.

要点翻译：

1. 恶性转化过程以离散的组织病理学步骤发生，其中许多步骤与特定遗传改变相关。多项证据表明有限数量的分子通路参与其中，这些通路的破坏在大多数（若非所有）癌症中起着关键作用。
2. 啮齿类与人类癌症实验模型促进了对特定癌症相关突变的理解。尽管这些癌症模型共享许多核心成分，但若干重要信号通路在人类与啮齿类转化模型中的功能存在差异。
3. 永生化是肿瘤细胞形成的必要前提。人类细胞必须克服两个限制细胞寿命的屏障——复制性衰老和细胞危机——才能实现永生化。这些屏障受端粒缩短以及RB和p53肿瘤抑制通路调控。
4. 消除ARF-p53通路足以使许多小鼠细胞永生化。端粒缩短似乎不限制近交系小鼠来源的细胞寿命。
5. 与这些永生化差异相对应的是：引入两个癌基因即可转化小鼠细胞，而人类细胞的转化则需要额外引入更多基因。
6. 识别并表征这些物种特异性差异将有助于构建日益模拟人类癌症表型的人类与啮齿类癌症模型。此类模型将为候选化学与生物抗癌疗法的筛选和测试带来革命性变革。

英文摘要：

Cancer arises from a stepwise accumulation of genetic changes that liberates neoplastic cells from the homeostatic mechanisms that govern normal cell proliferation. In humans, at least four to six mutations are required to reach this state, but fewer seem to be required in mice. By rationalizing the shared and unique elements of human and mouse models of cancer, we should be able to identify the molecular circuits that function differently in humans and mice, and use this knowledge to improve existing models of cancer.

摘要翻译： 

癌症源于一系列逐步累积的遗传改变，这些改变使肿瘤细胞脱离了调控正常细胞增殖的稳态机制。在人类中，至少需要四到六个突变才能达到这一状态，而在小鼠中似乎所需的突变更少。通过梳理人类和小鼠癌症模型中的共有与独特因素，我们应能识别在两者中功能不同的分子通路，并利用这些知识改进现有的癌症模型。

原文链接：

Modelling the molecular circuitry of cancer