文章：

从进化的角度看胰腺癌生物学和遗传学

Pancreatic cancer biology and genetics from an evolutionary perspective

原文发布日期：2016-07-22

DOI: 10.1038/nrc.2016.66

类型: Review Article

开放获取: 否

要点：

1. Pancreatic cancer evolves in three stages: initiation, expansion and survival in foreign microenvironments.
2. Factors that contribute to initiation are inherited (germline) mutations, somatic mutations acquired during organ growth and renewal, ageing, chronic inflammation, obesity and smoking.
3. Genetic mutations in KRAS, cyclin-dependent kinase inhibitor 2A (CDKN2A), TP53 and SMAD4 drive clonal expansion by conferring a selective growth advantage on pancreatic cancer cells.
4. Selection pressures and bottlenecks result from extension into new microenvironments of immune cells, stroma, organ-specific cell types and resource gradients that vary spatially and temporally. Metastasis requires dispersal, invasion and colonization of microenvironments distant from the pancreatic primary site.
5. Remaining questions include the order of early cancer-promoting events, the phenotypic importance of late-occurring mutations and the clinical relevance of genetic, microenvironmental and cellular heterogeneity.
6. Evolutionary thinking provides a framework for the biology of pancreatic cancer, revealing how and why this lethal tumour evolves.

要点翻译：

1. 胰腺癌的演变经历三个阶段：起始阶段、扩张阶段及在异质微环境中的存活阶段。
2. 促成肿瘤起始的因素包括遗传性（种系）突变、器官生长和更新过程中获得的体细胞突变、衰老、慢性炎症、肥胖及吸烟。
3. KRAS基因、细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A）、TP53和SMAD4的基因突变通过赋予胰腺癌细胞选择性生长优势来驱动克隆扩增。
4. 选择压力和瓶颈效应源于肿瘤向新微环境的扩展，这些微环境包含免疫细胞、基质、器官特异性细胞类型以及随空间和时间变化的资源梯度。转移需要扩散、侵袭并定植于远离胰腺原发部位的微环境。
5. 尚待解决的问题包括：早期促癌事件的发生顺序、晚期突变对表型的重要性，以及遗传异质性、微环境异质性和细胞异质性的临床意义。
6. 进化思维为胰腺癌生物学提供了理论框架，揭示了这种致命肿瘤如何以及为何发生演变。

英文摘要：

Cancer is an evolutionary disease, containing the hallmarks of an asexually reproducing unicellular organism subject to evolutionary paradigms. Pancreatic ductal adenocarcinoma (hereafter referred to as pancreatic cancer) is a particularly robust example of this phenomenon. Genomic features indicate that pancreatic cancer cells are selected for fitness advantages when encountering the geographic and resource-depleted constraints of the microenvironment. Phenotypic adaptations to these pressures help disseminated cells to survive in secondary sites, a major clinical problem for patients with this disease. In this Review we gather the wide-ranging aspects of pancreatic cancer research into a single concept rooted in Darwinian evolution, with the goal of identifying novel insights and opportunities for study.

摘要翻译： 

癌症是一种进化性疾病，具有无性繁殖的单细胞生物的特征，并遵循进化规律。胰腺导管腺癌（以下简称胰腺癌）是这一现象的典型例证。基因组特征表明，当面对微环境中地理和资源枯竭的限制时，胰腺癌细胞会因适应优势而被选择。对这些压力的表型适应有助于播散的细胞在继发部位存活，这是该病患者面临的主要临床问题。在本综述中，我们将胰腺癌研究的各个方面整合为一个以达尔文进化论为核心的概念，旨在发现新的研究视角和机会。

原文链接：

Pancreatic cancer biology and genetics from an evolutionary perspective