An evolutionary perspective on anti-tumor immunity.
An evolutionary perspective on anti-tumor immunity.
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DOI：
10.3389/fonc.2012.00202
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发表时间：
2012
影响因子：
4.7
通讯作者：
Klinke DJ 2nd
中科院分区：
文献类型：
--
作者：
Klinke DJ 2nd
使用分子靶向疗法在癌症中展示持久反应所面临的挑战，激发了人们从进化角度看待癌症的新兴趣。进化过程具有三个共同特征：异质性、动态性和选择性适应景观。诱变剂随机改变宿主细胞的基因组，产生含有不同体细胞突变的细胞群。这种基因组重排通过改变细胞与其组织微环境的相互作用来扰乱细胞稳态。为了平衡突变细胞争夺有限资源的能力，在细胞和器官系统内编码控制结构，例如先天免疫和适应性免疫，以恢复细胞稳态。这些控制结构塑造了选择性适应度，并决定了携带特定体细胞突变的细胞是被保留还是从细胞群中消除。虽然下一代测序揭示了致癌转化的复杂性和异质性，但了解肿瘤发生的动态以及癌细胞如何改变选择性适应度仍不清楚。在这篇技术综述中，我们将总结最新的技术进步如何影响我们对癌症作为一个进化过程的这三个属性的理解。特别是，我们将重点关注基因组测序的进步如何量化细胞异质性，计算能力的进步如何利用模拟根据可用数据对假定的细胞内和细胞间控制结构进行明确测试，以及蛋白质组学的进步如何识别癌细胞用来改变健康状况的细胞串扰的新机制。
The challenges associated with demonstrating a durable response using molecular-targeted therapies in cancer has sparked a renewed interest in viewing cancer from an evolutionary perspective. Evolutionary processes have three common traits: heterogeneity, dynamics, and a selective fitness landscape. Mutagens randomly alter the genome of host cells creating a population of cells that contain different somatic mutations. This genomic rearrangement perturbs cellular homeostasis through changing how cells interact with their tissue microenvironment. To counterbalance the ability of mutated cells to outcompete for limited resources, control structures are encoded within the cell and within the organ system, such as innate and adaptive immunity, to restore cellular homeostasis. These control structures shape the selective fitness landscape and determine whether a cell that harbors particular somatic mutations is retained or eliminated from a cell population. While next-generation sequencing has revealed the complexity and heterogeneity of oncogenic transformation, understanding the dynamics of oncogenesis and how cancer cells alter the selective fitness landscape remain unclear. In this technology review, we will summarize how recent advances in technology have impacted our understanding of these three attributes of cancer as an evolutionary process. In particular, we will focus on how advances in genome sequencing have enabled quantifying cellular heterogeneity, advances in computational power have enabled explicit testing of postulated intra- and intercellular control structures against the available data using simulation, and advances in proteomics have enabled identifying novel mechanisms of cellular cross-talk that cancer cells use to alter the fitness landscape.