Heppner G H, Miller F R
Karmanos Cancer Institute, Detroit, Michigan 48201, USA.
Int Rev Cytol. 1998;177:1-56. doi: 10.1016/s0074-7696(08)62230-5.
Variability in disease presentation and course is a hallmark of cancer. Variability is seen among similarly diagnosed cancers in different patients or animal hosts and in the same cancer at different periods of time. This latter type of variability, termed "tumor progression," was defined by Foulds in a series of six rules that describe the independent behavior of individual cancers and the independent evolution of different cancer characteristics. Tumor progression is believed to result from variability among subpopulations of tumor cells within individual cancers and from selection of these subpopulations by conditions within the cancer environment, such that different subpopulations come to prominence over the course of cancer development and growth. Interactions among subpopulations, however, modulate tumor behavior as well as tumor evolution. The leading hypothesis for the origin of tumor subpopulations is the genetic instability of cancer cells. There are a number of possible mechanisms of genetic instability, some internal to cancer cells (mutation, amplification, mutator phenotypes, DNA repair deficiencies) and some present in the tumor microenvironment (endogenous mutagens). There are also potential epigenetic mechanisms of variability, including alterations in gene regulation, differentiation, adaptation, and cell fusion. Regardless of mechanism, the heterogeneity of tumor subpopulations poses a number of challenges to the practice of cancer research, including the design of reproducible and meaningful experiments. Tumor heterogeneity also has significant consequences for the clinical assessment of tumor prognosis and the development of effective treatment regimens.
疾病表现和病程的变异性是癌症的一个标志。在不同患者或动物宿主中诊断相似的癌症之间以及同一癌症在不同时期都会出现变异性。后一种变异性类型，即“肿瘤进展”，由福尔兹在一系列六条规则中定义，这些规则描述了个体癌症的独立行为以及不同癌症特征的独立演变。肿瘤进展被认为是由于个体癌症内肿瘤细胞亚群之间的变异性以及癌症环境中的条件对这些亚群的选择所致，从而使得不同亚群在癌症发展和生长过程中变得突出。然而，亚群之间的相互作用会调节肿瘤行为以及肿瘤演变。关于肿瘤亚群起源的主要假说是癌细胞的基因不稳定性。存在多种基因不稳定的可能机制，一些是癌细胞内部的（突变、扩增、突变体表型、DNA修复缺陷），一些存在于肿瘤微环境中（内源性诱变剂）。也存在变异性的潜在表观遗传机制，包括基因调控、分化、适应和细胞融合的改变。无论机制如何，肿瘤亚群的异质性给癌症研究实践带来了诸多挑战，包括设计可重复且有意义的实验。肿瘤异质性对肿瘤预后的临床评估和有效治疗方案的制定也有重大影响。
