Nicolson G L
Cancer Metastasis Rev. 1984;3(1):25-42. doi: 10.1007/BF00047691.
The emergence of diversified tumor cell subpopulations in malignant neoplasms accounts for their heterogeneous cellular phenotypes and virtually ensures that some tumor cells will ultimately evolve with the most favorable properties for their enhanced abilities to survive, grow, invade and metastasize (tumor progression). The rates of cellular phenotypic diversification appear to vary greatly among different tumors and within the same tumor, and they are probably controlled, at least in part, by cellular instability due to chromosomal defects and random somatic mutational events, the rates of which are known to be higher in more malignant cells, and by epigenetic events, which may vary widely depending on the nature of the tumor cells and their microenvironments. As tumor progression proceeds, the most malignant cell subpopulations appear to lose their responsiveness to changes in tumor microenvironment while maintaining their high rates of phenotypic diversification. Tumor and normal cell-cell and cell-extracellular matrix interactions, as well as tumor cell nutrients, oxygen, hormones, growth factors, inducers and other regulatory molecules provide individual malignant cells with microenvironmental signals that could act through epigenetic cellular modifications, such as DNA methylation, and transcriptional, posttranscriptional, translational and posttranslational controls, or combinations of these. In addition, integration of viral gene sequences or viral modification of host DNA in critical regions could affect phenotypic stability. Finally, manipulation of tumor cells by antitumor therapy can also have profound effects on the rates of phenotypic diversification of the surviving tumor cells. A model for generating cellular phenotypic diversity based on the proposed mechanism for rapid generation of immunoglobulin molecular diversity in B cells may be applicable to malignant cells and to cells in general. In this model the expression and activity of gene products from multigene families are affected by a variety of genetic and epigenetic controlling mechanisms, and alterations in regulatory genes caused by recombination, methylation, mutation, or other changes could lead to differences in gene expression, resulting in widespread quantitative (and perhaps some qualitative) changes in particular gene products or their activities. As they proceed down different pathways of gene expression, each cell would be exposed to continual host selection pressures creating diverse, ever-changing malignant cell-populations.
恶性肿瘤中多样化肿瘤细胞亚群的出现，解释了其异质性细胞表型，并实际上确保了一些肿瘤细胞最终会演变成具有最有利特性的细胞，从而增强其生存、生长、侵袭和转移（肿瘤进展）的能力。细胞表型多样化的速率在不同肿瘤之间以及同一肿瘤内部似乎差异很大，并且它们可能至少部分地受由于染色体缺陷和随机体细胞突变事件导致的细胞不稳定性控制，已知在恶性程度更高的细胞中这些事件的发生率更高，还受表观遗传事件控制，表观遗传事件可能因肿瘤细胞及其微环境的性质而有很大差异。随着肿瘤进展，最恶性的细胞亚群似乎在保持其高表型多样化速率的同时，失去了对肿瘤微环境变化的反应能力。肿瘤细胞与正常细胞之间的细胞 - 细胞以及细胞 - 细胞外基质相互作用，以及肿瘤细胞的营养物质、氧气、激素、生长因子、诱导剂和其他调节分子，为单个恶性细胞提供微环境信号，这些信号可通过表观遗传细胞修饰（如DNA甲基化）以及转录、转录后、翻译和翻译后控制或这些的组合来发挥作用。此外，病毒基因序列的整合或宿主DNA在关键区域的病毒修饰可能影响表型稳定性。最后，抗肿瘤治疗对肿瘤细胞的操作也可能对存活肿瘤细胞的表型多样化速率产生深远影响。基于B细胞中免疫球蛋白分子多样性快速产生的拟议机制生成细胞表型多样性的模型，可能适用于恶性细胞乃至一般细胞。在这个模型中，多基因家族基因产物的表达和活性受多种遗传和表观遗传控制机制影响，重组、甲基化、突变或其他变化引起的调节基因改变可能导致基因表达差异，从而导致特定基因产物或其活性出现广泛的定量（也许还有一些定性）变化。当细胞沿着不同的基因表达途径发展时，每个细胞都会面临持续的宿主选择压力，从而产生多样化的、不断变化的恶性细胞群体。
