A cell's phenotype is the observable actualization of complex interactions between its genome, epigenome, and local environment. While traditional views in cancer have held that cellular and tumor phenotypes are largely functions of genomic instability, increasing attention has recently been given to epigenetic and microenvironmental influences. Such non-genetic factors allow cancer cells to experience intrinsic diversity and plasticity, and at the tumor level can result in phenotypic heterogeneity and treatment evasion. In 2006, Takahashi and Yamanaka exploited the epigenome's plasticity by "reprogramming" differentiated cells into a pluripotent state by inducing expression of a cocktail of four transcription factors. Recent advances in cancer biology have shown not only that cellular reprogramming is possible for malignant cells, but it may provide a foundation for future therapies. Nevertheless, cell reprogramming experiments are frequently plagued by low efficiency, activation of aberrant transcriptional programs, instability, and often rely on expertise gathered from systems which may not translate directly to cancer. Here, we review a theoretical framework tracing back to Waddington's epigenetic landscape which may be used to derive quantitative and qualitative understanding of cellular reprogramming. Implications for tumor heterogeneity, evolution and adaptation are discussed in the context of designing new treatments to re-sensitize recalcitrant tumors. This article is part of a Special Issue entitled: Evolutionary principles - heterogeneity in cancer?, edited by Dr. Robert A. Gatenby.

中文翻译：

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细胞表型调控和重编程的数学模型：使癌细胞再次敏感！

细胞的表型是其基因组，表观基因组和局部环境之间可观察到的复杂相互作用的实现。尽管传统的癌症观点认为细胞和肿瘤表型在很大程度上是基因组不稳定的功能，但近来人们越来越关注表观遗传和微环境的影响。这种非遗传因素使癌细胞能够经历固有的多样性和可塑性，并且在肿瘤水平上可能导致表型异质性和逃避治疗。2006年，高桥和山中通过诱导分化的细胞通过诱导四个转录因子混合物的表达“重编程”为多能状态，从而利用了表观基因组的可塑性。癌症生物学的最新进展不仅表明恶性细胞可能进行细胞重编程，而且还可能为将来的治疗提供基础。然而，细胞重编程实验经常被低效率，异常转录程序的激活，不稳定性所困扰，并且常常依赖于从不能直接转化为癌症的系统中收集的专业知识。在这里，我们回顾追溯到Waddington的表观遗传学格局的理论框架，该理论框架可用于获得对细胞重编程的定量和定性理解。在设计新的治疗方法以重新敏化顽固性肿瘤的背景下，讨论了对肿瘤异质性，进化和适应性的影响。本文是一个特殊问题的一部分，标题为：