Morphological and functional heterogeneity are found in tumors, with the latter reflecting the different levels of resistance against antitumor therapies. In a therapy-resistant subpopulation, the expression levels of differentiation markers decrease, and those of immature markers increase. In addition, this subpopulation expresses genes involved in drug metabolism, such as aldehyde dehydrogenase 1A1 (ALDH1A1). Because of their similarity to stem cells, cells in the latter therapy-resistant subpopulation are called cancer stem cells (CSCs). Like normal stem cells, CSCs were originally thought not to arise from non-CSCs, but this hierarchical model is too simple. It is now believed that CSCs are generated from non-CSCs. The plasticity of tumor phenotypes between CSCs and non-CSCs causes difficulty in completely curing tumors. In this review, focusing on ALDH1A1 as a marker for CSCs or immature tumor cells, the dynamics of ALDH1A1-expressing tumor cells and their regulatory mechanisms are described, and the plausible regulatory mechanisms of plasticity of ALDH1A1 expression phenotype are discussed. Genetic mutations are a significant factor for tumorigenesis, but non-mutational epigenetic reprogramming factors yielding tumor heterogeneity are also crucial in determining tumor characteristics. Factors influencing non-mutational epigenetic reprogramming in tumors are also discussed.

中文翻译：

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病理学家视角下的肿瘤异质性

肿瘤中存在形态和功能异质性，后者反映了抗肿瘤治疗的不同程度的耐药性。在治疗抵抗亚群中，分化标志物的表达水平降低，而未成熟标志物的表达水平增加。此外，该亚群还表达参与药物代谢的基因，例如乙醛脱氢酶 1A1 (ALDH1A1)。由于它们与干细胞相似，后一种治疗抵抗亚群中的细胞被称为癌症干细胞（CSC）。与正常干细胞一样，CSC 最初被认为不是由非 CSC 产生的，但这种分层模型过于简单。现在人们相信CSC是由非CSC产生的。CSCs和非CSCs之间肿瘤表型的可塑性导致肿瘤难以彻底治愈。在这篇综述中，重点关注 ALDH1A1 作为 CSC 或未成熟肿瘤细胞的标志物，描述了表达 ALDH1A1 的肿瘤细胞的动力学及其调控机制，并讨论了 ALDH1A1 表达表型可塑性的合理调控机制。基因突变是肿瘤发生的重要因素，但产生肿瘤异质性的非突变表观遗传重编程因素对于确定肿瘤特征也至关重要。还讨论了影响肿瘤非突变表观遗传重编程的因素。