在肿瘤中存在形态和功能的异质性，其中功能异质性反映了对抗肿瘤治疗的不同抵抗水平。在耐药亚种群中，分化标记物的表达水平降低，而不成熟标记物的表达则增加。此外，这个亚种群还表达参与药物代谢的基因，如乙醛脱氢酶1A1（ALDH1A1）。由于它们与干细胞的相似性，这个治疗耐药的亚种群被称为癌症干细胞（CSCs）。与正常干细胞类似，最初认为CSCs不是由非CSCs产生的，但这种分层模型过于简单。现在人们认为CSCs是由非CSCs产生的。CSCs和非CSCs之间的肿瘤表型可塑性导致了完全治愈肿瘤的困难。在本综述中，重点关注ALDH1A1作为CSCs或不成熟肿瘤细胞的标记物，描述了ALDH1A1表达肿瘤细胞的动态及其调控机制，并讨论了ALDH1A1表型可塑性的可能调控机制。遗传突变是肿瘤发生的重要因素，但非突变的表观遗传重编程因子导致的肿瘤异质性也在决定肿瘤特征中起着重要作用。还讨论了影响肿瘤非突变表观遗传重编程的因素。© 2023 日本病理学会和John Wiley & Sons Australia, Ltd.

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.© 2023 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.