Mirzayans Razmik
Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada.
Int J Mol Sci. 2025 Feb 22;26(5):1881. doi: 10.3390/ijms26051881.
What is apoptosis? The Nomenclature Committee on Cell Death and numerous other pioneering cancer/p53 biologists use the terms "apoptosis" and "cell death" interchangeably, disregard the mind-numbing complexity and heterogeneity that exists within a tumor (intratumor heterogeneity), disregard the contribution of polyploid giant cancer cells (PGCCs; the root causes of therapy resistance and relapse) to this heterogeneity, and then propose novel apoptosis-stimulating anticancer strategies. This is shocking for the following three reasons. First, clinical studies reported since the 1990s have revealed that increased apoptosis in solid tumors is associated with increased tumor diversity and poor prognosis. Second, we have known for years that dying (apoptotic) cancer cells release a panel of secretions (e.g., via phoenix rising and other pathways) that promote metastatic outgrowth. Third, over a decade ago, it was demonstrated that cancer cells can recover from late stages of apoptosis (after the formation of apoptotic bodies) via the homeostatic process of anastasis, resulting in the emergence of aggressive variants. The cell surface expression of CD24 has recently been reported to be preferentially enriched in recovered (anastatic) cancer cells that exhibit tumorigenic properties. These and related discoveries outlined herein call for a paradigm shift in oncology to focus on strategies that minimize the occurrence of treacherous apoptosis and other tumor-repopulating events (e.g., therapy-induced cancer cell dormancy and reactivation). They also raise an intriguing question: is deregulated anastasis (rather than evasion of apoptosis) a hallmark of cancer?
什么是细胞凋亡？细胞死亡命名委员会以及众多其他开创性的癌症/p53生物学家将“细胞凋亡”和“细胞死亡”这两个术语互换使用，无视肿瘤内部存在的令人头脑麻木的复杂性和异质性（肿瘤内异质性），无视多倍体巨癌细胞（PGCCs；治疗耐药性和复发的根本原因）对这种异质性的影响，然后提出新的促细胞凋亡抗癌策略。这令人震惊，原因有以下三点。首先，自20世纪90年代以来报道的临床研究表明，实体瘤中细胞凋亡增加与肿瘤多样性增加和预后不良有关。其次，多年来我们已经知道，正在死亡（凋亡）的癌细胞会释放一系列分泌物（例如，通过“浴火重生”和其他途径），这些分泌物会促进转移灶的生长。第三，十多年前就已证明，癌细胞可以通过稳态的复苏过程从凋亡后期（凋亡小体形成后）恢复，从而产生侵袭性变体。最近有报道称，CD24的细胞表面表达在具有致瘤特性的复苏（复苏后）癌细胞中优先富集。本文概述的这些及相关发现呼吁肿瘤学领域进行范式转变，以关注将危险的细胞凋亡和其他肿瘤再增殖事件（例如，治疗诱导的癌细胞休眠和重新激活）的发生降至最低的策略。它们还提出了一个有趣的问题：失控的复苏（而非逃避细胞凋亡）是否是癌症的一个标志？
