癌细胞与正常细胞不同，正常细胞通常只会复制约50次后停止，而癌细胞却可近乎无限分裂。约20%的人类癌症样本中，DNA会脱离正常结合的染色体形成环状外染色体DNA（ecDNA），从而使遗传分配不再严格遵循孟德尔规律并加速突变与耐药演化。 这种“非孟德尔”分配通过有丝分裂后的随机分散发生，导致基因在子代之间的不确定性上升，进而提升癌细胞快速适应治疗的几率。

保罗·米歇尔（Paul Mischel）团队指出，这一策略早在细菌和真菌中即有应用，癌症中的系统性证据主要在2012年后被确认。研究显示，ecDNA片段在肿瘤中高度富集与防御相关的基因，这些基因支持快速复制并帮助细胞避免被清除。 因此，携带ecDNA的细胞更易增殖，并且更可能在更短时间内出现不利性状扩张，相比严格染色体遗传体系表现出更强的进化速度。

米歇尔与AMGEN合作发现，子代细胞仅在有丝分裂后通过“锚定蛋白”和特定DNA序列使ecDNA重新整合进染色体时才能持续受益。也就是说，锚定蛋白与整合序列构成了潜在药物靶点。 目前治疗探索尚在早期阶段，临床试验仍在等待中；该机制虽关键但并非唯一因素，基因组不稳定与DNA修复缺陷可持续诱发ecDNA，抑制锚定蛋白可能只能降低其加速作用而不能消除根源。

Cancer cells deviate from normal cellular limits, where healthy cells typically cease dividing after about 50 replications, by proliferating with near-indefinite capacity. Around 20% of human cancer samples show DNA escaping chromosomes to form extrachromosomal circular DNA (ecDNA), and this bypass disrupts strict Mendelian inheritance to make gene transmission more stochastic and accelerate mutation and drug-resistance evolution.

As described by Paul Mischel’s team, this strategy was already known in bacteria and fungi, while systematic evidence in cancer became clear only after 2012. In tumors, ecDNA is enriched for defensive functions that support rapid growth and escape from destruction, making carriers proliferate more readily. That enrichment increases the probability that harmful traits emerge more quickly than would be expected under stable chromosomal inheritance rules.

Mischel’s group with AMGEN found that ecDNA confers advantage only when daughter cells re-integrate it into chromosomes after mitosis, through anchor proteins and specific DNA sequences. These components are therefore proposed therapeutic targets. The work is still early, with clinical trials pending; ecDNA is important but not the sole driver because genome instability and defective DNA repair can keep generating it even if anchor pathways are suppressed.

Source: Tumour cells use a genetic trick to become drug-resistant

Subtitle: The same trick could also be used against them

Dateline: 4月 16, 2026 08:16 上午