Minimal residual disease (MRD) is a major hurdle in the eradication of malignant tumors. Despite the high sensitivity of various cancers to treatment, some residual cancer cells persist and lead to tumor recurrence and treatment failure. Obvious reasons for residual disease include mechanisms of secondary therapy resistance, such as the presence of mutant cells that are insensitive to the drugs, or the presence of cells that become drug resistant due to activation of survival pathways. In addition to such unambiguous resistance modalities, several patients with relapsing tumors do not show refractory disease and respond again when the initial therapy is repeated. These cases cannot be explained by the selection of mutant tumor cells, and the precise mechanisms underlying this clinical drug resistance are ill-defined. In the current review, we put special emphasis on cell-intrinsic and -extrinsic mechanisms that may explain mechanisms of MRD that are independent of secondary therapy resistance. In particular, we show that studying genetically engineered mouse models (GEMMs), which highly resemble the disease in humans, provides a complementary approach to understand MRD. In these animal models, specific mechanisms of secondary resistance can be excluded by targeted genetic modifications. This allows a clear distinction between the selection of cells with stable secondary resistance and mechanisms that result in the survival of residual cells but do not provoke secondary drug resistance. Mechanisms that may explain the latter feature include special biochemical defense properties of cancer stem cells, metabolic peculiarities such as the dependence on autophagy, drug-tolerant persisting cells, intratumoral heterogeneity, secreted factors from the microenvironment, tumor vascularization patterns and immunosurveillance-related factors. We propose in the current review that a common feature of these various mechanisms is cancer cell dormancy. Therefore, dormant cancer cells appear to be an important target in the attempt to eradicate residual cancer cells, and eventually cure patients who repeatedly respond to anticancer therapy but lack complete tumor eradication.

中文翻译：

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癌症治疗中的残留病最少-小事情至关重要。

最小残留疾病（MRD）是根除恶性肿瘤的主要障碍。尽管各种癌症对治疗具有很高的敏感性，但一些残留的癌细胞仍然存在并导致肿瘤复发和治疗失败。残留疾病的明显原因包括继发治疗抗性的机制，例如对药物不敏感的突变细胞的存在，或由于生存途径的激活而变成药物抗性的细胞的存在。除了这种明确的抵抗方式外，几位复发性肿瘤患者也未显示出难治性疾病，并且在重复初始治疗后再次出现反应。这些情况不能通过选择突变的肿瘤细胞来解释，而这种临床耐药性的确切机制尚不清楚。在目前的评论中，我们特别强调细胞内源性和外源性机制，这些机制可能解释了MRD的机制，而该机制与继发治疗的耐药性无关。特别是，我们表明，研究与人类疾病高度相似的基因工程小鼠模型（GEMM），为理解MRD提供了一种补充方法。在这些动物模型中，可以通过有针对性的基因修饰来排除次级抗性的特定机制。这样就可以在选择具有稳定次级抗性的细胞与导致残留细胞存活但不会引起次级抗药性的机制之间做出明确区分。可以解释后者特征的机制包括癌症干细胞的特殊生化防御特性，代谢特性，例如对自噬的依赖性，药物耐受性持久性细胞，肿瘤内异质性，微环境分泌因子，肿瘤血管形成模式和免疫监视相关因子。我们在当前的综述中提出，这些各种机制的共同特征是癌细胞休眠。因此，休眠的癌细胞似乎是企图消灭残留癌细胞并最终治愈反复对抗癌疗法反应但缺乏彻底根除肿瘤的患者的重要靶标。