In the last decade, a large amount of research has focused on elucidating the mechanisms that account for homing disseminated cancer cells (DCCs) from solid tumours to distant organs, which successively progress to overt metastatic disease; this is currently incurable. A better understanding of DCC behaviour is expected to allow detectable metastasis prevention by more effectively targeting ‘metastatic seeds before they sprout’. As DCC biology co-evolved with that of the primary tumour, and due to the many similarities between them, the term ‘niche’ has been borrowed from normal adult stem cells (ASCs) to define the site of DCC metastatic colonisation. Moreover, heterogeneity, survival, protection, stemness and plasticity as well as the prolonged G0-G1 dormant state in the metastatic niche have been the main aspects of intense investigation. Consistent with these findings, in solid cancers with minimal residual disease (MRD), it has been proposed to prolong adjuvant therapy by targeting specific molecular pathway(s) involving DCC dormancy. However, so far, few disappointing clinical data have been reported. As an alternative strategy, because immune-surveillance contributes to the steady state of the DCC population and likely to the G0-G1 state of cancer cells, we have used prolonged immune-modulatory cytostatic chemotherapy, active immune stimulation with an INF-β/IL-2 sequence or drugs inhibiting myeloid-derived suppressor cell (MDSC)/Treg-mediated immune suppression. This strategy, mainly aimed at boosting the immune response, is based on recent findings suggesting the downregulation of immune escape mechanisms as well as other principal hallmarks during the G0-G1 state and/or in MRD. Preliminary clinical and/or laboratory data suggest the efficacy of this strategy in gastrointestinal and some endocrine-dependent cancers. Following this, we propose therapeutic schedules to prevent DCC activation and proliferation in solid cancers at a high risk of relapse or as maintenance therapy in metastatic patients after complete response (CR) to conventional treatment.

在过去十年中，大量研究集中在阐明将播散性癌细胞（DCCs）从实体瘤归巢到远处器官的机制，这些细胞逐渐发展为明显的转移性疾病；这是目前无法治愈的。对 DCC 行为的更好理解有望通过更有效地针对“发芽前的转移种子”来实现可检测的转移预防。由于 DCC 生物学与原发性肿瘤共同进化，并且由于它们之间有许多相似之处，“生态位”一词已从正常成体干细胞 (ASC) 中借用来定义 DCC 转移性定植位点。此外，异质性、存活、保护、干性和可塑性以及转移生态位中延长的 G0-G1 休眠状态一直是深入研究的主要方面。与这些发现一致，在具有最小残留病 (MRD) 的实体癌中，已提出通过靶向涉及 DCC 休眠的特定分子途径来延长辅助治疗。然而，到目前为止，几乎没有令人失望的临床数据被报道。作为一种替代策略，因为免疫监视有助于 DCC 群体的稳定状态，并且可能有助于癌细胞的 G0-G1 状态，我们使用了延长的免疫调节细胞抑制化疗，用 INF-β/IL 进行主动免疫刺激-2 序列或药物抑制髓源性抑制细胞 (MDSC)/Treg 介导的免疫抑制。这种策略主要是为了增强免疫反应，基于最近的发现，表明在 G0-G1 状态和/或 MRD 期间免疫逃逸机制以及其他主要标志的下调。初步临床和/或实验室数据表明该策略在胃肠道和一些内分泌依赖性癌症中的有效性。在此之后，我们提出了治疗方案，以防止高复发风险实体癌中 DCC 的活化和增殖，或作为对常规治疗完全缓解 (CR) 后转移性患者的维持治疗。