Background

The ability of a tumor to become dormant in response to suboptimal conditions has recently been recognized as a key step in tumor progression. Tumor dormancy has been found to be implicated in several tumor types as the culprit of therapy resistance and metastasis development, the deadliest features of a cancer. Several lines of evidence indicate that the development of these traits may rely on the de-differentiation of committed tumor cells that regain stem-like properties during a dormant state. Presently, dormancy is classified into cell- and population-level, according to the preponderance of cellular mechanisms that keep tumor cells quiescent or to a balance between overall cell division and death, respectively. Cellular dormancy is characterized by autophagy, stress-tolerance signaling, microenvironmental cues and, of prime relevance, epigenetic modifications. It has been found that the epigenome alters during cellular quiescence, thus representing the driving force for short-term cancer progression. Population-level dormancy is characterized by processes that counteract proliferation, such as inappropriate blood supply and intense immune responses. The latter two mechanisms are not mutually exclusive and may affect tumor masses both simultaneously and subsequently.

Conclusions

Overall, tumor dormancy may represent an additional step in the acquisition of cancer characteristics, and its comprehension may clarify both theoretical and practical aspects of cancer development. Clinically, only a deep understanding of dormancy may explain the course of tumor development in different patients, thus representing a process that may be targeted to prevent and/or treat advanced-stage cancers. That is especially the case for breast cancer, against which the mTOR inhibitor everolimus displays potent antitumor activity in patients with metastatic disease by impeding autophagy and tumor dormancy onset. Here we will also discuss other targeted therapies directed towards tumor dormancy onset, e.g. specific inhibitors of SFK and MEK, or aimed at keeping tumor cells dormant, e.g. prosaposin derivatives, that may shortly enter clinical assessment in breast, and possibly other cancer types.

中文翻译：

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肿瘤休眠作为化学抗性和转移发展的替代步骤-临床意义。

背景

最近，人们已经认识到，响应于次优条件而使肿瘤休眠的能力是肿瘤进展的关键步骤。已经发现，肿瘤的休眠与多种抵抗力和转移发展的罪魁祸首有关，这是癌症最致命的特征。几条证据表明，这些性状的发展可能依赖于在休眠状态下恢复干样特性的定型肿瘤细胞的去分化。当前，根据使肿瘤细胞保持静止或总体细胞分裂与死亡之间平衡的主要细胞机制，休眠被分为细胞水平和群体水平。细胞休眠的特征是自噬，耐压力信号传导，微环境提示，并且具有主要相关性，表观遗传修饰。已经发现表观基因组在细胞静止期间改变，因此代表了短期癌症进展的驱动力。群体级休眠的特征是可以抵消增殖的过程，例如不适当的血液供应和强烈的免疫反应。后两种机制不是互斥的，并且可能同时和随后影响肿瘤块。

结论

总体而言，肿瘤休眠可能代表着获得癌症特征的又一步骤，其理解力可能阐明癌症发展的理论和实践方面。临床上，只有对休眠的深入了解才能解释不同患者的肿瘤发展过程，从而代表了可能旨在预防和/或治疗晚期癌症的过程。对于乳腺癌而言尤其如此，mTOR抑制剂依维莫司通过抑制自噬和肿瘤休眠的发作，在转移性疾病患者中显示出强大的抗肿瘤活性。在这里，我们还将讨论针对肿瘤休眠开始的其他靶向疗法，例如SFK和MEK的特异性抑制剂，或旨在保持肿瘤细胞处于休眠状态的疗法，例如prosaposin衍生物，