Tumor dormancy as an alternative step in the development of chemoresistance and metastasis - clinical implications.

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.