Dormancy and cancer stem cells: An enigma for cancer therapeutic targeting.

Dormancy occurs when cells remain viable but stop proliferating. When most of a cancer population undergoes this phenomenon, the result is called tumor dormancy, and when a single cancer cell undergoes this process, it is termed quiescence. Cancer stem cells (CSCs) share several overlapping characteristics and signaling pathways with dormant cancer cells, including therapy resistance, and an ability to metastasize and evade the immune system. Cancer cells can be broadly grouped into dormancy-competent CSCs (DCCs), cancer-repopulating cells (CRCs), dormancy-incompetent CSCs and disseminated tumor cells (DTCs). The settings in which cancer cells exploit the dormancy phase to survive and adapt are: (i) primary cancer dormancy; (ii) metastatic dormancy; (iii) therapy-induced dormancy; and (iv) immunologic dormancy. Dormancy, therapy resistance and plasticity of CSCs are fundamentally interconnected processes mediated through mechanisms involving reversible genetic alterations. Niches including metastatic, bone marrow, and perivascular are known to harbor dormant cancer cells. Mechanisms of dormancy induction are complex and multi-factorial and can involve angiogenic switching, addictive oncogene inhibition, immunoediting, anoikis, therapy, autophagy, senescence, epigenetic, and biophysical regulation. Therapy can have opposing effects on cancer cells with respect to dormancy; some therapies can induce dormancy, while others can reactivate dormant cells. There is a lack of consensus relative to the value of therapy-induced dormancy, i.e., some researchers view dormancy induction as a beneficial strategy as it can lead to metastasis inhibition, while others argue that reactivating dormant cancer cells and then eliminating them through therapy are a better approach. More focused investigations of intrinsic cell kinetics and environmental dynamics that promote and maintain cancer cells in a dormant state, and the long-term consequences of dormancy are critical for improving current therapeutic treatment outcomes.