Potential Role of the Circadian Clock in the Regulation of Cancer Stem Cells and Cancer Therapy

Circadian rhythms, including sleep/wake cycles as well as hormonal, immune, metabolic, and cell proliferation rhythms, are fundamental biological processes driven by a cellular time-keeping system called the circadian clock. Disruptions in these rhythms due to genetic alterations or irregular lifestyles cause fundamental changes in physiology, from metabolism to cellular proliferation and differentiation, resulting in pathological consequences including cancer. Cancer cells are not uniform and static but exist as different subtypes with phenotypic and functional differences in the tumor microenvironment. At the top of the heterogeneous tumor cell hierarchy, cancer stem cells (CSCs), a self-renewing and multi-potent cancer cell type, are most responsible for tumor recurrence and metastasis, chemoresistance, and mortality. Phenotypically, CSCs are associated with the epithelial-mesenchymal transition (EMT), which confers cancer cells with increased motility and invasion ability that is characteristic of malignant and drug-resistant stem cells. Recently, emerging studies of different cancer types, such as glioblastoma, leukemia, prostate cancer, and breast cancer, suggest that the circadian clock plays an important role in the maintenance of CSC/EMT characteristics. In this review, we describe recent discoveries regarding how tumor intrinsic and extrinsic circadian clock-regulating factors affect CSC evolution, highlighting the possibility of developing novel chronotherapeutic strategies that could be used against CSCs to fight cancer.