Metastatic Cell Dormancy and Re-activation: An Overview on Series of Molecular Events Critical for Cancer Relapse

Cancer patients, though frequently entering complete remission after successful surgery, and/or irradiation, and chemotherapy years or even decades later may exhibit overt metastases and aggressive, mostly fatal recurrence on the basis of clinically silent persistence of disseminated tumor cells. Cellular dormancy is a mode of hibernation/ inactivity caused by a temporary mitotic arrest. It represents the critical phenomenon of latency making metastatic cancer cells highly refractory to conventional therapies. Regarding host-tumor interactions a broad range of dynamic, interrelated molecular events may influence the dormancy state of quiescence, like regulators of cell cycle arrest, stress signaling pathways, autophagy, microenvironmental, angiogenic and immunologic factors, genetic and epigenetic effects. Nonetheless, the underlying mechanisms are still poorly understood. Moreover, a distinct subset of circulating and disseminated cancer cells exhibits stem cell-like properties with direct tumor-provoking and metastatis-initiating capacity, being at least partly responsible for the specific dormancy features. In residual disease a future more detailed molecular and phenotypic characterization of disseminated tumor cells could represent the prerequisite not only for prognostic and staging purposes, but for a specific design of therapeutic targeting, as well. By understanding the elusive dormancy signatures of tumor cells, their cell- and context (microenvironment)-dependent modulation should provide novel potential therapeutic approaches to avoid or overcome metastatic cancer relapse.