Metabolic Features of Tumor Dormancy: Possible Therapeutic Strategies

SIMPLE SUMMARY: Tumor recurrence still represents a major clinical challenge for cancer patients. Cancer cells may undergo a dormant state for long times before re-emerging. Both intracellular- and extracellular-driven pathways are involved in maintaining the dormant state and the subsequent awakening, with a mechanism that is still mostly unknown. In this scenario, cancer metabolism is emerging as a critical driver of tumor progression and dissemination and have gained increasing attention in cancer research. This review focuses on the metabolic adaptations characterizing the dormant phenotype and supporting tumor re-growth. Deciphering the metabolic adaptation sustaining tumor dormancy may pave the way for novel therapeutic approaches to prevent tumor recurrence based on combined metabolic drugs. ABSTRACT: Tumor relapse represents one of the main obstacles to cancer treatment. Many patients experience cancer relapse even decades from the primary tumor eradication, developing more aggressive and metastatic disease. This phenomenon is associated with the emergence of dormant cancer cells, characterized by cell cycle arrest and largely insensitive to conventional anti-cancer therapies. These rare and elusive cells may regain proliferative abilities upon the induction of cell-intrinsic and extrinsic factors, thus fueling tumor re-growth and metastasis formation. The molecular mechanisms underlying the maintenance of resistant dormant cells and their awakening are intriguing but, currently, still largely unknown. However, increasing evidence recently underlined a strong dependency of cell cycle progression to metabolic adaptations of cancer cells. Even if dormant cells are frequently characterized by a general metabolic slowdown and an increased ability to cope with oxidative stress, different factors, such as extracellular matrix composition, stromal cells influence, and nutrient availability, may dictate specific changes in dormant cells, finally resulting in tumor relapse. The main topic of this review is deciphering the role of the metabolic pathways involved in tumor cells dormancy to provide new strategies for selectively targeting these cells to prevent fatal recurrence and maximize therapeutic benefit.