Role of the orexin system in modulating the tumor microenvironment: implications for tumor progression and cancer therapy.

The orexin system is involved in wakefulness, eating behaviour, energy homeostasis, motivation and addiction. It influences central arousal systems, together with the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. The two known orexin receptors are widely distributed throughout the mammalian brain, as well as in peripheral tissues. They belong to the G-protein coupled receptors and trigger the action of specific signaling pathways. Many neurotransmitters and neuropeptides, including orexin, have been implicated in cancers, not just those of the nervous system. Their role in cancer initiation and progression remains unclear. Referring to the orexin receptors, they have been reported in several types of cancer cells. In this review, we highlight the role of orexin receptors in modulating the tumour microenvironment. Their reported expression and regulatory effects on adipocytes, endothelial cells and immune cells, as well as cancer cells, suggest that OXRs are potent regulators of tumour initiation and progression. OXRs have been shown to be elements in the machinery that shape cancer-associated exosomes and trigger the cellular mechanisms that deal with hypoxia, both of which are critical for tumour initiation and progression. On the other hand, the potential of OXRs in restoring anti-cancer immunity and overcoming chemo-resistance may become a therapeutic adjunct. An important aspect of orexin action is its role in the management of chemotherapy-induced fatigue and its potential to regulate the composition of the gut microbiota - suggested as a potential regulator of cancer progression. Overall, the supportive role of the orexin system in cancer treatment should be considered.