The effects of orexins on tumors

The orexin system consists of two peptides, named orexin-A and orexin-B, and of their two receptors, named orexin receptor 1 (OX1) and orexin receptor 2 (OX2). In the central nervous system, orexins are produced by a population of neurons in the hypothalamus, whose function is lost in patients with narcolepsy type 1. Orexins and their receptors have also been reported in nonneuronal cells outside the central nervous system, although their expression and physiological activity there are still unclear. It is also presently unclear whether the orexin system plays a role in the natural history of tumor development and progression in and outside of the central nervous system. Nevertheless, preclinical evidence supports effects of orexins on different types of tumors. Orexin-A may limit the growth of glioblastoma, pancreatic ductal adenocarcinoma, colon cancer, and prostate cancer. Orexins may also decrease the risk of hepatocellular carcinoma in conditions of high-fat diet feeding. On the other hand, orexins may increase secretion by pheochromocytoma and adrenocortical adenomas and increase proliferation of gastric adenocarcinoma. However, the available evidence is still entirely preclinical, mostly limited to in vitro experiments on tumor cell lines, and often lacking independent replication. More research on the effects of orexins on tumors is clearly warranted, also considering the lack of physiological knowledge on nonneuronal peripheral orexin actions, the rapid clinical development of orexin receptor antagonists and agonists, and the unmet need for more effective therapies for many tumors.