Focus on the Complex Interconnection between Cancer, Narcolepsy and Other Neurodegenerative Diseases: A Possible Case of Orexin-Dependent Inverse Comorbidity

SIMPLE SUMMARY: This narrative review first describes from several points of view the complex interrelationship between cancer and neurodegeneration, with special attention to the mechanisms that might underlie an inverse relationship between them. In particular, the mechanisms that might induce an imbalance between cell apoptotic and proliferative stimuli are discussed. Second, the review summarizes findings on orexins and their involvement in narcolepsy, neurodegenerative diseases, and cancer, starting from epidemiological data then addressing laboratory findings, animal models, and human clinical observational and interventional investigations. Important research efforts are warranted on these topics, as they might lead to novel therapeutic approaches to both neurodegenerative diseases and cancer. ABSTRACT: Conditions such as Alzheimer’s (AD) and Parkinson’s diseases (PD) are less prevalent in cancer survivors and, overall, cancer is less prevalent in subjects with these neurodegenerative disorders. This seems to suggest that a propensity towards one type of disease may decrease the risk of the other. In addition to epidemiologic data, there is also evidence of a complex biological interconnection, with genes, proteins, and pathways often showing opposite dysregulation in cancer and neurodegenerative diseases. In this narrative review, we focus on the possible role played by orexin signaling, which is altered in patients with narcolepsy type 1 and in those with AD and PD, and which has been linked to β-amyloid brain levels and inflammation in mouse models and to cancer in cell lines. Taken together, these lines of evidence depict a possible case of inverse comorbidity between cancer and neurodegenerative disorders, with a role played by orexins. These considerations suggest a therapeutic potential of orexin modulation in diverse pathologies such as narcolepsy, neurodegenerative disorders, and cancer.