Abstract
Simple SummaryThis 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.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.
Highlights
The incidence and prevalence of neurodegenerative diseases are high
The Framingham heart study, a longitudinal community based cohort study, in which 221 cases were evaluated for a 10-year follow-up, indicated a lower risk of Alzheimer’s disease (AD) for cancer survivors: the risk of AD was lower in survivors of smoking-related cancers; this model for cancer is similar to that seen in Parkinson’s disease (PD) and suggests an inverse association between cancer and neurodegeneration; the effect was stronger for lung cancer and preserved for participants who survived at least to 80 years of age [12]
Other potentially common factors in cancer and neurodegenerative diseases include the PARK7 (DJ-1) and amyloid precursor protein (APP) oncogenes, the PFDN5 (MM-1) and PRKN (Parkin) tumor suppressors, and the PDAP1 (PAP1) and PINK1 modulators [44]
Summary
The World Health Organization (WHO) highlights cancer as one of the most common causes of death, which accounted for almost 10 million deaths worldwide in 2020 [1]. The incidence and prevalence of neurodegenerative diseases are high. Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by brain β-amyloid plaques and neurofibrillary tangles formed by phosphorylated tau (P-Tau) protein deposits. AD is the most frequent neurodegenerative disease and affects 24 million people worldwide. The second most frequent neurodegenerative disease is Parkinson’s disease (PD), characterized by Lewy bodies and neurites formed by alpha-synuclein deposits. Despite being an inflammatory demyelinating disease, MS can be viewed as a neurodegenerative disease because of the cascade of events triggered by neuroinflammation and leading to neurodegeneration [3,4,5]. Amyotrophic lateral sclerosis (ALS), which is characterized by the progressive loss of motor neurons in the brain and spinal cord, is rare, with a prevalence of 2–3 per 100,000 [8]
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