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Parkinson's Disease and Melanoma. What Is the Possible Link?

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Parkinson's Disease and Melanoma. What Is the Possible Link? REVIEW ARTICLE Magdalena Chrabąszcz, Joanna Czuwara, Lidia Rudnicka Department of Dermatology, Medical University of Warsaw, Poland Odd correlation: Parkinson’s disease and melanoma. What is the possible link? Address for correspondence: ABSTRACT Dr n. med. Joanna Czuwara Parkinson’s disease (PD) is a neurodegenerative disorder, characterised by depletion of dopamine in the stria- Katedra i Klinika Dermatologiczna tum and loss of melanin-positive, dopaminergic neurons in the substantia nigra. Melanoma is a skin neoplasm Warszawskiego Uniwersytetu Medycznego arising from epidermal melanocytes. The epidemiology of melanoma focuses on well-known risk factors such ul. Koszykowa 82a, Warszawa 02–008 as light skin and hair colour, gender, eye pigmentation, and ultraviolet (UV) exposure. Many studies have sug- Tel.: 22 502 13 11 gested an association between Parkinson’s disease and melanoma. The mechanism underlying the possible e-mail: [email protected] connection between PD and melanoma is not clear and has aroused lots of interest. More interesting is that the link between these two diseases runs both ways. What is the underlying cause of this reciprocal association? Is it due to Parkinson’s treatment? Is levodopa the reason for increased incidence of melanoma in people with the neurodegenerative condition? Are there any genetic, immune system irregularities or environmental risk factors that serve as the common denominator between these two conditions? Should we consider melanoma comorbidity with Parkinson’s disease and vice versa? Some hypotheses include pigmentation changes in melanin and/or melanin synthesis enzyme like tyrosinase hydroxylase, autophagy deficits, disturbed form of metabolically controlled cell death, and changes of PD-related genes such as Parkin or a-synuclein. Learning more about the Oncology in Clinical Practice relationship between PD and melanoma may lead to a better understanding of each disease and contribute to 2019, Vol. 15, No. 1, 62–70 more effective treatments of both. DOI: 10.5603/OCP.2019.0004 Key words: Parkinson’s disease, melanoma, melanin, dopamine Translation: dr n. med. Dariusz Stencel Copyright © 2019 Via Medica ISSN 2450–1654 Oncol Clin Pract 2019; 15, 1: 62–70 Introduction Epidemiological and toxicological studies emphasise the influence of environmental factors on the development Parkinson’s disease (PD) is a progressive neurode- of PD, and genetic studies show the role of specific gene generative disease of the central nervous system (CNS), mutations. Parkinson’s disease affects up to 1% of the the second most frequent after Alzheimer’s disease [1]. population over 60 years of age. It is a progressive dis- Its essence is the loss of substantia nigra in the brain, ease that leads to increased dementia, mortality, and risk which is the area responsible for synthesis of dopamine, of death with decreased risk of cancer, except melanoma. neurotransmitter necessary for proper functioning of Only symptomatic treatment of PD is possible — it is the nervous system. Dopamine deficiency leads to neu- aimed at improving the patient’s quality of life and pro- rotransmission disorders and the occurrence of typical longing surviving for as long as possible in the best physical symptoms, including: general slowness of movement, and mental form. Pharmacological treatment is introduced leaning forward, trembling hands (less commonly legs when the symptoms start to impact the patient’s daily or headaches), problems with movement initiation, dif- functioning. The therapy consists of simulating the func- ficulty with standing up and performing everyday life tion of dopamine as a transmitter (dopaminergic receptor activities such as washing, eating, or dressing [2]. The agonists) or its supplementation (levodopa); however, it cause of the disease is not fully understood. It probably does not significantly increase patients’ overall survival [4]. involves genetic and environmental factors, and the Melanoma is a malignant tumour from pigmented risk of developing the disease increases with age [3]. skin cells — melanocytes — that originate from neural 62 Magdalena Chrabąszcz et al., Melanoma and Parkinson’s disease cells located in body integuments. Melanocytes produce shown that people with PD are four times more likely an endogenous pigment melanin that protects the skin to develop melanoma, in contrast to other malignan- against the harmful carcinogenic effects of ultravio- cies of internal organs related to, for example, smoking let radiation. Melanocytes are found in the skin and [12]. Also, in people with melanoma, there is a four-fold additionally in the eye, mucosal epithelium, and the greater risk of developing PD [10]. The reasons for this meninges. Skin melanomas are divided based on the interaction remain unexplained. melanocyte transformation site. They account for over 90% of all melanomas (3.7% of melanocytic tumours are localised in the eye, and 1.4% in the mucous mem- Pathogenesis of Parkinson’s disease branes) [5]. In recent years, the incidence of melanoma has been constantly increasing worldwide. The annual The essence of the disease is the irreversible pro- increase in incidence of this cancer is about 3–7% [6]. gressive loss of dopamine-producing neurons contain- The peak of incidence is, on average, at 52 years of ing neuromelanin in the substantia nigra (hence the age. In Poland, the number of melanoma cases in the name) with the presence of eosinophilic protein inclu- last thirty years has increased threefold. Annually over sions, termed Lewy bodies (LBs), in their cytoplasm [3]. 3000 new cases are found and 1500 people die from Lewy bodies result from accumulation of aggregated this disease [7]. form of a-synuclein (a-Syn) protein. The loss and The main risk factors include genetic factors, a fair degeneration of dopaminergic neurons translates into phototype of the skin, excessive exposure to ultraviolet a significant deficiency of dopaminergic transmission radiation from solar and artificial radiation, sunburn at and associated neurological disorders (motor and an early age, and individual predispositions [6]. Early mental retardation, resting tremor, muscle stiffness). identification of the primary tumour (excision biopsy Intravital diagnosis of Parkinson’s disease is based on of primary lesion) and potential metastases to regional clinical symptoms and neurological differential diag- lymph nodes (sentinel lymph node biopsy) give a unique nosis, which in the early stages of disease is difficult opportunity to cure patients with non-advanced skin and in the advanced phase does not translate into any melanoma, evaluated in Breslow metric scale in terms of therapeutic benefits [4]. Degeneration and loss of depth of dermis infiltration below 1 mm. In about 80% dopaminergic neurons is a progressive process, with of patients, melanoma is a localized lesion at diagnosis, no effective treatment so far. 15% of patients present with regionally advanced stage, The following are considered as the main factors and in 5% of patients have the disease in disseminated involved in neurons damage: stage at presentation [7]. — oxidative stress, because it intensifies the enzymatic Parkinson’s disease is diagnosed with a frequency and non-enzymatic oxidation of dopamine; of 10–50 people per 100,000 population per year. The — mutations of genes from the PARK family; disease occurs in 100–300 people per 100,000 individuals — abnormal deposition and aggregation of cytoplasmic in the population [1]. This frequency increases with age, proteins, especially a-Syn that accumulates in the especially after 60 years of age. The relationship between form of Lewy bodies; PD and melanoma was noticed about half a century — mitochondrial dysfunction; ago. The first suspicions concerned the drug levodopa, — apoptosis disturbances; which was used to treat PD [8]. Subsequent observations — improper autophagy process; did not confirm this relationship because the increased — mechanism of cell death through ferroptosis. incidence of PD in people with melanoma is unrelated Physiological production of dopamine involves the to dopaminergic therapy [9]. Many publications in pres- formation of numerous intermediates that are highly tigious journals and meta-analyses confirm the existing reactive and generate oxidative stress in neurons (Fig- relationship between PD and melanoma, and emphasise ure 1) [13]. Dopamine itself does not accumulate in not only the role of genetic and immunological factors, the cytosol of dopaminergic neurons and is protected but also the common origin of embryonic melanocytes in synaptic vesicles VMAT-2 because it is a highly and neurons [10, 11]. Although the correlations them- reactive compound that damages the cytoplasmic and selves seem to be confirmed, new hypotheses are still mitochondrial proteins of the dopaminergic neuron. being proposed in an effort to explain them. The aim of Parkinson’s disease occurs in older age, perhaps due to this article is to review the most interesting hypotheses. the depletion of mechanisms that counteract reactive Numerous epidemiological studies and meta-analy- oxygen. Post-mortem brain examinations of patients ses support the relationship between PD and melanoma with PD show signs of damage to dopaminergic neurons [10, 11]. The researchers also point out that this link is due to oxidative stress [1, 3]. Clinical and experimental bi-directional and that melanoma also increases the studies also indicate the effect of oxidative stress as- risk of PD. Recent
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