Parkinson’s disease involved genes identified in cancer.
Abstract
Increasing number of genetic studies suggest that the pathogenesis of Parkinson’s disease (PD) and cancer may involve similar genes, pathways, and mechanisms. The differences in the pathological and cellular mechanisms, and the associated genetic mutations, may result in two such divergent diseases. However, the links between the molecular mechanisms that cause PD and cancer remain to be elucidated. This article appraises the overlapping molecular features of these diseases and discusses the implications for prevention and treatment. We propose that chronic inflammation (CI) in neurons and tumors contributes to a microenvironment that favors the amassing of DNA mutations and facilitating disease formation. CI may therefore play a key role in the development of PD and cancer, and provide a link between these two diseases.
Keywords
- Parkinson’s disease
- cancer
- chronic inflammation
- neurodegenerative disease
- genetic mutation
1. Introduction
Parkinson’s disease (PD) is the second most common neurodegenerative disease, after Alzheimer’s disease [1]. Typical symptoms include static tremors, muscle rigidity, and bradykinesia. These are caused by the premature death of dopaminergic neurons in the midbrain. The motor symptoms can be treated with dopaminergic drugs; however, the effectiveness diminishes as the severity of the clinical symptoms increases due to the development of the primary neuro-degeneration [2]. In contrast, cancer is a type of selectively advantageous cells with clonal proliferation. Although the two may appear distinctive, early epidemiological surveys have shown a connection between them. In 1954, Doshay [3] reported that the cancer incidence rate was lower among PD patients, but the reason for this was undistinguishable. Later, several epidemiological studies of cancer showed that the incidence of cancer was generally low among PD patients, regardless of whether they smoke or not [4]. However, the incidence of thyroid cancer, breast cancer, and melanoma was relatively high [5]. A recent study covering 219,194 people with PD displayed that the rate ratio (RR) for all subsequent primary malignant cancers combined was 0.92 [95% confidence interval (CI): 0.91–0.93], including increased RRs (p < 0.05) of breast cancer and melanoma cancer, and decreased RRs of 11 cancers [6]. This has been the most commanding epidemiological evidence for a connection between PD and cancer. Surely, there is a difference between association and causality, and it has been proposed that the association between PD and skin cancer could be linked to the way of therapy, such as Levodopa treatment, rather than with the disease itself. However, some observations did not support the causality [7, 8]. Moreover, some people thought that the low incidence of cancer in PD patients comes from the negative relationship between PD and smoking [4]. This may widely explain the decrease of smoking-related cancers, but the reduction of non-smoking-related cancers cannot be resolved.
The unusual epidemiological relation between PD and cancer has drawn the attention of many investigators. The genetic assessment encouraged an additional understanding: most of these familial PD genes had been found and summarized to be associated with cancer (Table 1). Mutations found in
Gene | PD locus | Chromosome location | Inheritance in PD* |
Expression in cancer |
Proliferation in Cancer† |
Cancer |
---|---|---|---|---|---|---|
4q21–q23 | AD | Overexpressed (not express in normal tissue) |
+ | Brain tumors [74] Melanoma [75] Ovary cancer [76] |
||
6q25.2–q27 | AR | Decreased§ | − | Glioblastoma [9] Colon cancer [9] Lung cancer [9] |
||
4p14 | AD | Silenced (via CpG methylation) |
− | Nasopharyngeal carcinoma [77] Colorectal cancer [78] |
||
1p35–p36 | AR | Decreased§ | − | Breast cancer [79] | ||
1p36 | AR | Overexpressed | + | Non-small-cell lung cancer [80] | ||
12p11.2–q13.1 | AD | Overexpressed | + | Papillary renal cell carcinoma [64], Thyroid cancer [64] |
If genetic defect was “the match that lights the fire” of PD and cancer, chronic inflammation (CI) might supply “the fuel that feeds the flames.” Over the past decades, the insight on cytokine and chemokine network has contributed to invention of a series of cytokine/chemokine antagonists used for inflammatory diseases. The first clinic practice, tumor necrosis factor antagonists, has shown encouraging efficacy [13]. CI is considered as a driving force behind many chronic diseases including cancerization and neurodegeneration. In PD, there are many activated microglia surrounding the lost neuron, and experiments have shown that inflammatory reaction does help killing neurons [14]. Epidemiological surveys have shown that taking non-steroidal anti-inflammatory drugs (NSAIDs) can reduce the risk of PD development. CI has long been known to mediate a wide variety of illnesses, including neurodegenerative disease and malignant tumors [15]. In 1863, Rudolf Virchow noticed leucocytes in neoplastic tissues and proposed a connection between inflammation and cancer. The role for inflammation in tumorigenesis is now mostly accepted, and it has become an evident that an inflammatory microenvironment is an essential piece for most tumors [16]. Inflammatory mediators in the microenvironment of CI not only benefit cancer cells proliferation and escape from immunological surveillance but also cause a large number of random mutations [17]. Amassing research evidence supports the view that inflammatory mediators, some of that are direct mutagens, directly or indirectly downregulate DNA repair pathways and cell cycle checkpoints, consequently destabilizing cell genome and contributing to the accumulation of random genetic alterations. Thus, inflammation is considered as the seventh most important sign of cancer [18].
The cellular pathways and its associated mechanisms (Figure 1) that involve genes common to PD and cancer have been discussed in our previous paper [19]. In this manuscript, we further explain the environmental factors that cause PD and cancer from the perspective of CI and related genes to provide a better understanding and treatment options of these two diseases. To emphasize the multiple pathological functions of these gene mutations, they are discussed separately.
2. Chronic inflammation
The blood–brain barrier (BBB) prevents the lymphatic infiltration and neurotoxins diffusion from the blood to the CNS. Conventionally, the CNS was regarded as the immunological restriction due to its limited inflammatory reaction and lymphatic infiltration. Nonetheless, accumulating evidence indicates that the CNS actually is the immunological specialization by the resident innate immune cell in the brain: microglia. Activated microglia could prevent the CNS injury from pathogenic factors (physiological disrupt and toxic insult) through releasing a number of cytokines and chemokines [20]. These inflammatory mediators could trigger or modulate the remove of neurotoxins and inhibit their detrimental effects. Thus, acute inflammatory responses are consider to be beneficial, but long-term, high-level CI can severely damage the body. Two of the pathological characteristics of PD are loss of dopaminergic neurons and accumulation of LBs in the nigrostriata of the midbrain. LBs are abnormal intracytoplasmic filamentous aggregates of α-synuclein present, respectively, in neurons and axons. Recent studies have shown that neurons able to release α-synuclein oligomers, which can bind to toll-like receptors (TLR) to activate microglia, activating the nuclear factor kappa B (NF-kB) pathway, and releasing of inflammatory factors. These immune factors not only act directly on dopaminergic neurons to cause neuronal death but also aggravate the inflammatory reaction and continue to activate microglia. Activated microglia surround dead neurons in the substantia nigra pars compacta (SNc) of PD patients. Studies have shown that inhibition of microglia cascade reactions can prevent degradation of neurons [21]. Increasing studies demonstrated that there was a positive correlation between SNc cell loss and microglia activation in both animal models and PD patients. Timing analysis displayed that reduce microglial activation can rescue SNc neurons loss in animal models, suggesting an active effect of microglia in killing SNc cell following a range of stimuli. It is increasingly clear that activation of microglia is a highly localized inflammatory reaction rather than generalized. Even though the degenerating neuronal terminals of SNc cell cannot stimulate the similar response but only the dopaminergic neurons in the SNc [22]. Therefore, cell death of PD directly relates to a substantial increase of microglia activation. At the same time, overproduction of free radicals (superoxide and peroxynitrite) damages the balance of the redox potential of neurons and acts on biomacromolecules to modulate their roles, or causes lipid peroxidation leading to cell death eventually. Alternatively, microglia might kill SNc cells by producing other noxious compounds including cytokines and proinflammatory prostaglandins. Patients with PD have selective degeneration of neurons in the SNc accompanied by microglial activation and a challenged immune system.
The presence of activated microglia in PD might reflect a scavenging role in the wake of a primary pathologic process. However, evidence for a more sinister role comes from animal models of PD. MPTP, 6-OHDA, lipopolysaccharide, rotenone, viruses, and SNc extracts all can lead to degeneration of the dopaminergic neurons and loss of striatal dopamine in primates, rodents, and other species [23]. Each of them can cause an inflammatory response that associated with the enhancement of microglia activation in the SNc. The best evidence for the significance of inflammation during neoplastic progression maybe come from study of cancer risk among long-term users of aspirin and NSAIDs. A big prospective study of hospital workers indicated that the incidence of PD in chronic users of over-the-counter NSAIDs which scavenge free oxygen radicals and inhibit cyclooxygenase (COX) activity was 46% lower than that of age-matched non-users [24]. Inhibition of COX-mediated dopaminergic neurons oxidation, as well as inhibition of microglial-derived toxic mediator production, is likely to be among the mechanisms that contribute to decreased incidence of PD in chronic NSAIDs users [25]. Therapeutically, these findings raise the possibility that early involvement with NSAIDs or similar anti-inflammatory therapy may be neuroprotective and could delay or prevent onset of PD. That anti-inflammatory medications downregulate microglial responses to a toxic insult and directly reduce neuronal loss strongly, which indicates that localized inflammation is pathogenic in the SNc rather than merely a late response to neuronal death.
3. NOD2
Crohn’s disease (CD), also known as regional enteritis, is a type of inflammatory bowel disease. In 2001, three laboratories found CD associate with genetic variants. Nucleotide-binding oligomerization domain protein 2 (NOD2) also known as caspase recruitment domain protein 15 (CARD15) is a protein that in humans which is encoded by the
Whether the CD’s-associated
4. COX2
COX is the central enzyme in prostaglandin biosynthesis. There are two different isoforms of COX: COX-1 and COX-2. Constitutive expression of COX-1 is commonly found in many tissues. Because COX-1 is responsible for the biosynthesis of prostaglandins which regulate some physiological homeostasis, including modulation of renal blood flow and preservation of the gastric mucosa. Normally, COX-2 could not be discovered in most tissues except for stimulating by some mitogenic and inflammatory mediators [39]. COX2 is not only key to the synthesis of prostaglandin in inflammatory reactions but also an important contributor to the degradation of neurons in PD. Inhibiting COX2 activity in mice and rats can alleviate neuronal death caused by MPTP [40] and 6-ODHA [41], respectively. Macrophages, neurons, and glial cells in the central nervous system can all express COX2. Unlike COX1, which is constitutively expressed, COX2 expression is induced by inflammatory conditions. The COX2 level in the dopaminergic neurons of PD patients is elevated, and prostanoid and ROS produced by COX2 can directly act on dopaminergic neurons causing cell toxicity [42]. The role of COX2 in inflammation and neuronal degradation has yet to be verified. However, it has been shown that NSAIDs nonselectively inhibit the activities of COX1 and COX2, thus reducing prostaglandin production and promoting clearance of ROS. An epidemiological survey has revealed that individuals who take NSAIDs have a lower risk of PD than those who do not [25]. However, there has not been any report on the effects of specific COX2 inhibitors on the occurrence and development of PD.
COX-2, the inducible isoform of prostaglandin H synthase, has been implicated in the growth and progression of a variety of human cancers [43]. There are many evidence support that COX-2 is involved in the development of cancer. Because the overexpression of COX-2 is commonly found in the premalignant and malignant tissues. The most powerful findings from genetic studies support the view that it exists a cause-and-effect relationship between COX-2 and tumorigenesis. Multiple lines of evidence indicate that COX-2 is a
5. LRRK2
Leucine-rich-repeat kinase 2 (
More directly supporting a role of LRRK2 in cancer, chromosomal amplification of the LRRK2 locus is required for oncogenic signaling in papillary renal and thyroid carcinomas [64]. Genetic studies have implicated LRRK2 in the pathogenesis of several human diseases, including cancer and CD [65–67]. In 2011, Liu et al. [68] found that LRRK2 could suppress the activity of the transcription factor Nuclear factor of activated T-cells (NFAT). Overexpression of LRRK2 led to increased retention of NFAT in the cytosol. When
6. Perspective and conclusion
Increasingly epidemiologic findings demonstrated the correlation between cancer and PD in recent years, but the conclusions were not completely consistent. This is because of the differences of study management. Our understanding of the control of signaling pathways is further advanced in cancer studies compared to neurodegeneration. As a result, many small molecule inhibitors have been approved as anticancer agents or are currently being tested in clinical trials. In 2010, Datamonitor Inc. (USA) estimated that there were over 1.5 million PD patients in the USA, Japan, France, Germany, Italy, Spain, and UK combined, one-third of them in the USA. With the increasing aging of world population, the incidence of PD is increasing yearly [71]. Medication is usually the first option in the treatment of PD. Levodopa is currently the most effective medication, but long-term use can reduce the effectiveness of treatment and cause complications such as motor dysfunction. Thus, discoveries in cancer research are likely to provide a solid base upon which scientists will study the pathophysiology of neurodegenerative diseases, especially PD.
The origins of the association and interplay between cancer and PD are still a matter of debate, but increasing epigenetic modifications such as DNA acetylation, DNA methylation, and miRNA scan conspire with genetic alterations in disease pathogenesis [72]. Recently, Gehrke et al. [73] found that
Most degenerative diseases of the brain are incurable and the study of tissue from the brains of people with significant neurodegeneration is difficult, so the postmortem specimen is probably the most valuable research material. However, academic and clinic of cancer research have accumulated a wide range of achievement in the past long time, and these results and experience must be important and beneficial to neurodegeneration study. Understanding the nature of their relationship must help scientist find novel and more efficacious therapeutic approaches for both diseases.
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