Amit Sharma
Ullrich Wüllner2
Ingo G. H. Schmidt-Wolf
Jarek Maciaczyk- 1Department of Neurosurgery, University Hospital of Bonn, Bonn, Germany
- 2Department of Neurology, University Hospital of Bonn, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
- 3Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital of Bonn, Bonn, Germany
- 4Department of Surgical Sciences, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
Cancer and neurodegenerative diseases (NDD) appear mechanistically distinct, i.e., the former acquires mechanisms to resist and evade cell death, while the latter is characterized by progressive cellular demise and degeneration in specific neuronal populations. Nevertheless, there is an ongoing debate about the inverse epidemiologic relationship between cancer and NDD. A substantial number of cancer survivors have a lower risk of developing NDD, particularly Parkinson's disease (PD) and Alzheimer's disease (AD), whereas less malignancies are observed in PD and AD patients. Several biological hypotheses have been put forward (Wang et al., 2013; Catalá-López et al., 2014; Majd et al., 2019; Panegyres and Chen, 2021; Zabłocka et al., 2021; Lee et al., 2022), but exact underlying mechanisms behind this “inverse association” remain to be explored. Interestingly the correlation between cancer and AD appears to be purely negative/inverse, suggesting that susceptibility to one disease may be protective against the other (Musicco et al., 2013; Driver, 2014; Zhang et al., 2015; Papageorgakopoulos et al., 2017). Contrary in PD, patients showed a low risk to develop colon, rectal, colorectal cancer and lung cancers but increased risks of brain cancer and melanoma (Ye et al., 2020). The possible involvement of certain genes and signaling pathways behind this inverse comorbidity has been discussed (Ibáñez et al., 2014). In particular, the authors elaborated on the possible roles of Wnt and p53 signaling pathways and protein degradation processes (Ubiquitin/proteasome system) underlying the observed differences in CNS diseases and cancers. The putative role of non-coding genomes (LnRNAs, miRNAs) has also been briefly investigated. Pandini et al. (2021), recently discussed the mechanisms of action associated with MYC-induced long non-coding RNA (MINCR) and its potential implications in both cancer and NDD. Likewise, miR-519a-3p, which is normally upregulated in certain cancers, appears to be downregulated in PD (via possible engagement of its target gene PARP1) (Salemi et al., 2022).
Since most NDD and cancer patients are sporadic, the notion of inverse association in familial cases is still unexplored. Notably, mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are associated with both familial and sporadic PD. There is plethora of knowledge indicating the “overlapping” molecular mechanisms between these two entities. For instance, TP53—the most frequently mutated gene in human cancers, often named as—“guardian of the genome” (Chen et al., 2022), turns out to be one of the discriminating tools also in NDD (Chang et al., 2012; Checler and da Alves Costa, 2014; Talebi et al., 2021). It has been shown that the mononuclear cells from AD patients express higher levels of mutant-like p53 (conformationally altered p53) compared to non-AD patients (Lanni et al., 2008). Likewise, p53 protein levels were found markedly elevated in caudate nucleus of PD patients (Mogi et al., 2007). Similar to TP53 PIN1 (Peptidyl-prolyl isomerase), has been reported to inactivate and activate more than 26 tumor suppressors and 56 oncogenes, in numerous malignancies (Yu et al., 2020). Besides cancer, a number of studies highlighted the possible involvement of PIN1 in NDDs (Pastorino et al., 2006; Ryo et al., 2006). Driver et al. (2015) discussed the diverse priorities of PIN1 in cyclic cells and neurons, and suggested that understanding its role may explain the inverse association between cancer and AD. Of interest, in cancers that originate mainly in the brain (e.g., glioblastoma/GBM), an obvious communication between the cancer cells and adjacent neuronal cells can be expected. In such scenario, some genetic/molecular resemblances shared by both cancer and neuronal cells would not be surprising, and genes such as PARK7 (which encodes the protein DJ-1) fit well into this scenario. More specifically, whereas the mutation/deletion of PARK7 leads to the early onset of PD (Dolgacheva et al., 2019), this gene seems to play a role in cancerogenesis (Kawate et al., 2017). Particularly in GBM, the immunohistochemical staining showed enhanced expression of PARK7 in glioma tissues compared to the normal brain tissues (Kim et al., 2021). Thus, a multifunctional protein like PARK7 represents a prime candidate explaining the pathological interactions between cancer (GBM) and PD, which occur in the anatomically different regions yet in same organ. Similarly, Tau protein (encoded by the MAPT gene), one of the major hallmarks of AD, is assumed to bind cancer-related kinase proteins due to its ability to accumulate both intracellularly and extracellularly (Papin and Paganetti, 2020; Hedna et al., 2022). Certain miRNAs are also instrumental in these overlapping mechanisms. Notably, miRNAs that are differentially expressed in NDDs (e.g., miR-9, the miR-29 family, and the miR-34 family) have also been implicated as potential tumor suppressors (Saito and Saito, 2012). Strikingly, the substantial epigenetic constraint on cancer progression appears to be a mediating rather than a causative factor when compared with NDD. For instance, rapid divisions in cancer cells requires a continuous rewriting of epigenetic marks (e.g., DNMTs, HAT/HDACs) in their daughter cells, whereas in NDD all the established epigenetic marks vanished with the loss/degeneration of neuronal cells.
Beyond the aforementioned—inverse or overlapping—mechanisms, another avenue that remains to be explored is the identification of distant molecular contributors involved in these two entities. A prerequisite for such possible causative contributors should be their ability to play a dichotomous functional role in cancer (i.e., both tumor suppressor and tumor promoter), having open access to the epigenetic landscape/chromatin machinery (to control transcriptional activity) and a strong tendency to cross-talk with other non-cancerous hallmarks. Interesting candidate are the ubiquitin C-terminal hydrolases (UCHs: UCH-L1, UCH-L3, UCH-L5, and BAP1), a subfamily of deubiquitinating enzymes, which we have recently shown to be involved in both cancer and NDD (Sharma et al., 2020). Specifically, UCH-L1 and BAP1 are of interest. UCH-L1 (also known as PARK5 and PGP9.5) was previously found to be enriched in neurons, shown to promote alpha-synuclein neurotoxicity in PD patients (Liu et al., 2009) at the same time being proposed as an oncogene (Hurst-Kennedy et al., 2012; Zhong et al., 2012). Likewise, BAP1 gene has been implicated in several types of cancer and is considered pivotal to constrain histone H2A monoubiquitylation (H2AK119ub1) in the genome (Sharma et al., 2019; Fursova et al., 2021). Several cancer-associated mutations within this gene were found to destabilize the protein structure and promoted β-amyloid aggregation in vitro, constituting a pathological hallmark of AD (Bhattacharya et al., 2015). Though apparently distant (not directly linked), understanding the multifaceted involvement of UCH-L1 and BAP1 in cancer and NDD could be of importance. Other potential candidates are adenosine receptors (ARs), a family of G protein-coupled receptors (GPCRs) whose four (A1, A2A, A2B, and A3) members have all been involved in one way or another in the regulation of tumor progression (Franco et al., 2021). A1 and A2A show the highest expression in the brain but their relevance for NDD has yet to be defined (Stockwell et al., 2017).
It is widely accepted that NDD start long before clinical symptoms (Sharma et al., 2021), i.e., parkinsonism or dementia arise and affect the patients substantially, thus tracking the subsequent overt disease progression or severity may not reveal information relevant to the primary cause (Surguchov, 2022). Similarly, in cancer it appeared crucial to determine the “disease onset point” by understanding the aforementioned overlapping/inverse molecular mechanisms. Given the rapid development of sequencing technology it can be envisioned that defining genotype of sporadic and familial cases across populations may improve insight into the shared genetic architecture connecting disease specific phenotypes, ranging from cancer to NDD. Consequently, such approaches will also help identify aging-related exponential accumulation of mutations that may possibly be correlated with the proteins/proteolytic fragments released by degenerating neurons in order to develop advanced novel therapies.
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Bhattacharya, S., Hanpude, P., and Maiti, T. K. (2015). Cancer associated missense mutations in Bap1 catalytic domain induce amyloidogenic aggregation: a new insight in enzymatic inactivation. Sci. Rep. 5, 18462. doi: 10.1038/srep18462
Catalá-López, F., Suárez-Pinilla, M., Suárez-Pinilla, P., Valderas, J. M., Gómez-Beneyto, M., Martinez, S., et al. (2014). Inverse and direct cancer comorbidity in people with central nervous system disorders: a meta-analysis of cancer incidence in 577,013 participants of 50 observational studies. Psychother. Psychosomat. 83, 89–105. doi: 10.1159/000356498
Chang, J. R., Ghafouri, M., Mukerjee, R., Bagashev, A., Chabrashvili, T., Sawaya, B. E., et al. (2012). Role of P53 in neurodegenerative diseases. Neuro Degenerat. Dis. 9, 68–80. doi: 10.1159/000329999
Checler, F., and da Alves Costa, C. (2014). P53 in neurodegenerative diseases and brain cancers. Pharmacol. Ther. 142, 99–113. doi: 10.1016/j.pharmthera.2013.11.009
Chen, X., Zhang, T., Su, W., Dou, Z., Zhao, D., Jin, X., et al. (2022). Mutant P53 in cancer: from molecular mechanism to therapeutic modulation. Cell Death Dis. 13, 974. doi: 10.1038/s41419-022-05408-1
Dolgacheva, L. P., Berezhnov, A. V., Fedotova, E. I., Zinchenko, V. P., and Abramov, A. Y. (2019). Role of Dj-1 in the mechanism of pathogenesis of Parkinson's disease. J. Bioenerget. Biomembranes 51, 175–188. doi: 10.1007/s10863-019-09798-4
Driver, J. A. (2014). Inverse association between cancer and neurodegenerative disease: review of the epidemiologic and biological evidence. Biogerontology 15, 547–557. doi: 10.1007/s10522-014-9523-2
Driver, J. A., Zhou, X. Z., and Lu, K. P. (2015). Pin1 dysregulation helps to explain the inverse association between cancer and Alzheimer's disease. Biochim. Biophys. Acta. 1850, 2069–2076. doi: 10.1016/j.bbagen.2014.12.025
Franco, R., Rivas-Santisteban, R., Navarro, G., and Reyes-Resina, I. (2021). Adenosine receptor antagonists to combat cancer and to boost anti-cancer chemotherapy and immunotherapy. Cells 10, 2831. doi: 10.3390/cells10112831
Fursova, N. A., Turberfield, A. H., Blackledge, N. P., Findlater, E. L., Lastuvkova, A., Huseyin, M. K., et al. (2021). Bap1 constrains pervasive H2ak119ub1 to control the transcriptional potential of the genome. Genes Dev. 35, 749–770. doi: 10.1101/gad.347005.120
Hedna, R., Kovacic, H., Pagano, A., Peyrot, V., Robin, M., Devred, F., et al. (2022). Tau protein as therapeutic target for cancer? Focus on glioblastoma. Cancers 14, 5386. doi: 10.3390/cancers14215386
Hurst-Kennedy, J., Chin, L. S., and Ubiquitin, Li, L. (2012). C-terminal hydrolase L1 in tumorigenesis. Biochem. Res. Int. 2012, 123706. doi: 10.1155/2012/123706
Ibáñez, K., Boullosa, C., Tabarés-Seisdedos, R., Baudot, A., and Valencia, A. (2014). Molecular evidence for the inverse comorbidity between central nervous system disorders and cancers detected by transcriptomic meta-analyses. PLoS Genet. 10, e1004173. doi: 10.1371/journal.pgen.1004173
Kawate, T., Tsuchiya, B., and Iwaya, K. (2017). Expression of Dj-1 in cancer cells: its correlation with clinical significance. Adv. Exp. Med. Biol. 1037, 45–59. doi: 10.1007/978-981-10-6583-5_4
Kim, J. Y., Kim, H. J., Jung, C. W., Choi, B. I., Lee, D. H., Park, M. J., et al. (2021). Park7 maintains the stemness of glioblastoma stem cells by stabilizing epidermal growth factor receptor variant III. Oncogene 40, 508–521. doi: 10.1038/s41388-020-01543-1
Lanni, C., Racchi, M., Mazzini, G., Ranzenigo, A., Polotti, R., Sinforiani, E., et al. (2008). Conformationally altered P53: a novel Alzheimer's disease marker? Mol. Psychiatry 13, 1641–1647. doi: 10.1038/sj.mp.4002060
Lee, J. Y. S., Ng, J. H., Saffari, S. E., and Tan, E. K. (2022). Parkinson's disease and cancer: a systematic review and meta-analysis on the influence of lifestyle habits, genetic variants, and gender. Aging 14, 2148–2173. doi: 10.18632/aging.203932
Liu, Z., Meray, R. K., Grammatopoulos, T. N., Fredenburg, R. A., Cookson, M. R., Liu, Y., et al. (2009). Membrane-associated farnesylated Uch-L1 promotes alpha-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease. Proc. Natl. Acad. Sci. U.S.A. 106, 4635–40. doi: 10.1073/pnas.0806474106
Majd, S., Power, J., and Majd, Z. (2019). Alzheimer's disease and cancer: when two monsters cannot be together. Front. Neurosci. 13, 155. doi: 10.3389/fnins.2019.00155
Mogi, M., Kondo, T., Mizuno, Y., and Nagatsu, T. (2007). P53 protein, interferon-gamma, and Nf-kappab levels are elevated in the Parkinsonian brain. Neurosci. Lett. 414, 94–97. doi: 10.1016/j.neulet.2006.12.003
Musicco, M., Adorni, F., Di Santo, S., Prinelli, F., Pettenati, C., Caltagirone, C., et al. (2013). Inverse occurrence of cancer and Alzheimer disease: a population-based incidence study. Neurology 81, 322–328. doi: 10.1212/WNL.0b013e31829c5ec1
Pandini, C., Garofalo, M., Rey, F., Garau, J., Zucca, S., Sproviero, D., et al. (2021). Mincr: a long non-coding rna shared between cancer and neurodegeneration. Genomics 113:4039–4051. doi: 10.1016/j.ygeno.2021.10.008
Panegyres, P. K., and Chen, H. Y. (2021). Alzheimer's disease, Huntington's disease and cancer. J. Clin. Neurosci. 93, 103–105. doi: 10.1016/j.jocn.2021.09.012
Papageorgakopoulos, T. N., Moraitou, D., Papanikolaou, M., and Tsolaki, M. (2017). The association between Alzheimer's disease and cancer: systematic review - meta-analysis. Hellenic J. Nuclear Med. 20(Suppl.), 45–57.
Papin, S., and Paganetti, P. (2020). Emerging evidences for an implication of the neurodegeneration-associated protein tau in cancer. Brain Sci. 10, 862. doi: 10.3390/brainsci10110862
Pastorino, L., Sun, A., Lu, P. J., Zhou, X. Z., Balastik, M., Finn, G., et al. (2006). The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature 440, 528–534. doi: 10.1038/nature04543
Ryo, A., Togo, T., Nakai, T., Hirai, A., Nishi, M., Yamaguchi, A., et al. (2006). Prolyl-isomerase Pin1 accumulates in lewy bodies of Parkinson disease and facilitates formation of alpha-synuclein inclusions. J. Biol. Chem. 281, 4117–25. doi: 10.1074/jbc.M507026200
Saito, Y., and Saito, H. (2012). Micrornas in cancers and neurodegenerative disorders. Front. Genet. 3, 194. doi: 10.3389/fgene.2012.00194
Salemi, M., Mogavero, M. P., Lanza, G., Mongioì, L. M., Calogero, A. E., Ferri, R., et al. (2022). Examples of inverse comorbidity between cancer and neurodegenerative diseases: a possible role for noncoding Rna. Cells 11, 1930. doi: 10.3390/cells11121930
Sharma, A., Biswas, A., Liu, H., Sen, S., Paruchuri, A., Katsonis, P., et al. (2019). Mutational landscape of the Bap1 locus reveals an intrinsic control to regulate the mirna network and the binding of protein complexes in uveal melanoma. Cancers 11, 1600. doi: 10.3390/cancers11101600
Sharma, A., Liu, H., Tobar-Tosse, F., Chand Dakal, T., Ludwig, M., Holz, F. G., et al. (2020). Ubiquitin carboxyl-terminal hydrolases (Uchs): potential mediators for cancer and neurodegeneration. Int J. Mol. Sci. 21, 3910. doi: 10.3390/ijms21113910
Sharma, A., Müller, J., Schuetze, K., Rolfes, V., Bissinger, R., Rosero, N., et al. (2021). Comprehensive profiling of blood coagulation and fibrinolysis marker reveals elevated plasmin-antiplasmin complexes in Parkinson's disease. Biology 10, 716. doi: 10.3390/biology10080716
Stockwell, J., Jakova, E., and Cayabyab, F. S. (2017). Adenosine A1 and A2a receptors in the brain: current research and their role in neurodegeneration. Molecules 22, 676. doi: 10.3390/molecules22040676
Surguchov, A. (2022). “Biomarkers in Parkinson's Disease,” in Neurodegenerative Diseases Biomarkers: Towards Translating Research to Clinical Practice, eds P. V. Peplow, B. Martinez, and T. A. Gennarelli (New York, NY: Humana), 155–180. doi: 10.1007/978-1-0716-1712-0_7
Talebi, M., Talebi, M., Kakouri, E., Farkhondeh, T., Pourbagher-Shahri, A. M., Tarantilis, P. A., et al. (2021). Tantalizing Role of P53 molecular pathways and its coherent medications in neurodegenerative diseases. Int. J. Biol. Macromol. 172, 93–103. doi: 10.1016/j.ijbiomac.2021.01.042
Wang, J. Z., Zhang, Y. H., Sun, X. W., Li, Y. L., Li, S. R., Zhang, Y., et al. (2013). Focusing on the structure and the function of Pin1: new insights into the opposite effects of fever on cancers and Alzheimer's disease. Med. Hypoth. 81, 282–284. doi: 10.1016/j.mehy.2013.04.029
Ye, Q., Wen, Y., Al-Kuwari, N., and Chen, X. (2020). Association between Parkinson's disease and melanoma: putting the pieces together. Front. Aging Neurosci. 12, 60. doi: 10.3389/fnagi.2020.00060
Yu, J. H., Im, C. Y., and Min, S. H. (2020). Function of Pin1 in cancer development and its inhibitors as cancer therapeutics. Front. Cell Dev. Biol. 8, 120. doi: 10.3389/fcell.2020.00120
Zabłocka, A., Kazana, W., Sochocka, M., Stańczykiewicz, B., Janusz, M., Leszek, J., et al. (2021). Inverse correlation between Alzheimer's disease and cancer: short overview. Mol. Neurobiol. 58, 6335–49. doi: 10.1007/s12035-021-02544-1
Zhang, Q., Guo, S., Zhang, X., Tang, S., Shao, W., Han, X., et al. (2015). Inverse relationship between cancer and Alzheimer's disease: a systemic review meta-analysis. Neurol. Sci. 36, 1987–94. doi: 10.1007/s10072-015-2282-2
Keywords: cancer, neurodegeneration, genome, epigenome, pathway
Citation: Sharma A, Wüllner U, Schmidt-Wolf IGH and Maciaczyk J (2023) Marginalizing the genomic architecture to identify crosstalk across cancer and neurodegeneration. Front. Mol. Neurosci. 16:1155177. doi: 10.3389/fnmol.2023.1155177
Received: 31 January 2023; Accepted: 10 February 2023;
Published: 27 February 2023.
Edited by:
Andrei Surguchov, University of Kansas Medical Center, United StatesReviewed by:
Irina G. Sourgoutcheva, University of Kansas Medical Center, United StatesCopyright © 2023 Sharma, Wüllner, Schmidt-Wolf and Maciaczyk. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jarek Maciaczyk, 
jaroslaw.maciaczyk@ukbonn.de