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Inverse association between cancer and neurodegenerative disease: review of the epidemiologic and biological evidence

Abstract

Growing evidence suggests an unusual epidemiologic association between cancer and certain neurological conditions, particularly age-related neurodegenerative diseases. Cancer survivors have a 20–50 % lower risk of developing Parkinson’s and Alzheimer’s disease, and patients with these neurodegenerative conditions have a substantially lower incidence of cancer. We review the epidemiologic evidence for this inverse co-morbidity and show that it is not simply an artifact of survival bias or under-diagnosis. We then review the potential biological explanations for this association, which is intimately linked to the very different nature of dividing cells and neurons. The known genetic and metabolic connections between cancer and neurodegeneration generally fall within two categories. The first includes shared genes and pathways such as Pin1 and the ubiquitin proteasome system that are dysregulated in different directions to cause one disease or the other. The second includes common pathophysiological mechanisms such as mitochondrial dysfunction, oxidative stress and DNA damage that drive both conditions, but with different cellular fates. We discuss examples of these biological links and their implications for developing new approaches to prevention and treatment of both diseases.

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References

  1. Ackman JB, Ramos RL, Sarkisian MR, Loturco JJ (2007) Citron kinase is required for postnatal neurogenesis in the hippocampus. Dev Neurosci 29:113–123. doi:10.1159/000096216

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  2. Aljada A, Mousa SA (2012) Metformin and neoplasia: Implications and indications. Pharmacol Ther 133:108–115. doi:10.1016/j.pharmthera.2011.09.004

    CAS  PubMed  Article  Google Scholar 

  3. Bajaj A, Driver JA, Schernhammer ES (2009) Parkinson’s disease and cancer risk: A systematic review and meta-analysis. Cancer Causes & Control. Accepted pending revisions

  4. Bakkour A, Morris JC, Dickerson BC (2009) The cortical signature of prodromal AD: Regional thinning predicts mild AD dementia. Neurology 72:1048–1055. doi:10.1212/01.wnl.0000340981.97664.2f

    PubMed Central  PubMed  Article  Google Scholar 

  5. Bao L, Sauter G, Sowadski J, Lu KP, Wang D (2004) Prevalent overexpression of prolyl isomerase Pin1 in human cancers. Am J Pathol 164:1727–1737

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  6. Behrens MI, Lendon C, Roe CM (2009) A common biological mechanism in cancer and Alzheimer’s disease? Curr Alzheimer Res 6:196–204

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  7. Benedict C, Kern W, Schultes B, Born J, Hallschmid M (2008) Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin. J Clin Endocrinol Metab 93:1339–1344. doi:10.1210/jc.2007-2606

    CAS  PubMed  Article  Google Scholar 

  8. Catala-Lopez F 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 Psychosom 83:89–105. doi:10.1159/000356498

    PubMed  Article  Google Scholar 

  9. Corsellis J (1962) Mental illness and the ageing brain. Oxford University Press, London

    Google Scholar 

  10. Craft S et al (2012) Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: A pilot clinical trial. Arch Neurol 69:29–38. doi:10.1001/archneurol.2011.233

    PubMed Central  PubMed  Article  Google Scholar 

  11. Crawford LJ, Walker B, Irvine AE (2011) Proteasome inhibitors in cancer therapy. J Cell Commun Signal 5:101–110. doi:10.1007/s12079-011-0121-7

    PubMed Central  PubMed  Article  Google Scholar 

  12. de la Monte SM (2009) Insulin resistance and Alzheimer’s disease. BMB Rep 42:475–481

    PubMed  Article  Google Scholar 

  13. de la Monte SM, Luong T, Neely TR, Robinson D, Wands JR. (2000) Mitochondrial DNA damage as a mechanism of cell loss in Alzheimer’s disease laboratory investigation; a journal of technical methods and pathology 80:1323–1335

  14. Demetrius LA, Driver J (2013) Alzheimer’s as a metabolic disease. Biogerontology 14:641–649. doi:10.1007/s10522-013-9479-7

    CAS  PubMed  Article  Google Scholar 

  15. Demetrius LA, Simon DK (2012) An inverse-warburg effect and the origin of Alzheimer’s disease. Biogerontology 13:583–594. doi:10.1007/s10522-012-9403-6

    CAS  PubMed  Article  Google Scholar 

  16. Demetrius LA, Simon DK (2014) The inverse association of cancer and Alzheimer’s disease: A bioenergetic mechanism. J R Soc Interface 10: 20130006. 10.1098/rsif.2013.0006

  17. Devine MJ, Plun-Favreau H, Wood NW (2011) Parkinson’s disease and cancer: Two wars, one front. Nat Rev Cancer 11:812–823

    CAS  PubMed  Article  Google Scholar 

  18. Dickerson BC et al (2009) The cortical signature of Alzheimer’s disease: Regionally specific cortical thinning relates to symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloid-positive individuals. Cereb Cortex 19:497–510. doi:10.1093/cercor/bhn113

    PubMed Central  PubMed  Article  Google Scholar 

  19. Doshay LJ (1954) Problem situations in the treatment of paralysis agitans. JAMA 156:680–684

    CAS  Article  Google Scholar 

  20. Drachman DA (2006) Aging of the brain, entropy, and Alzheimer disease. Neurology 67:1340–1352. doi:10.1212/01.wnl.0000240127.89601.83

    CAS  PubMed  Article  Google Scholar 

  21. Driver JA (2012) Understanding the link between cancer and neurodegeneration. J Geriatr Oncol 3:58–67

    Article  Google Scholar 

  22. Driver JA et al (2011) Inverse association between cancer and Alzheimer’s disease: Results from the Framingham Study. BMJ (in press)

  23. Driver JA, Lu KP (2010) Pin1: a new genetic link between Alzheimer’s disease, cancer and aging. Curr Aging Sci 3:158–165

    CAS  PubMed  Article  Google Scholar 

  24. Driver JA, Kurth T, Buring JE, Gaziano JM, Logroscino G (2007a) Prospective case-control study of nonfatal cancer preceding the diagnosis of Parkinson’s disease. Cancer Causes Control 18:705–711. doi:10.1007/s10552-007-9005-9

    PubMed  Article  Google Scholar 

  25. Driver JA, Logroscino G, Buring JE, Gaziano JM, Kurth T (2007b) A prospective cohort study of cancer incidence following the diagnosis of Parkinson’s disease. Cancer Epidemiol Biomarkers Prev 16:1260–1265. doi:10.1158/1055-9965.EPI-07-0038

    PubMed  Article  Google Scholar 

  26. Driver JA, Kurth T, Buring JE, Gaziano JM, Logroscino G (2008) Parkinson disease and risk of mortality: a prospective comorbidity-matched cohort study. Neurology 70:1423–1430. doi:10.1212/01.wnl.0000310414.85144.ee

    CAS  PubMed  Article  Google Scholar 

  27. Elbaz A et al (2002) Nonfatal cancer preceding Parkinson’s disease: A case-control study. Epidemiology 13:157–164

    PubMed  Article  Google Scholar 

  28. Elbaz A et al (2005) Risk of cancer after the diagnosis of Parkinson’s disease: A historical cohort study. Mov Disord 20:719–725

    PubMed  Article  Google Scholar 

  29. Fois AF, Wotton CJ, Yeates D, Turner MR, Goldacre MJ (2009) Cancer in patients with motor neuron disease, multiple sclerosis and Parkinson’s disease: Record linkage studies. J Neurol Neurosurg Psychiatry 81:215–221. doi:10.1136/jnnp.2009.175463

    PubMed  Article  Google Scholar 

  30. Fois AF, Wotton CJ, Yeates D, Turner MR, Goldacre MJ (2010) Cancer in patients with motor neuron disease, multiple sclerosis and Parkinson’s disease: Record linkage studies. J Neurol Neurosurg Psychiatry 81:215–221. doi:10.1136/jnnp.2009.175463

    PubMed  Article  Google Scholar 

  31. Folch J et al (2012) Role of cell cycle re-entry in neurons: A common apoptotic mechanism of neuronal cell death. Neurotox Res 22:195–207. doi:10.1007/s12640-011-9277-4

    PubMed  Article  Google Scholar 

  32. Freedman DM, Wu J, Daugherty SE, Kuncl RW, Enewold LR, Pfeiffer RM (2014) The risk of amyotrophic lateral sclerosis after cancer in U.S. elderly adults: A population-based prospective study. International journal of cancer. doi:10.1002/ijc.28795

  33. Hernan MA, Takkouche B, Caamano-Isorna F, Gestal-Otero JJ (2002) A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson’s disease. Ann Neurol 52:276–284. doi:10.1002/ana.10277

    PubMed  Article  Google Scholar 

  34. Holohan KN, Lahiri DK, Schneider BP, Foroud T, Saykin AJ (2012) Functional microRNAs in Alzheimer’s disease and cancer: differential regulation of common mechanisms and pathways Frontiers in genetics 3:323. doi:10.3389/fgene.2012.00323

    Google Scholar 

  35. Huang L, Chen CH (2009) Proteasome regulators: Activators and inhibitors. Curr Med Chem 16:931–939

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  36. Huang WK, Chiou MJ, Kuo CF, Lin YC, Yu KH, See LC (2014) No overall increased risk of cancer in patients with rheumatoid arthritis: A nationwide dynamic cohort study in Taiwan. Rheumatol Int. doi:10.1007/s00296-014-2982-6

    Google Scholar 

  37. Ibanez K, Boullosa C, Tabares-Seisdedos R, Baudot A, 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

    PubMed Central  PubMed  Article  Google Scholar 

  38. Inestrosa NC, Toledo EM (2008) The role of Wnt signaling in neuronal dysfunction in Alzheimer’s disease. Mol Neurodegener 3:9. doi:10.1186/1750-1326-3-9

    PubMed Central  PubMed  Article  Google Scholar 

  39. Jalving M, Gietema JA, Lefrandt JD, de Jong S, Reyners AK, Gans RO, de Vries EG (2010) Metformin: Taking away the candy for cancer? Eur J Cancer 46:2369–2380. doi:10.1016/j.ejca.2010.06.012

    CAS  PubMed  Article  Google Scholar 

  40. Katsiki M, Chondrogianni N, Chinou I, Rivett AJ, Gonos ES (2007) The olive constituent oleuropein exhibits proteasome stimulatory properties in vitro and confers life span extension of human embryonic fibroblasts. Rejuvenation Res 10:157–172. doi:10.1089/rej.2006.0513

    CAS  PubMed  Article  Google Scholar 

  41. Kwak MK, Wakabayashi N, Greenlaw JL, Yamamoto M, Kensler TW (2003) Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway. Mol Cell Biol 23:8786–8794

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  42. Lombardi VR, Garcia M, Rey L, Cacabelos R (1999) Characterization of cytokine production, screening of lymphocyte subset patterns and in vitro apoptosis in healthy and Alzheimer’s disease (AD) individuals. J Neuroimmunol 97:163–171

    CAS  PubMed  Article  Google Scholar 

  43. Lu KP, Zhou XZ (2007) The prolyl isomerase PIN1: A pivotal new twist in phosphorylation signalling and disease. Nat Rev Mol Cell Biol 8:904–916. doi:10.1038/nrm2261

    CAS  PubMed  Article  Google Scholar 

  44. Lu J et al (2009) A novel functional variant (−842G > C) in the PIN1 promoter contributes to decreased risk of squamous cell carcinoma of the head and neck by diminishing the promoter activity. Carcinogenesis 30:1717–1721. doi:10.1093/carcin/bgp171

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  45. Manczak M, Park BS, Jung Y, Reddy PH (2004) Differential expression of oxidative phosphorylation genes in patients with Alzheimer’s disease: Implications for early mitochondrial dysfunction and oxidative damage. Neuromol Med 5:147–162. doi:10.1385/NMM:5:2:147

    CAS  Article  Google Scholar 

  46. Marambaud P, Zhao H, Davies P (2005) Resveratrol promotes clearance of Alzheimer’s disease amyloid-beta peptides. J Biol Chem 280:37377–37382. doi:10.1074/jbc.M508246200

    CAS  PubMed  Article  Google Scholar 

  47. McNaught KS, Jnobaptiste R, Jackson T, Jengelley TA (2010) The pattern of neuronal loss and survival may reflect differential expression of proteasome activators in Parkinson’s disease. Synapse 64:241–250. doi:10.1002/syn.20719

    CAS  PubMed  Article  Google Scholar 

  48. Musicco M et al (2013) Inverse occurrence of cancer and Alzheimer disease: A population-based incidence study. Neurology 81:322–328. doi:10.1212/WNL.0b013e31829c5ec1

    PubMed  Article  Google Scholar 

  49. Nagy Z, Esiri MM, LeGris M, Matthews PM (1999) Mitochondrial enzyme expression in the hippocampus in relation to Alzheimer-type pathology. Acta Neuropathol 97:346–354

    CAS  PubMed  Article  Google Scholar 

  50. Noto H, Goto A, Tsujimoto T, Noda M (2012) Cancer risk in diabetic patients treated with metformin: A systematic review and meta-analysis. PLoS One 7:e33411. doi:10.1371/journal.pone.0033411

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  51. Nunomura A et al (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60:759–767

    CAS  PubMed  Google Scholar 

  52. Olsen JH, Friis S, Frederiksen K, McLaughlin JK, Mellemkjaer L, Moller H (2005) Atypical cancer pattern in patients with Parkinson’s disease. Br J Cancer 92:201–205

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  53. Olsen JH, Friis S, Frederiksen K (2006) Malignant melanoma and other types of cancer preceding Parkinson disease. Epidemiology 17:582–587

    PubMed  Article  Google Scholar 

  54. Paisan-Ruiz C, Houlden H (2010) Common pathogenic pathways in melanoma and Parkinson disease. Neurology 75:1653–1655. doi:10.1212/WNL.0b013e3181fb4466

    PubMed  Article  Google Scholar 

  55. Plun-Favreau H, Lewis PA, Hardy J, Martins LM, Wood NW (2010) Cancer and neurodegeneration: between the devil and the deep blue sea PLOS. Genetics 6:1–8

    Google Scholar 

  56. Raina AK, Zhu X, Rottkamp CA, Monteiro M, Takeda A, Smith MA (2000) Cyclin’ toward dementia: cell cycle abnormalities and abortive oncogenesis in Alzheimer disease. J Neurosci Res 61:128–133. doi:10.1002/1097-4547(20000715)61:2<128:AID-JNR2>3.0.CO;2-H

    CAS  PubMed  Article  Google Scholar 

  57. Roe CM, Behrens MI, Xiong C, Miller JP, Morris JC (2005) Alzheimer disease and cancer. Neurology 64:895–898

    CAS  PubMed  Article  Google Scholar 

  58. Roe CM et al (2010) Cancer linked to Alzheimer disease but not vascular dementia. Neurology 74:106–112. doi:10.1212/WNL.0b013e3181c91873

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  59. Rugbjerg K, Friis S, Lassen CF, Ritz B, Olsen JH (2012) Malignant melanoma, breast cancer and other cancers in patients with Parkinson’s disease. Int J Cancer 131:1904–1911. doi:10.1002/ijc.27443

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  60. Segat L et al (2007) PIN1 promoter polymorphisms are associated with Alzheimer’s disease. Neurobiol Aging 28:69–74. doi:10.1016/j.neurobiolaging.2005.11.009

    CAS  PubMed  Article  Google Scholar 

  61. Seo H, Sonntag KC, Kim W, Cattaneo E, Isacson O (2007) Proteasome activator enhances survival of Huntington’s disease neuronal model cells. PLoS One 2:e238. doi:10.1371/journal.pone.0000238

    PubMed Central  PubMed  Article  Google Scholar 

  62. Shemesh E, Rudich A, Harman-Boehm I, Cukierman-Yaffe T (2012) Effect of intranasal insulin on cognitive function: A systematic review. J Clin Endocrinol Metab 97:366–376. doi:10.1210/jc.2011-1802

    CAS  PubMed  Article  Google Scholar 

  63. Sherman MY, Goldberg AL (2001) Cellular defenses against unfolded proteins: A cell biologist thinks about neurodegenerative diseases. Neuron 29:15–32

    CAS  PubMed  Article  Google Scholar 

  64. Sorensen SA, Fenger K, Olsen JH (1999) Significantly lower incidence of cancer among patients with Huntington disease: An apoptotic effect of an expanded polyglutamine tract? Cancer 86:1342–1346

    CAS  PubMed  Article  Google Scholar 

  65. Staropoli JF (2008) Tumorigenesis and neurodegeneration: Two sides of the same coin? BioEssays 30:719–727. doi:10.1002/bies.20784

    CAS  PubMed  Article  Google Scholar 

  66. Stobart JL, Anderson CM (2013) Multifunctional role of astrocytes as gatekeepers of neuronal energy supply. Front Cell Neurosci 7:38. doi:10.3389/fncel.2013.00038

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  67. Tabares-Seisdedos R, Rubenstein JL (2013) Inverse cancer comorbidity: A serendipitous opportunity to gain insight into CNS disorders nature reviews. Neuroscience 14:293–304. doi:10.1038/nrn3464

    CAS  PubMed  Google Scholar 

  68. Tabares-Seisdedos R et al (2011) No paradox, no progress: Inverse cancer comorbidity in people with other complex diseases. Lancet Oncol 12:604–608. doi:10.1016/S1470-2045(11)70041-9

    PubMed  Article  Google Scholar 

  69. Tacutu R, Budovsky A, Fraifeld VE (2010) The NetAge database: A compendium of networks for longevity, age-related diseases and associated processes. Biogerentology 11:513–522

    CAS  Article  Google Scholar 

  70. Tirumalasetti F, Han L, Birkett DP (1991) The relationship between cancer and Alzheimer’s disease. J Am Geriatr Soc 39:840

    CAS  PubMed  Google Scholar 

  71. van Heemst D et al (2005) Variation in the human TP53 gene affects old age survival and cancer mortality. Exp Gerontol 40:11–15

    PubMed  Article  Google Scholar 

  72. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 324:1029–1033. doi:10.1126/science.1160809

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  73. Whitmer RA, Queensberry C, J. A. Karter AJ (2013) Anti-hyperglycemic therapy and risk of dementia: A new user cohort study. Alzheimer’s Dementia 9:136

    Article  Google Scholar 

  74. Wolfson M, Budovsky A, Tacutu R, Fraifeld VE (2009) The signaling hubs at the crossroad of longevity and age-related disease networks. Int J Biochem Cell Biology 41:516–520

    CAS  Article  Google Scholar 

  75. Xiang Z et al (2002) Cyclooxygenase (COX)-2 and cell cycle activity in a transgenic mouse model of Alzheimer’s disease neuropathology. Neurobiol Aging 23:327–334

    CAS  PubMed  Article  Google Scholar 

  76. Yaffe MB et al (1997) Sequence-specific and phosphorylation-dependent proline isomerization: A potential mitotic regulatory mechanism. Science 278:1957–1960

    CAS  PubMed  Article  Google Scholar 

  77. Yamada M et al (1999) Prevalence and risks of dementia in the Japanese population: RERF’s adult health study Hiroshima subjects. Radiation effects research foundation. J Am Geriatr Soc 47:189–195

    CAS  PubMed  Google Scholar 

  78. Zheng B et al. (2010) PGC-1alpha, a potential therapeutic target for early intervention in Parkinson’s disease Science translational medicine 2:52ra73 doi:10.1126/scitranslmed.3001059

  79. Zhu X, Lee HG, Perry G, Smith MA (2007) Alzheimer disease, the two-hit hypothesis: An update. Biochim Biophys Acta 1772:494–502. doi:10.1016/j.bbadis.2006.10.014

    CAS  PubMed  Article  Google Scholar 

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Acknowledgments

Dr. Driver is supported by a Merit Review Award from the Veteran’s Administration.

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Correspondence to Jane A. Driver.

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Driver, J.A. Inverse association between cancer and neurodegenerative disease: review of the epidemiologic and biological evidence. Biogerontology 15, 547–557 (2014). https://doi.org/10.1007/s10522-014-9523-2

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Keywords

  • Cancer
  • Neurodegeneration
  • Alzheimer’s disease
  • Parkinson’s disease
  • Epidemiology