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High sensitivity to carcinogens in the brain of a mouse model of Alzheimer's disease

Oncogene volume 29, pages 2165–2171 (2010)Cite this article

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Abstract

Cancer and Alzheimer's disease (AD) are commonly found among elderly patients. Chronic inflammation is the characteristic of both diseases. Amyloid-β peptide is the main inducer of inflammation in AD. Moreover, chronic inflammation promotes cancer, suggesting that AD patients may be more prone to develop cancer than non-demented people. To test this hypothesis, we injected the carcinogen 20-methylcholanthrene in the brain of transgenic mice overexpressing the mutant forms of amyloid precursor protein (APP) and presenilin 1 (PS1), as a model of AD, and their wild-type (WT) littermates. Mutant mice developed tumors faster and with higher incidence than their WT counterparts. Expression of the inflammatory markers interleukin (IL)-1α, IL-1β, IL-6, IP-10 and tumor necrosis factor-α (TNF-α) was measured in AD and WT mice of 3 and 12 months of age that had not been exposed to the carcinogen. These cytokines were elevated in older AD mice, indicating the existence of a highly inflammatory milieu in these animals. We also found elevated expression of a mutated form of p53 in older AD mice, suggesting an alternative mechanism for the predisposition of AD brains to develop brain tumors. Clinical studies reporting comorbidity of AD and brain cancer are needed to understand whether our observations hold true for humans.

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References

  • Anisimov VN . (2007). Biology of aging and cancer. Cancer Control 14: 23–31.

    Article  PubMed  Google Scholar 

  • Apte RN, Dotan S, Elkabets M, White MR, Reich E, Carmi Y et al. (2006). The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions. Cancer Metastasis Rev 25: 387–408.

    Article  CAS  PubMed  Google Scholar 

  • Beard CM, Kokmen E, Sigler C, Smith GE, Petterson T, O′Brien PC . (1996). Cause of death in Alzheimer's disease. Ann Epidemiol 6: 195–200.

    Article  CAS  PubMed  Google Scholar 

  • Borchelt DR, Ratovitski T, van LJ, Lee MK, Gonzales V, Jenkins NA et al. (1997). Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19: 939–945.

    Article  CAS  PubMed  Google Scholar 

  • Chang CY, Li MC, Liao SL, Huang YL, Shen CC, Pan HC . (2005). Prognostic and clinical implication of IL-6 expression in glioblastoma multiforme. J Clin Neurosci 12: 930–933.

    Article  CAS  PubMed  Google Scholar 

  • Chicoine MR, Silbergeld DL . (1997). Mitogens as motogens. J Neurooncol 35: 249–257.

    Article  CAS  PubMed  Google Scholar 

  • Chu GC, Kimmelman AC, Hezel AF, DePinho RA . (2007). Stromal biology of pancreatic cancer. J Cell Biochem 101: 887–907.

    Article  CAS  PubMed  Google Scholar 

  • Correa P, Houghton J . (2007). Carcinogenesis of Helicobacter pylori. Gastroenterology 133: 659–672.

    Article  CAS  PubMed  Google Scholar 

  • Coussens LM, Werb Z . (2002). Inflammation and cancer. Nature 420: 860–867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Di DF, Cenini G, Sultana R, Perluigi M, Uberti D, Memo M et al. (2009). Glutathionylation of the pro-apoptotic protein p53 in Alzheimer's disease brain: implications for AD pathogenesis. Neurochem Res 34: 727–733.

    Article  Google Scholar 

  • Driver JA, Djousse L, Logroscino G, Gaziano JM, Kurth T . (2008). Incidence of cardiovascular disease and cancer in advanced age: prospective cohort study. BMJ 337: a2467.

    Article  PubMed  PubMed Central  Google Scholar 

  • Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J et al. (1996). Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383: 710–713.

    Article  CAS  PubMed  Google Scholar 

  • Formiga F, Fort I, Robles MJ, Barranco E, Espinosa MC, Riu S . (2007). Medical comorbidity in elderly patients with dementia. Differences according age and gender. Rev Clin Esp 207: 495–500.

    Article  CAS  PubMed  Google Scholar 

  • Formiga F, Fort I, Robles MJ, Riu S, Rodriguez D, Sabartes O . (2008). Features differentiating comorbidity in elderly patients with Alzheimer-type dementia or with vascular dementia. Rev Neurol 46: 72–76.

    CAS  PubMed  Google Scholar 

  • Gambassi G, Lapane KL, Landi F, Sgadari A, Mor V, Bernabie R . (1999). Gender differences in the relation between comorbidity and mortality of patients with Alzheimer's disease. Systematic assessment of geriatric drug use via epidemiology (SAGE) study group. Neurology 53: 508–516.

    Article  CAS  PubMed  Google Scholar 

  • Gasper MC, Ott BR, Lapane KL . (2005). Is donepezil therapy associated with reduced mortality in nursing home residents with dementia? Am J Geriatr Pharmacother 3: 1–7.

    Article  CAS  PubMed  Google Scholar 

  • Giunta B, Fernandez F, Nikolic WV, Obregon D, Rrapo E, Town T et al. (2008). Inflammaging as a prodrome to Alzheimer's disease. J Neuroinflammation 5: 51.

    Article  PubMed  PubMed Central  Google Scholar 

  • Griffin RJ, Moloney A, Kelliher M, Johnston JA, Ravid R, Dockery P et al. (2005). Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology. J Neurochem 93: 105–117.

    Article  CAS  PubMed  Google Scholar 

  • Harikumar KB, Aggarwal BB . (2008). Resveratrol: a multitargeted agent for age-associated chronic diseases. Cell Cycle 7: 1020–1035.

    Article  CAS  PubMed  Google Scholar 

  • Hong SH, Ondrey FG, Avis IM, Chen Z, Loukinova E, Cavanaugh Jr PF et al. (2000). Cyclooxygenase regulates human oropharyngeal carcinomas via the proinflammatory cytokine IL-6: a general role for inflammation? FASEB J 14: 1499–1507.

    Article  CAS  PubMed  Google Scholar 

  • Hoozemans JJ, Rozemuller JM, van Haastert ES, Veerhuis R, Eikelenboom P . (2008). Cyclooxygenase-1 and -2 in the different stages of Alzheimer's disease pathology. Curr Pharm Des 14: 1419–1427.

    Article  CAS  PubMed  Google Scholar 

  • Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S et al. (1996). Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274: 99–102.

    Article  CAS  PubMed  Google Scholar 

  • Hu M, Polyak K . (2008). Molecular characterisation of the tumour microenvironment in breast cancer. Eur J Cancer 44: 2760–2765.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hussain SP, Hofseth LJ, Harris CC . (2003). Radical causes of cancer. Nat Rev Cancer 3: 276–285.

    Article  CAS  PubMed  Google Scholar 

  • Kamer AR, Dasanayake AP, Craig RG, Glodzik-Sobanska L, Bry M, de Leon MJ . (2008). Alzheimer's disease and peripheral infections: the possible contribution from periodontal infections, model and hypothesis. J Alzheimers Dis 13: 437–449.

    Article  CAS  PubMed  Google Scholar 

  • Kim S, Takahashi H, Lin WW, Descargues P, Grivennikov S, Kim Y et al. (2009). Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457: 102–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lanni C, Racchi M, Uberti D, Mazzini G, Stanga S, Sinforiani E et al. (2008). Pharmacogenetics and pharmagenomics, trends in normal and pathological aging studies: focus on p53. Curr Pharm Des 14: 2665–2671.

    Article  CAS  PubMed  Google Scholar 

  • Leonard BE . (2007). Inflammation, depression and dementia: are they connected? Neurochem Res 32: 1749–1756.

    Article  CAS  PubMed  Google Scholar 

  • Mbeunkui F, Johann Jr DJ . (2009). Cancer and the tumor microenvironment: a review of an essential relationship. Cancer Chemother Pharmacol 63: 571–582.

    Article  PubMed  Google Scholar 

  • Murat A, Migliavacca E, Hussain SF, Heimberger AB, Desbaillets I, Hamou MF et al. (2009). Modulation of angiogenic and inflammatory response in glioblastoma by hypoxia. PLoS ONE 4: e5947.

    Article  PubMed  PubMed Central  Google Scholar 

  • Nelson JS . (2002). Alzheimer pathology in elderly patients with glioblastoma multiforme. Arch Pathol Lab Med 126: 1515–1517.

    PubMed  Google Scholar 

  • Paugh BS, Bryan L, Paugh SW, Wilczynska KM, Alvarez SM, Singh SK et al. (2009). Interleukin-I regulates the expression of sphingosine Kinase I in glioblastoma cells. J Biol Chem 284: 3408–3417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peebles KA, Lee JM, Mao JT, Hazra S, Reckamp KL, Krysan K et al. (2007). Inflammation and lung carcinogenesis: applying findings in prevention and treatment. Expert Rev Anticancer Ther 7: 1405–1421.

    Article  CAS  PubMed  Google Scholar 

  • Psaila B, Lyden D . (2009). The metastatic niche: adapting the foreign soil. Nat Rev Cancer 9: 285–293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quante M, Wang TC . (2008). Inflammation and stem cells in gastrointestinal carcinogenesis. Physiology (Bethesda) 23: 350–359.

    CAS  Google Scholar 

  • Ribatti D, Mangialardi G, Vacca A . (2006). Stephen Paget and the ‘seed and soil’ theory of metastatic dissemination. Clin Exp Med 6: 145–149.

    Article  CAS  PubMed  Google Scholar 

  • Rodrigo J, Fernandez-Vizarra P, Castro-Blanco S, Bentura ML, Nieto M, Gomez-Isla T et al. (2004). Nitric oxide in the cerebral cortex of amyloid-precursor protein (SW) Tg2576 transgenic mice. Neuroscience 128: 73–89.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Rogers J . (2008). The inflammatory response in Alzheimer's disease. J Periodontol 79: 1535–1543.

    Article  CAS  PubMed  Google Scholar 

  • Saetre P, Emilsson L, Axelsson E, Kreuger J, Lindholm E, Jazin E . (2007). Inflammation-related genes up-regulated in schizophrenia brains. BMC Psychiatry 7: 46.

    Article  PubMed  PubMed Central  Google Scholar 

  • Salminen A, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T . (2009). Inflammation in Alzheimer's disease: amyloid-beta oligomers trigger innate immunity defence via pattern recognition receptors. Prog Neurobiol 87: 181–194.

    Article  CAS  PubMed  Google Scholar 

  • Sanders P, De KJ . (2007). Janus faces of microglia in multiple sclerosis. Brain Res Rev 54: 274–285.

    Article  CAS  PubMed  Google Scholar 

  • Sastre M, Walter J, Gentleman SM . (2008). Interactions between APP secretases and inflammatory mediators. J Neuroinflammation 5: 25.

    Article  PubMed  PubMed Central  Google Scholar 

  • Serrano J, Fernandez AP, Sanchez J, Rodrigo J, Martinez A . (2008). Adrenomedullin expression is up-regulated by acute hypobaric hypoxia in the cerebral cortex of the adult rat. Brain Pathol 18: 434–442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steinman L . (2008). Nuanced roles of cytokines in three major human brain disorders. J Clin Invest 118: 3557–3563.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stock D, Groome PA, Siemens DR . (2008). Inflammation and prostate cancer: a future target for prevention and therapy? Urol Clin North Am 35: 117–130.

    Article  PubMed  Google Scholar 

  • Stolt CC, Lommes P, Sock E, Chaboissier MC, Schedl A, Wegner M . (2003). The Sox9 transcription factor determines glial fate choice in the developing spinal cord. Genes Dev 17: 1677–1689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tansey MG, Frank-Cannon TC, McCoy MK, Lee JK, Martinez TN, McAlpine FE et al. (2008). Neuroinflammation in Parkinson's disease: is there sufficient evidence for mechanism-based interventional therapy? Front Biosci 13: 709–717.

    Article  CAS  PubMed  Google Scholar 

  • Uberti D, Lanni C, Racchi M, Govoni S, Memo M . (2008). Conformationally altered p53: a putative peripheral marker for Alzheimer's disease. Neurodegener Dis 5: 209–211.

    Article  CAS  PubMed  Google Scholar 

  • Vesce S, Rossi D, Brambilla L, Volterra A . (2007). Glutamate release from astrocytes in physiological conditions and in neurodegenerative disorders characterized by neuroinflammation. Int Rev Neurobiol 82: 57–71.

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Yang J, Zheng H, Tomasek GJ, Zhang P, McKeever PE et al. (2009). Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model. Cancer Cell 15: 514–526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamada M, Sasaki H, Mimori Y, Kasagi F, Sudoh S, Ikeda J 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.

    Article  CAS  PubMed  Google Scholar 

  • Yeruva S, Ramadori G, Raddatz D . (2008). NF-kappaB-dependent synergistic regulation of CXCL10 gene expression by IL-1beta and IFN-gamma in human intestinal epithelial cell lines. Int J Colorectal Dis 23: 305–317.

    Article  PubMed  Google Scholar 

  • Zimmerman H, Arnold H . (1941). Experimental brain tumors. I. Tumors produced with methylcholantrene. Cancer Res 1: 919–938.

    CAS  Google Scholar 

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Acknowledgements

We gratefully acknowledge Professor Ignacio Torres (Instituto Cajal, Madrid, Spain) for the breeding pairs to initiate the mouse colony. We are also grateful to Dr Josune García-Sanmartín (CIBIR, Logroño, Spain) for her valuable help in statistical analysis. This work was supported by Spanish Ministry of Science and Innovation Grant SAF2007-60010, and Instituto de Salud Carlos III Grant RD06/0026/1001.

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  1. R Martínez-Murillo and A Martínez: These two authors contributed equally to this work as co-directors and should be considered last authors.

Authors and Affiliations

  1. Department of Molecular, Cellular, and Developmental Neurobiology, Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

    J Serrano, A P Fernández & R Martínez-Murillo

  2. Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain

    A Martínez

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Correspondence to R Martínez-Murillo.

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Serrano, J., Fernández, A., Martínez-Murillo, R. et al. High sensitivity to carcinogens in the brain of a mouse model of Alzheimer's disease. Oncogene 29, 2165–2171 (2010). https://doi.org/10.1038/onc.2009.503

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