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Failing to adapt – the ageing immune system's role in cancer pathogenesis

Published online by Cambridge University Press:  24 February 2011

Christopher M Jones
Christopher M Jones*
Affiliation:
School of Clinical & Experimental Medicine, University of Birmingham, UK
*
Address for correspondence: Christopher Jones, School of Clinical & Experimental Medicine, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT. Email: cmj744@bham.ac.uk
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Summary

A person's risk of developing cancer rises exponentially with age, an increase that is widely considered to result from cumulative exposure to mutagenic agents. However, cancer incidence rates decelerate and plateau beyond 85 years of age and numerous malignant pathologies peak in incidence during early or middle life, indicating an important role for additional factors in controlling the timing and nature of cancer development. Given that immune function is known to decrease with age, malignant neoplastic change may be induced by increased chronic infection and the onset of a pervasive low grade inflammatory environment. This article discusses in detail the ageing immune system's role in cancer pathogenesis and demonstrates that key polymorphisms coding for relatively low pro-inflammatory cytokine production act to protect some populations from age-induced neoplastic transformation.

Keywords

ageingcancerimmunosenescenceinflammationneoplasms
Type
Biological gerontology
Information
Reviews in Clinical Gerontology , Volume 21 , Issue 3 , August 2011 , pp. 209 - 218
Copyright
Copyright © Cambridge University Press 2011

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References

1Office for National Statistics. Registrations of cancer diagnosed in 2006, England. Series MB1, No. 37. London: Office for National Statistics, 2008.Google Scholar
2Information Services Division, Scotland. Cancer in Scotland. Information Services Division, NHS National Services Scotland, 2010. Available at: http://www.isdscotland.org/isd/6454.html (accessed 22 December 2010).Google Scholar
3Welsh Cancer Intelligence and Surveillance Unit. WCISU Annual Publication No. SA9/01 – Cancer Incidence in Wales 2003–2007. Available at: http://www.wales.nhs.uk/sites3/Documents/242/Cancer%20Incidence%20in%20Wales%202003-2007.pdf (accessed 22 December 2010).Google Scholar
4Donnelly, DW, Gavin, AT, Comber, H. Cancer in Ireland: A summary report. Northern Ireland Cancer Registry/National Cancer Registry, Ireland; 2009.Google Scholar
5Arbeev, KG, Ukraintseva, SV, Arbeeva, LS, Yashin, AI. Decline in human cancer incident rates at old ages: Age-period-cohort considerations. Demographic Res 2005; 12: 273–300.CrossRefGoogle Scholar
6Ferlay, J. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007; 18: 581–92.CrossRefGoogle ScholarPubMed
7Troen, BR. The biology of aging. Mt Sinai J Med 2003; 70: 3–22.Google ScholarPubMed
8Sarkar, D, Fisher, PB. Molecular mechanisms of ageing-associated inflammation. Cancer Lett 2006; 236: 13–23.CrossRefGoogle Scholar
9Miyaishi, O, Ando, F, Matsuzawa, K, Kanawa, R, Isobe, K. Cancer incidence in old age. Mech Ageing Dev 2000; 117: 47–55.CrossRefGoogle ScholarPubMed
10Krontiris, TG. The emerging genetics of human cancer. N Engl J Med 1983; 309: 404–9.Google ScholarPubMed
11Hoeijmakers, JHJ. DNA damage, aging and cancer. N Engl J Med 2009; 361: 1475–85.CrossRefGoogle ScholarPubMed
12Kuperwasser, C, Chavarria, T, Wu, M, Magrane, G, Gray, JW, Carey, L, Richardson, A, Weinberg, RA. Reconstruction of functionally normal and malignant human breast titssues in mice. Proc Natl Acad Sci USA 2004; 101: 4966–71.CrossRefGoogle ScholarPubMed
13Bissell, MJ, Rizki, A, Mian, SI. Tissue architecture: the ultimate regulator of breast epithelial function. Curr Opin Cell Biol 2003; 15: 753–82.CrossRefGoogle ScholarPubMed
14Schwartsburd, PM. Age-promoted creation of a pro-cancer microenvironment by inflammation: pathogenesis of dyscoordinated feedback control. Mech Ageing Dev 2004; 125: 581–90.CrossRefGoogle ScholarPubMed
15Braakhuis, BJM, Tabor, MP, Kummer, JA, Leemans, CR, Brakenhoff, RH. A genetic explanation of Slaughter's concept of field cancerisation: evidence and clinical implications. Cancer Res 2003; 63: 1727–30.Google Scholar
16Liotta, LA, Kohn, E. The microenvironment of the tumour-host interface. Nature 2001; 411: 375–79.CrossRefGoogle ScholarPubMed
17Hall, AJ, Yee, LJ, Thomas, SL. Life course epidemiology and infectious diseases. Int J Epidemiol 2002; 31: 300–1.CrossRefGoogle ScholarPubMed
18Coussens, LM, Werb, Z. Inflammation and cancer. Nature 2002; 420: 860–67.CrossRefGoogle ScholarPubMed
19Ginaldi, L, De Martinis, M, D'Ostilio, A, Marini, L, Loreto, MF, Corsi, MP, Quaglino, D. The immune system in the elderly: I – Specific humoral immunity. Immunol Res 1999; 20: 101–8.CrossRefGoogle ScholarPubMed
20Ginaldi, L, De Martinis, M, D'Ostilio, A, Marini, L, Loreto, MF, Martorelli, V, Quaglino, D. The immune system in the elderly: II – Specific cellular immunity. Immunol Res 1999; 20: 109–15.CrossRefGoogle ScholarPubMed
21Gavazzi, G, Krause, KH. Ageing and infection. Lancet Infect Dis 2002; 2: 659–66.CrossRefGoogle ScholarPubMed
22Fein, AM. Pneumonia in the elderly: overview of diagnostic and therapeutic approaches. Clin Infect Dis 1999; 28: 726–29.CrossRefGoogle ScholarPubMed
23Reacher, MH, Shah, A, Livermore, DM, Wale, MC, Graham, C, Johnson, AP, Heine, H, Monnickendam, MA, Barker, KF, James, D, George, RC. Bacteraemia and antibiotic resistance of its pathogens reported in England and Wales between 1990 and 1998: trend analysis. BMJ 2000; 320: 213–16.CrossRefGoogle ScholarPubMed
24Dhawan, VK. Infective endocarditis in elderly patients. Clin Infect Dis 2002; 34: 806–12.CrossRefGoogle ScholarPubMed
25Choi, C. Bacterial meningitis in ageing adults. Clin Infect Dis 2001; 33: 1380–85.CrossRefGoogle Scholar
26Bruunsgaard, H, Pedersen, M, Pedersen, BK. Aging and proinflammatory cytokines. Curr Opin Haematol 2001; 8: 131–36.CrossRefGoogle ScholarPubMed
27Franceschi, C, Bonafè, M, Valensin, S, Olivieri, F, De Luca, M, Ottaviani, E, De Benedictis, G. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann NY Acad Sci 2000; 908: 244–54.CrossRefGoogle ScholarPubMed
28De Martinis, M, Franceschi, C, Monti, D, Ginaldi, L. Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett 2005; 579: 2035–39.CrossRefGoogle ScholarPubMed
29Chin, L, Artandi, SE, Shen, Q. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis.Cell 1999; 97: 527–38.CrossRefGoogle ScholarPubMed
30Agrawal, A, Agrawal, S, Tay, J, Gupta, S. Biology of dendritic cells in aging. J Clin Immunol 2008; 43: 718–28.Google Scholar
31Araki, N, Johnson, MT, Swanson, JA. A role for phospoinositide 3-kinase in the completion of macropinocytosis and phagocytosis by macrophages. J Cell Biol 1996; 135: 1249–60.CrossRefGoogle Scholar
32Clague, MJ, Thorpe, C, Jones, AT. Phosphatidylinositol 3-kinase regulation of fluid phase endocytosis. FEBS Lett 1995; 367: 272–74.CrossRefGoogle ScholarPubMed
33Del Prete, A, Vermi, W, Dander, E, Otero, K, Barberis, L, Luini, W. Defective dendritic cell migration and activation of adaptive immunity in PI3K gamma-deficient mice. EMBO J 2004; 23: 3505–15.CrossRefGoogle Scholar
34Della Bella, S, Bierti, L, Presicce, P, Arienti, R, Valenti, M, Saresella, M, Vergani, C, Villa, ML. Peripheral blood dendritic cells and monocytes are differently regulated in the elderly. Clin Immunol 2007; 122: 220–28.CrossRefGoogle ScholarPubMed
35Potack, J, Itzkowitz, SH. Colorectal cancer in inflammatory bowel disease. Gut Liver 2008; 2: 61–73.CrossRefGoogle ScholarPubMed
36Michaud, DS. Chronic inflammation and bladder cancer. Urol Oncol 2007; 25: 260–68.CrossRefGoogle ScholarPubMed
37Abdel-Latif, MMM, Duggan, S, Reynolds, JV, Kelleher, D. Inflammation and oesophageal carcinogenesis. Curr Opin Pharmacol 2009; 9: 396–404.CrossRefGoogle Scholar
38Sugar, LM. Inflammation and prostate cancer. Can J Urol 2006; 13 (suppl 1): 46–47.Google ScholarPubMed
39Wilson, KT, Crabtree, JE. Immunology of Helicobacter pylori: insights into the failure of the immune response and perspectives on vaccine studies. Gastroenterology 2007; 133: 288–308.CrossRefGoogle ScholarPubMed
40Correa, P, Houghton, J. Carcinogenesis of Helicobacter pylori. Rev Basic Clin Gastroenterol 2007; 133: 659–72.Google ScholarPubMed
41Gomez, CR, Nomellini, V, Faunce, DE, Kovacs, EJ. Innate immunity and aging. Exp Gerontol 2008; 43: 718–28.CrossRefGoogle ScholarPubMed
42Gomez, CR, Hirano, S, Cutro, BT, Birjandi, S, Baila, H, Nomellini, V, Kovacs, EJ. Advanced age exacerbates the pulmonary inflammatory response after lipopolysaccharide exposure. Crit Care Med 2007; 35: 246–51.CrossRefGoogle ScholarPubMed
43Swift, ME, Burns, AL, Gray, KL, DiPietro, LA. Age-related alterations in the inflammatory response to dermal injury. J Invest Dermatol 2001; 117: 1027–35.CrossRefGoogle ScholarPubMed
44Tortorella, C, Simone, O, Piazzolla, G, Stella, I, Cappiello, V, Antonaci, S. Role of phosphoinositide 3-kinase and extracellular signal-regulated kinase pathways in granulocyte macrophage-colony-stimulating factor failure to delay fas-induced neutrophil apoptosis in elderly humans. J Gerontol A Biol Sci Med Sci 2006; 71: 1111–18.CrossRefGoogle Scholar
45Fulop, T Jr, Larbi, A, Linteau, A, Desgeorges, S, Douziech, N. The role of Mcl-I and Bax expression alteration in the decreased rescue of human neutrophils from apoptosis by GM-CSF with aging. Ann NY Acad Sci 2002; 973: 305–8.CrossRefGoogle Scholar
46Fortin, CF, Larbi, A, Dupuis, G, Lesur, O, Fulop, T Jr. GM-CSF activates the Jak/STAT pathway to rescue polymorphonuclear neutrophils from spontaneous apoptosis in young but not elderly individuals. Biogerontology 2007; 8: 173–87.CrossRefGoogle Scholar
47Butcher, SK, Chahal, H, Nayak, L, Sinclair, A, Henriquez, NV, Sapey, E, O'Mahony, D, Lord, JM. Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans. J Leukoc Biol 2001; 70: 881–86.CrossRefGoogle ScholarPubMed
48Fulop, T, Larbi, A, Douziech, N, Fortin, C, Guérard, KP, Lesur, O, Khalil, A, Dupuis, G. Signal transduction and functional changes in neutrophils with aging. Aging Cell 2004; 3: 217–26.CrossRefGoogle ScholarPubMed
49Vignola, AM, Bonanno, A, Profita, M, Riccobono, L, Scichilone, N, Spatafora, M, Bousquet, J, Bonsignore, G, Bellia, V. Effect of age and asthma duration upon elastase and alpha1-antitrypsin levels in adult asthmatics. Eur Resp J 2003; 22: 795–801.CrossRefGoogle ScholarPubMed
50Braman, SS. Asthma in the elderly. Clin Geriatr Med 2003; 19: 57–75.CrossRefGoogle ScholarPubMed
51Leng, S, Xue, QL, Huang, Y, Semba, R, Chaves, P, Bandeen-Roche, K, Fried, L, Walston, J. Total and differential white blood cell counts and their associations with circulating interleukin-6 levels in community-dwelling older women. J Gerontol A Biol Sci Med Sci 2005; 60: 195–99.CrossRefGoogle ScholarPubMed
52Gon, Y, Hashimoto, S, Hayashi, S, Koura, T, Matsumoto, K, Horie, T. Lower serum concentrations of cytokines in elderly patients with pneumonia and the impaired production of cytokines by peripheral blood monocytes in the elderly. Clin Exp Immunol 1996; 106: 120–26.Google ScholarPubMed
53Roubenoff, R, Harris, TB, Abad, LW, Wilson, PW, Dallal, GE, Dinarello, CA. Monocyte cytokine production in an elderly population: effect of age and inflammation. J Gerontol A Biol Sci Med Sci 1998; 53: M20–26.CrossRefGoogle Scholar
54Agius, E, Lacy, KE, Vukmanovic-Stejic, M, Jagger, AL, Papageorgiou, AP, Hall, S, Reed, JR, Curnow, SJ, Fuentes-Duculan, J, Buckley, CD, Salmon, M, Taams, LS, Krueger, J, Greenwood, J, Klein, N, Rustin, MH, Akbar, AN. Decreased TNF-α synthesis by macrophages restricts cutaenous immunosurveillance by memory CD4+ T cells during aging. J Exp Med 2009; 206: 1929–40.CrossRefGoogle Scholar
55Mariani, E, Pulsatelli, L, Neri, S, Dolzani, P, Meneghetti, A, Silvestri, T, Ravaglia, G, Forti, P, Cattini, L, Facchini, A. RANTES and MIP-1alpha production by T lymphocytes, monocytes and NK cells from nonagenarian subjects. Exp Gerontol 2002; 37: 219–26.CrossRefGoogle Scholar
56Sebastian, C, Espia, M, Serra, M, Celada, A, Lloberas, J. MacrophAging: a cellular and molecular review. Immunobiology 2005; 210: 121–26.CrossRefGoogle ScholarPubMed
57Ligthart, GJ, van Blockhoben, PC, Schuit, HR, Hijmans, W. The expanded null cell compartment in ageing: increase in the number of natural killer cells and changes in T-cell and NK-cell subsets in human blood. Immunology 1986; 59: 353–57.Google ScholarPubMed
58Jamieson, BD, Douek, DC, Killian, S, Hultin, LE, Scripture-Adams, DD, Giorgi, JV, Marelli, D, Koup, RA, Zack, JA. Generation of functional thymocytes in the human adult. Immunity 1999; 10: 569–75.CrossRefGoogle ScholarPubMed
59Steinmann, GG. Changes in the human thymus during aging. Curr Top Pathol 1986; 75: 43–48.Google ScholarPubMed
60Czesnikiewicz-Guzik, M, Lee, WW, Cui, D, Hiruma, Y, Lamar, DL, Yang, ZZ, Ouslander, JG, Weyand, CM, Goronzy, JJ. T cell subset-specific susceptibility to aging. Clin Immunol 2008; 127: 107–18.CrossRefGoogle ScholarPubMed
61Nikolich-Zugich, J. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol 2008; 8: 512–22.CrossRefGoogle ScholarPubMed
62Lages, CS, Suffia, I, Velilla, PA, Huang, B, Warshaw, G, Hildeman, DA, Belkaid, Y, Chougnet, C. Functional regulatory T cells accumulate in aged hosts and promote chronic infectious disease reactivation. J Immunol 2008; 181: 1835–48.CrossRefGoogle ScholarPubMed
63Dunn, GP, Burce, AT, Ikeda, H, Old, LJ, Schreiber, RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002; 3: 991–98.CrossRefGoogle ScholarPubMed
64Krabbe, KS, Pedersen, M, Bruunsgaard, H. Inflammatory mediators in the elderly. Exp Gerontol 2004; 39: 687–99.CrossRefGoogle ScholarPubMed
65Szlosarek, PW, Balkwill, FR. Tumor necrosis factor α: a potential target for the therapy of solid tumors. Lancet Oncol 2003; 4: 565–73.CrossRefGoogle Scholar
66Bojarska-Junak, A, Rolinski, J, Wasik-Szczepaneko, E, Kaluzny, Z, Dmoszynska, A. Intracellular tumor necrosis factor production by T- and B-cells in B-cell chronic lymphocytic leukemia. Haematologica 2002; 87: 490–99.Google Scholar
67Ohba, T, Haro, H, Ando, T, Wako, M, Suenaga, F, Aso, Y, Koyama, K, Hamada, Y, Nakao, A. TNF-alpha-induced NF-kappaB signalling reverses age-related declines in VEGF induction and angiogenic activity in intervertebral disc tissues. J Orthop Res 2009; 27: 229–35.CrossRefGoogle ScholarPubMed
68Russo, MP, Bennett, BL, Manning, AM, Brenner, DA, Jobin, C. Differential requirement for NF-kappa B-inducing kinase in the induction of NF-kappa B by IL-1beta, TNF-alpha, and FAS. Am J Physiol Cell Physiol 2002; 283: 347–57.CrossRefGoogle Scholar
69Balkwill, F. Tumor necrosis factor or tumor promoting factor? Cytokine Growth Factor Rev 2002; 13: 135–41.CrossRefGoogle ScholarPubMed
70Bruunsgaard, H, Andersen-Ranberg, K, Jeune, B, Pedersen, AN, Skinhoj, P, Pedersen, BK. A high plasma concentration of TNF-alpha is associated with dementia in centenarians. J Gerontol A Biol Sci Med Sci 1999; 54A: M357–64.CrossRefGoogle Scholar
71Paolisso, G, Rizzo, MR, Mazziotti, G, Tagliamonte, MR, Gambardella, A, Rotondi, M, Carella, C, Giugliano, D, Varricchio, M, D'Onofrio, F. Advancing age and insulin resistance: role of plasma tumor necrosis factor-α. Am J Physiol 1998; 275: E294–99.Google ScholarPubMed
72Bruunsgaard, H, Skinhoj, P, Qvist, J, Pedersen, BK. Elderly humans show prolonged in vivo inflammatory activity during pneumococcal infections. J Infect Dis 1999; 180: 551–54.CrossRefGoogle ScholarPubMed
73Vane, JR, Mitchell, JA, Appleton, I, Tomlinson, A, Bishop-Bailey, D, Croxtall, J, Willoughby, DA. Inducible isoforms of cyclooxygenase and nitric oxide synthase in inflammation. Proc Natl Acad Sci USA 1994; 91: 2046–50.CrossRefGoogle ScholarPubMed
74Landino, LM, Crews, BC, Timmons, MD, Morrow, JD, Marnett, LJ. Perioxynitrite, the coupling product of nitric oxide and superoxide activates prostaglandin biosynthesis. Proc Natl Acad Sci USA 1996; 93: 15069–74.CrossRefGoogle Scholar
75Fosslien, E. Review: Molecular pathology of cyclooxygenase-2 in cancer-induced angiogenesis. Ann Clin Lab Sci 2001; 31: 325–48.Google ScholarPubMed
76Thun, MJ, Henley, SJ, Patrono, C. Non-steroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic and clinical issues. J Natl Cancer Inst 2002; 94: 252–66.CrossRefGoogle ScholarPubMed
77Vasto, S, Candore, G, Balistreri, CR et al. . Inflammatory networks in ageing, age-related diseases and longevity. Mech Ageing Dev 2007; 128: 83–91.CrossRefGoogle ScholarPubMed
78Lio, D, Scola, L, Crivello, A, Colonna-Romano, G, Candore, G, Bonafé, M, Cavallone, L, Marchegiani, F, Olivieri, F, Franceschi, C, Caruso, C. Inflammation, genetics and longevity: further studies on the protective effects in men of IL-10–1082 promoter SNP and its interaction with TNF-alpha-308 promoter SNP. J Med Genet 2003; 40: 296–99.CrossRefGoogle ScholarPubMed
79Culig, Z, Steiner, H, Bartsch, G, Hobisch, A. Interleukin-6 regulation of prostate cancer cell growth. J Cell Biol 2005; 95: 497–505.Google ScholarPubMed
80Hong, DS, Angelo, LS, Kurzrock, R. Interleukin-6 and its receptor in cancer: implications for translational therapeutics. Cancer 2007; 110: 1911–28.CrossRefGoogle ScholarPubMed
81Hutchins, D, Steel, CM. Regulation of ICAM-I (CD54) expression in human breast cancer cell lines by interleukin 6 and fibroblast-derived factors. Int J Cancer 1994; 58: 80–84.CrossRefGoogle ScholarPubMed
82Cohen, T, Nahari, D, Cerem, LW, Neufeld, G, Levi, BZ. Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem 1996; 271: 736–41.CrossRefGoogle ScholarPubMed
83Hefler, LA, Grimm, C, Ackermann, S, Malur, S, Radjabi-Rahat, AR, Leodolter, S, Beckmann, MW, Zeillinger, R, Koelbl, H, Tempfer, CB. An interleukin-6 gene promoter polymorphism influences the biological phenotype of ovarian cancer. Cancer Res 2003; 63: 8051–56.Google ScholarPubMed
84Heikkila, K, Ebrahim, S, Rumley, A, Lowe, G, Lawlor, DA. Associations of circulating C-reactive protein and interleukin-6 with survival in women with and without cancer: findings from the British Women's Heart and Health Study. Cancer Epidemiol Biomarkers Prev 2007; 16: 1155–59.CrossRefGoogle ScholarPubMed
85Mysliwska, J, Bryl, E, Foerster, J, Mysliwski, A. Increase of interleukin-6 and decrease of interleukin-2 production during the ageing process are influenced by the health status. Mech Ageing Dev 1998; 100: 313–28.CrossRefGoogle ScholarPubMed
86Mazhar, D, Ngan, S. C-reactive protein and colorectal cancer. QJM 2006; 99: 555–59.CrossRefGoogle ScholarPubMed
87Balistreri, CR, Candore, G, Colonna-Romano, G, Lio, D, Caruso, M, Hoffmann, E, Franceschi, C, Caruso, C. Role of Toll-like receptor 4 in acute myocardial infarction and longevity. JAMA 2004; 292: 2339–40.Google ScholarPubMed
88Sun, Q, Liu, Q, Zheng, Y, Cao, X. Rapamycin suppresses TLR4-triggered IL-6 and PGE(2) production of colon cancer cells by inhibiting TLR4 expression and NK-kappaB activation. Mol Immunol 2008; 45: 2929–36.CrossRefGoogle Scholar
89Sakkoula, E, Pipili-Synetos, E, Maragoudakis, ME. Involvement of nitric oxide in the inhibition of angiogenesis by interleukin-2. Br J Pharmacol 1997; 122: 793–95.CrossRefGoogle ScholarPubMed
90Brivio, F, Lissoni, P, Rovelli, F, Nespoli, A, Uggeri, F, Fumagalli, L, Gardani, G. Effects of IL-2 pre-operative immunotherapy-induced changes in angiogenic regulation and its prevention of VEGF increase and IL-12 decline. Hepatogastroenterology 2002; 49: 385–87.Google Scholar