Skip to main content
SpringerLink
Log in

Breast Cancer and Immunosenescence

  • Living reference work entry
  • First Online:
Handbook of Immunosenescence

  • 322 Accesses

Abstract

Breast cancer is a disease primarily of older women and, since the elderly population is rapidly expanding, so too will the number of breast cancer patients. The increased incidence of breast cancer in elderly people and its lower aggressiveness have been both related to the age-associated changes occurring in the immune system, the so-called immunosenescence. This phenomenon is best characterized by a remodeling of the immune system, which appears early on and progresses throughout a person’s life. The immunosenescence may not only impact on the incidence of breast cancer but also on the effectiveness of preventive and therapeutic approaches based on immune system activation. Immune adjuvants as well as anticancer substances which primarily exert a direct action on tumor cells may have an additive effect on immune-based anticancer approaches, thus playing an important role for the enhancement of immune responses in old ages. This review aims to perform a brief analysis of the age-related alterations of the cell populations involved in antitumor immunity and to analyze the main immunological targets of breast cancer, the effectiveness of immune-based prevention, therapy for breast cancer, and the adjuvant or additive approaches to activate an anticancer immune response in aging.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2:675

    Article  CAS  PubMed  Google Scholar 

  • Al-Joudi FS, Iskandar ZA (2006) Autoantibodies to survivin in the sera of patients with infiltrating ductal carcinoma of the breast. Med J Malaysia 61:302–306

    CAS  PubMed  Google Scholar 

  • Amici A, Smorlesi A, Noce G, Santoni G, Cappelletti P, Capparuccia L, Coppari R, Lucciarini R, Petrelli F, Provinciali M (2000) DNA vaccination with full-length or truncated Neu induced protective immunity against the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Gene Ther 7:703

    Article  CAS  PubMed  Google Scholar 

  • Angelis P, Scharf S, Christophidis N (1997) Effects of age on neutrophil function and its relevance to bacterial infections in the elderly. J Clin Lab Immunol 49:33

    CAS  PubMed  Google Scholar 

  • Anisimov VN (2003) The role of pineal gland in breast cancer development. Crit Rev Oncol Hematol 46:221–234

    Article  PubMed  Google Scholar 

  • Anisimov VN, Khavinson VK, Provinciali M, Alimova IN, Baturin DA, Popovich IG, Zabezhinski MA, Imyanitov EN, Mancini R, Franceschi C (2002) Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Int J Cancer 101(1):7–10

    Article  CAS  PubMed  Google Scholar 

  • Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, Kovalenko IG, Poroshina TE, Semenchenko AV, Provinciali M, Re F, Franceschi C (2005) Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol 40:685–693

    Article  CAS  PubMed  Google Scholar 

  • Antonaci S, Jirillo E, Ventura MT, Garofalo AR, Bonomo L (1984) Non-specific immunity in ageing: deficiency of monocyte and polymorphonuclear cell-mediated functions. Mech Ageing Dev 24:367

    Article  CAS  PubMed  Google Scholar 

  • Antonilli M, Rahimi H, Visconti V, Napoletano C, Ruscito I, Zizzari IG, Caponnetto S, Barchiesi G, Iadarola R, Pierelli L, Rughetti A, Bellati F, Panici PB, Nuti M. (2016) Triple peptide vaccination as consolidation treatment in women affected by ovarian and breast cancer: Clinical and immunological data of a phase I/II clinical trial. Int J Oncol. 48(4):1369–1378.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Apostolopoulos V, Pietersz GA, Tsibanis A, Tsikkinis A, Drakaki H, Loveland BE, Piddlesden S, Plebanski M, Pouniotis DS, Alexis MN, Mcenzie IF, Vassilaros S (2006) Pilot phase III immunotherapy study in early-stage breast cancer patients using oxidized mannan-MUC1 (ISRCTN71711835). Breast Cancer Res 8:R27

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Argentati K, Bartozzi B, Bernardini G, Di Stasio G, Provinciali M (2000) Induction of NK cell activity and perforin and Granzyme B expression following continuous culture or short pulse with IL-12 in young and old mice. Eur Cytokine Netw 11:59–65

    CAS  PubMed  Google Scholar 

  • Argentati K, Re F, Donnini A, Tucci MG, Franceschi C, Bartozzi B, Bernardini G, Provinciali M (2002) Numerical and functional alterations of circulating gd T lymphocytes in aged people and centenarians. J Leukoc Biol 72:65

    CAS  PubMed  Google Scholar 

  • Atmaca H, Uzunoglu S (2014) Anti-angiogenic effects of trabectedin (Yondelis; ET-743) on human breast cancer cells. Eur Cytokine Netw 25(1):1–7

    PubMed  Google Scholar 

  • Atmaca H, Bozkurt E, Uzunoglu S, Uslu R, Karaca B (2013) A diverse induction of apoptosis by trabectedin in MCF-7 (HER2-/ER+) and MDA-MB-453 (HER2+/ER-) breast cancer cells. Toxicol Lett 221(2):128–136

    Article  CAS  PubMed  Google Scholar 

  • Baatjes KJ, Apffelstaedt JP, Kotze MJ, Conradie M (2016) Postmenopausal breast cancer, aromatase inhibitors, and bone health: what the surgeon should know. World J Surg 40(9):2149–2156

    Google Scholar 

  • Balducci L, Siliman RA, Bekey P (1998) Breast cancer: an oncological perspective. In: Balducci L, Lyman GH, Ershler WB (eds) Comprehensive geriatric oncology. Harwood Academic Publishers, Amsterdam, pp 629–666

    Google Scholar 

  • Bar-Eli M, Gallily R (1979) Age-dependent macrophage functions in New Zealand black mice. Cell Immunol 45:309

    Article  CAS  PubMed  Google Scholar 

  • Barnd DL, Lan MS, Metzgar RS, Finn OJ (1989) Specific, major histocompatibility complex- unrestricted recognition of tumor-associated mucins by human cytotoxic T cells. Proc Natl Acad Sci U S A 86:7159–7163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baturin DA, Alimova IN, Anisimov VN, Popovich IG, Zabezhinski MA, Provinciali M, Mancini R, Franceschi C (2001) The effect of light regimen and melatonin on the development of spontaneous mammary tumors in HER-2/neu transgenic mice is related to a downregulation of HER-2/neu gene expression. Neuroendocrinol Lett 22:441–447

    CAS  PubMed  Google Scholar 

  • Berchuck A, Kamel A, Whitaker R, Kerns B, Olt G, Kinney R, Soper JT, Dodge R, Clarke-Pearson DL, Marks P (1990) Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer Res 50(13):4087

    CAS  PubMed  Google Scholar 

  • Bernhard H, Salazar L, Schiffman K, Smorlesi A, Schmidt B, Knutson KL, Disis ML (2002) Vaccination against the HER-2/neu oncogenic protein. Endocr Relat Cancer 9:33

    Article  CAS  PubMed  Google Scholar 

  • Blum JL, Gonçalves A, Efrat N, Debled M, Conte P, Richards PD, Richards D, Lardelli P, Nieto A, Cullell-Young M, Delaloge S (2016) Breast Cancer Res Treat 155(2):295–302

    Article  CAS  PubMed  Google Scholar 

  • Bonavita E, Galdiero MR, Jaillon S, Mantovani A (2015) Phagocytes as corrupted policemen in cancer-related inflammation. Adv Cancer Res 128:141–171

    Article  PubMed  Google Scholar 

  • Born J, Uthgenannt D, Dodt C, Nunninghoff D, Ringvolt E, Wagner T, Fehm HL (1995) Cytokine production and lymphocyte subpopulations in aged humans. An assessment during nocturnal sleep. Mech Ageing Dev 84:113

    Article  CAS  PubMed  Google Scholar 

  • Burns EA, Goodwin JS (1998) Immunological changes of aging. In: Balducci L, Lyman GH, Ershler WB (eds) Comprehensive geriatric oncology. Harwood Academic Publishers, Amsterdam, p 213

    Google Scholar 

  • Cahill DP, Kinzler KW, Vogelstein B, Lengaver C (1999) Genetic instability and darwinian selection in tumours. Trends Cell Biol 9:M57

    Article  CAS  PubMed  Google Scholar 

  • Carillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ (2005) A review of the multiple actions of melatonin on the immune system. Endocrine 27(2):189–200

    Article  Google Scholar 

  • Cavallo F, Giovarelli M, Gulino A, Vacca A, Stoppacciaro A, Modesti A, Forni G (1992) Role of neutrophils and CD4+ T lymphocytes in the primary and memory response to nonimmunogenic murine mammary adenocarcinoma made immunogenic by IL-2 gene. J Immunol 149:3627

    CAS  PubMed  Google Scholar 

  • Cavallo F, Signorelli P, Giovarelli M, Musiani P, Modesti A, Brunda MJ, Colombo MP, Forni G (1997) Antitumor efficacy of adenocarcinoma cells engineered to produce interleukin 12 (IL-12) or other cytokines compared with exogenous IL-12. J Natl Cancer Inst 89(14):1049. Breast Cancer and Immunosenescence 1165

    Article  CAS  PubMed  Google Scholar 

  • Chakradeo S, Elmore LW, Gewirtz DA (2016) Is senescence reversible? Curr Drug Targets 17:460–466

    Article  CAS  PubMed  Google Scholar 

  • Charpentier B, Fournier C, Fries D, Mathieu D, Noury J, Bach JF (1981) Immunological studies in human ageing. I. In vitro functions of T cells and polymorphs. J Clin Lab Immunol 5:87

    CAS  PubMed  Google Scholar 

  • Chatta GS, Andrews RG, Rodger E, Schrag M, Hammond WP, Dale DC (1993) Hematopoietic progenitors and ageing: alterations in granulocytic precursors and responsiveness to recombinant human G-CSF, GM-CSF, and IL-3. J Gerontol 48:M207

    Article  CAS  PubMed  Google Scholar 

  • Chen Y et al (1998) DNA vaccines encoding full-length or truncated neu induce protective immunity against neu-expressing mammary tumors. Cancer Res 58:1965–1971

    CAS  PubMed  Google Scholar 

  • Chidambara Murthy KN, Jayaprakasha GK, Patil BS (2012) The natural alkaloid berberine targets multiple pathways to induce cell death in cultured human colon cancer cells. Eur J Pharmacol 688:14–21

    Article  CAS  PubMed  Google Scholar 

  • Chiu BC, Stolberg VR, Zhang H, Chensue SW (2007) Increased Foxp3(+) Treg cell activity reduces dendritic cell co-stimulatory molecule expression in aged mice. Mech Ageing Dev 128:618–627

    Article  CAS  PubMed  Google Scholar 

  • Choi MS et al (2009) Berberine inhibits p53-dependent cell growth through induction of apoptosis of prostate cancer cells. Int J Oncol 34:1221–1230

    Article  CAS  PubMed  Google Scholar 

  • Chougnet CA, Tripathi P, Lages CS, Raynor J, Sholl A, Fink P, Plas DR, Hildeman DA (2011) A major role for Bim in regulatory T cell homeostasis. J Immunol 186:156–163

    Article  CAS  PubMed  Google Scholar 

  • Colombo MP, Forni G (1994) Cytokine gene transfer in tumor inhibition and tumor therapy: where are we now? Immunol Today 15(2):48

    Article  CAS  PubMed  Google Scholar 

  • Colonna-Romano G, Potestio M, Aquino A, Candore G, Lio D, Caruso C (2002) Gamma/delta T lymphocytes are affected in the elderly. Exp Gerontol 37:205

    Article  CAS  PubMed  Google Scholar 

  • Corberand J, Ngyen F, Laharrague P, Fontanilles AM, Gleyzes B, Gyrard E, Senegas C (1981) Polymorphonuclear functions and ageing in humans. J Am Geriatr Soc 29:391

    Article  CAS  PubMed  Google Scholar 

  • Corsini E, Battaini F, Lucchi L, Marinovich M, Racchi M, Govoni S, Galli CL (1999) Reduction of transendothelial migration of mononuclear cells in interferon-beta1b-treated multiple sclerosis patients. Ann Neurol 46:435

    Article  CAS  PubMed  Google Scholar 

  • Criscitiello C, Curigliano G (2015) Immunotherapy of breast cancer. Prog Tumor Res 42:30–43

    PubMed  Google Scholar 

  • Curcio C, Di Carlo E, Clynes R, Smyth MJ, Boggio K, Quaglino E, Spadaio M, Colombo MP, Amici A, Lollini PL, Musini P, Forni G (2003) Nonredundant roles of antibody, cytokines and perforin for the immune eradication of established HER-2/neu carcinomas. J Clin Invest 111:1161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Czerniecki BJ, Kosi GK, Koldovsky U, Xu S, Cohen PA, Mick R, Nisenbaum H, Pasha T, Xu M, Fox KR, Weinstein S, Orel SG, Vonderheide R, Coukos G, DeMichele A, Araujo L, Spitz FR, Rosen M, Levine BL, June C, Zhang PJ (2007) Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion. Cancer Res 67:1842–1852

    Article  CAS  PubMed  Google Scholar 

  • D’Incalci M, Galmarini CM (2010) A review of trabectedin (ET-743): a unique mechanism of action. Mol Cancer Ther 9:2157

    Article  PubMed  CAS  Google Scholar 

  • D’Incalci M, Zambelli A (2016) Trabectedin for the treatment of breast cancer. Expert Opin Investig Drugs 25(1):105–115

    Article  PubMed  CAS  Google Scholar 

  • Disis ML, Calenoff E, McLaughlin G, Murphy AE, Chen W, Groner B, Jeschke M, Lydon N, McGlynn E, Livingston RB (1994) Existent T-cell and antibody immunity to HER-2/neu protein in patients with breast cancer. Cancer Res 54(1):16

    CAS  PubMed  Google Scholar 

  • Disis ML, Pupa SM, Gralow JR, Dittadi R, Menard S, Cheever MA (1997) High-titer HER- 2/neu protein-specific antibody can be detected in patients with early-stage breast cancer. J Clin Oncol 15(11):3363

    Article  CAS  PubMed  Google Scholar 

  • Disis ML, Gooley TA, Rinn K, Davis D, Piepkorn M, Cheever MA, Knutson KL, Schiffman K (2002) Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines. J Clin Oncol 20:2624

    Article  CAS  PubMed  Google Scholar 

  • Donnini A, Argentati K, Mancini R, Smorlesi A, Bartozzi B, Bernardini G, Provinciali M (2002) Phenotype, antigen-presenting capacity, and migration of antigen-presenting cells in young and old age. Exp Gerontol 37:1097

    Article  CAS  PubMed  Google Scholar 

  • Enioutina EY, Bareyan D, Daynes RA (2011) A role for immature myeloid cells in immune senescence. J Immunol 186:697–707

    Article  CAS  PubMed  Google Scholar 

  • Ershler W, Longo DL (1997) Aging and cancer: issues of basic and clinical science. J Natl Cancer Inst 8:1489

    Article  Google Scholar 

  • Fabre-Lafay S et al (2007) Nectin-4 is a new histological and serological tumor associated marker for breast cancer. BMC Cancer 7:73

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fabris N, Provinciali M (1989) Hormones. In: Nelson D (ed) Natural immunity. Academic, New York, p 306

    Google Scholar 

  • Fabris N, Mocchegiani E, Provinciali M (1994) Plasticity of neuroendocrine-immune interactions during aging. In: Berczi S (ed) Advances in psychoneuroimmunology. Plenum Press, New York, p 331

    Chapter  Google Scholar 

  • Fabris N, Mocchegiani E, Provinciali M (1997) Plasticity of neuroendocrine-thymus interactions during aging. Exp Gerontol 32:415

    Article  CAS  PubMed  Google Scholar 

  • Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lavagetto G, Casti A, Franceschi C, Passeri M, Sansoni P (2000) Shortage of circulating naive CD8+ T cells provides new insights on immunodeficiency in aging. Blood 95:2860

    CAS  PubMed  Google Scholar 

  • Femel J, Huijbers EJ, Saupe F, Cedervall J, Zhang L, Roswall P, Larsson E, Olofsson H, Pietras K, Dimberg A, Hellman L, Olsson AK (2014) Therapeutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer. Oncotarget. 5(23):12418–12427

    Google Scholar 

  • Finn OJ (2003) Cancer vaccines: between the idea and the reality. Nat Immunol 3:630–641

    Article  CAS  Google Scholar 

  • Finn OJ, Jerome KR, Henderson RA, Pecher G, Domenech N, Magarian-Blander J (1995) MUC-1 epithelial tumor mucin-based immunity and cancer vaccines. Immunol Rev 145:61–89

    Article  CAS  PubMed  Google Scholar 

  • Fisk B, Blevins TL, Wharton JT, Ioannides CG (1995) Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines. J Exp Med 181(6):2109

    Article  CAS  PubMed  Google Scholar 

  • Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F et al (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128(1):92–105

    Article  CAS  PubMed  Google Scholar 

  • Frauwirth KA, Thompson CB (2004) Regulation of T lymphocyte metabolism. J Immunol 172:4661–4665

    Article  CAS  PubMed  Google Scholar 

  • Frega N, Mozzon M, Bocci F (1998) Identification and estimation of tocotrienols in the annatto lipid fraction by gas chromatography–mass spectrometry. JAOCS 75:1723–1727

    CAS  Google Scholar 

  • Fulop T Jr, Foris G, Worum I, Leovey A (1985) Age-dependent alterations of Fc gamma receptor-mediated effector functions of human polymorphonuclear leucocytes. Clin Exp Immunol 61:425

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gardyan A, Osen W, Zörnig I, Podola L, Agarwal M, Aulmann S, Ruggiero E, Schmidt M, Halama N, Leuchs B, von Kalle C, Beckhove P, Schneeweiss A, Jäger D, Eichmüller SB (2015) Identification of NY-BR-1-specific CD4(+) T cell epitopes using HLA-transgenic mice. Int J Cancer. 136(11):2588–2597.

    Google Scholar 

  • Giachino C, Granziero L, Modena V, Maiocco V, Lomater C, Fantini F, Lanzavecchia A, Migone N (1994) Clonal expansions of V delta 1+ and V delta 2+ cells increase with age and limit the repertoire of human gamma delta T cells. Eur J Immunol 24:1914

    Article  CAS  PubMed  Google Scholar 

  • Goodwin JS, Messner RP (1979) Sensitivity of lymphocytes to prostaglandin E2 increases in subjects over age 70. J Clin Invest 64:434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gottenberg JE, Lavie F, Abbed K, Gasnault J, Le Nevot E, Delfraissy JF, Taoufik Y, Mariette X (2005) CD4 CD25 high regulatory T cells are not impaired in patients with primary Sjogren’s syndrome. J Autoimmun 24:235–242

    Article  CAS  PubMed  Google Scholar 

  • Gregg R, Smith CM, Clark FJ, Dunnion D, Khan N, Chakraverty R, Nayak L, Moss PA (2005) The number of human peripheral blood CD4+ CD25 high regulatory T cells increases with age. Clin Exp Immunol 140:540–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grycová L, Dostál J, Marek R (2007) Quaternary protoberberine alkaloids. Phytochemistry 68:150–175

    Article  PubMed  CAS  Google Scholar 

  • Herrero C, Marques L, Lloberas J, Celada A (2001) IFN-gamma-dependent transcription of MHC class II IA is impaired in macrophages from aged mice. J Clin Invest 107:485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hinnis AR, Luckett JC, Walker RA (2007) Survivin is an independent predictor of short-term survival in poor prognostic breast cancer patients. Br J Cancer 96:639–645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Imanshahidi M, Hosseinzadeh H (2008) Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytother Res 22:999–1012

    Article  CAS  PubMed  Google Scholar 

  • Jager D, Karbach J, Pauligk C, Seil I, Frei C, Chen YT, Old LJ, Knuth A, Jäger E. (2005) Humoral and cellular immune responses against the breast cancer antigen NY-BR-1: definition of two HLA-A2 restricted peptide epitopes. Cancer Immun. 5:11–17.

    PubMed  Google Scholar 

  • Jagger A, Shimojima Y, Goronzy JJ, Weyand CM (2014) Regulatory T cells and the immune aging process: a mini-review. Gerontology 60:130–137

    Article  CAS  PubMed  Google Scholar 

  • Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CWW, Fong HHS, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218–220

    Article  CAS  PubMed  Google Scholar 

  • Jaramillo A, Majumder K, Manna PP, Fleming TP, Doherty G, Dipersio JF, Mohanakumar T (2002) Identification of HLA-A3-restricted CD8+ T cell epitopes derived from mammaglobin-A, a tumor-associated antigen of human breast cancer. Int J Cancer 102:499–506

    Article  CAS  PubMed  Google Scholar 

  • Jaroslow BN, Larrick JW (1973) Clearance of foreign red cells from the blood of ageing mice. Mech Ageing Dev 2:23

    Article  CAS  PubMed  Google Scholar 

  • Kaesberg PR, Ershler WB (1989) The importance of immunosenescence in the incidence and malignant properties of cancer in hosts of advancer age. J Gerontol 44:63

    Article  CAS  PubMed  Google Scholar 

  • Kapasi ZF, Murali-Krishna K, McRae ML, Ahmed R (2002) Defective generation but normal maintenance of memory T cells in old mice. Eur J Immunol 32:1567

    Article  CAS  PubMed  Google Scholar 

  • Khare V, Sodhi A, Singh SM (1996) Effect of ageing on the tumoricidal functions of murine peritoneal macrophages. Nat Immunol 15:285

    Google Scholar 

  • Kheir MM, Wang Y, Hua L, Hu J, Li L, Lei F, Du L (2010) Acute toxicity of berberine and its correlation with the blood concentration in mice. Food Chem Toxicol 48(4):1105–1110

    Article  CAS  PubMed  Google Scholar 

  • Kim SW, Goedegebuure P, Gillanders WE (2016) Mammaglobin-A is a target for breast cancer vaccination. Oncoimmunology 26;5(2):e1069940. eCollection 2016 Feb.

    Google Scholar 

  • Ko BK, Murray JL, Disis ML, Efferson CL, Kuerer HM, Peoples GE, Ioannides CG (2003) Clinical studies of vaccines targeting breast cancer. Clin Cancer Res 9:3222

    Google Scholar 

  • Kong W, Wei J, Abidi P, Lin M, Inaba S et al (2004) Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 10:1344–1351

    Article  CAS  PubMed  Google Scholar 

  • Kotera Y, Fontenot JD, Pecher G, Metzgar RS, Finn OJ (1994) Humoral immunity against a tandem repeat epitope of human mucin MUC-1 in sera from breast, pancreatic, and colon cancer patients. Cancer Res 54:2856–2860

    CAS  PubMed  Google Scholar 

  • Kreisle RA, Stebler BA, Ershler WB (1990) Effect of host age on tumor-associated angiogenesis in mice. J Natl Cancer Inst 82:44

    Article  CAS  PubMed  Google Scholar 

  • Kren V, Walterová D (2005) Silybin and silymarin – new effects and applications. Biomed Pap 149:29–41

    Article  CAS  Google Scholar 

  • Krishnaraj R (1997) Senescence and cytokines modulate the NK cell expression. Mech Ageing Dev 96:89

    Article  CAS  PubMed  Google Scholar 

  • Kroemer G, Senovilla L, Galluzzi I, Andrè F, Zitvogel L (2015) Natural and therapy-induced immunosurveillance in breast cancer. Nat Med 21:1128–1138

    Article  CAS  PubMed  Google Scholar 

  • Kurtz JM, Jacquemier J, Amalric R et al (1990) Why are local recurrences after breast-conserving therapy more frequent in younger patients. J Clin Oncol 10:141–152

    Google Scholar 

  • Kutza J, Murasko DM (1996) Age-associated decline in IL-2 and IL-12 induction of LAK cell activity of human PBMC samples. Mech Ageing Dev 90:209

    Article  CAS  PubMed  Google Scholar 

  • Lages CS, Suffia I, Velilla PA, Huang B, Warshaw G, Hildeman DA, Belkaid Y, Chougnet C (2008) Functional regulatory T cells accumulate in aged hosts and promote chronic infectious disease reactivation. J Immunol 181:1835–1848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li W et al (2014) Berberine regulates AMP-activated protein kinase signaling pathways and inhibits colon tumorigenesis in mice. Mol Carcinog. https://doi.org/10.1002/mc.22179

  • Linehan DC, Goedegebuure PS, Peoples GE, Rogers SO, Eberlein TJ (1995) Tumor-specific and HLA-A2-restricted cytolysis by tumor-associated lymphocytes in human metastatic breast cancer. J Immunol 155:4486–4491

    CAS  PubMed  Google Scholar 

  • Lipschitz DA, Udupa KB, Boxer LA (1988) The role of calcium in the age-related decline of neutrophil function. Blood 71:659

    CAS  PubMed  Google Scholar 

  • Lollini P-L, Forni G (2003) Cancer immunoprevention: tracking down persistent tumor antigens. Trends Immunol 24:62

    Article  CAS  PubMed  Google Scholar 

  • Lung TL, Saurwein-Teissl M, Parson W, Schonitzer D, Grubeck-Loebenstein B (2000) Unimpaired dendritic cells can be derived from monocytes in old age and can mobilize residual function in senescent T cells. Vaccine 18:1606

    Article  CAS  PubMed  Google Scholar 

  • Ly LV, Baghat A, Versluis M, Jordanova ES, Luyten GP, van Rooijen N, van Hall T, van der Velden PA, Jager MJ (2010) In aged mice, outgrowth of intraocular melanoma depends on proangiogenic M2-type macrophages. J Immunol 185:3481–3488

    Article  CAS  PubMed  Google Scholar 

  • Macaskill EJ, Renshaw L, Dixon JM (2006) Neoadjuvant use of hormonal therapy in elderly patients with early or locally advancer hormone receptor-positive breast cancer. Oncologist 11:1081–1088

    Article  CAS  PubMed  Google Scholar 

  • Manna PP, Jaramillo A, Majumder K, Campbell LG, Fleming TP, Dietz JR, Dipersio JF, Mohanakumar T (2004) Generation of CD8+ cytotoxic T lymphocytes against breast cancer cells by stimulation with mammaglobin-A-pulsed dendritic cells. Breast Cancer Res 96:138896

    Google Scholar 

  • Mariani E, Pulsatelli L, Meneghetti A, Dolzani P, Mazzetti I, Neri S, Ravaglia G, Forti P, Facchini A (2001) Different IL-8 production by T and NK lymphocytes in elderly subjects. Mech Ageing Dev 122:1383

    Article  CAS  PubMed  Google Scholar 

  • McIntyre BS, Briski KP, Gapor A, Sylvester PW (2000) Antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary epithelial cells. Proc Soc Exp Biol Med 224:292–301

    Article  CAS  PubMed  Google Scholar 

  • McLachlan JA, Serkin CD, Morrey KM, Bakouche O (1995) Antitumoral properties of aged human monocytes. J Immunol 154:832

    CAS  PubMed  Google Scholar 

  • Miller RA (1996) The ageing immune system: primer and prospectus. Science 273:70

    Article  CAS  PubMed  Google Scholar 

  • Miller C, Kelsoe G, Han S (1994) Lack of B7-2 expression in the germinal centers of aged mice. Ageing Immunol Infect Dis 5:249

    Google Scholar 

  • Mukherjee P, Madsen CS, Ginardi AR, Tinder TL, Jacobs F, Parker J, Agrawal B, Longenecker BM, Gendler SJ (2003) Mucin-1-specific immunotherapy in a mouse model of spontaneous breast cancer. J Immunother 26:47

    Article  CAS  PubMed  Google Scholar 

  • Muñoz-Espín D, Serrano M (2014) Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 15:482–496

    Article  PubMed  CAS  Google Scholar 

  • Narayanan K, Jaramillo A, Benshoff ND, Campbell LG, Fleming TP, Dietz JR, Mohanakumar T (2004) Response of established human breast tumors to vaccination with mammaglobin-A cDNA. J Natl Cancer Inst 96:1388–1396

    Article  CAS  PubMed  Google Scholar 

  • Narita M, Lowe SW (2005) Senescence comes of age. Nat Med 11:920–922

    Article  CAS  PubMed  Google Scholar 

  • Nesaretnam K et al (2004) Tocotrienol-rich fraction from palm oil affects gene expression in tumors resulting from MCF-7 cell inoculation in athymic mice. Lipids 39:459–467

    Article  CAS  PubMed  Google Scholar 

  • O’Mahony L, Holland J, Jackson J, Feighery C, Hennessy TP, Mealy K (1998) Quantitative intracellular cytokine measurement: age-related changes in proinflammatory cytokine production. Clin Exp Immunol 113:213

    Article  PubMed  PubMed Central  Google Scholar 

  • Oshikawa K, Shi F, Rakhmilevich AL, Sondel PM, Mahvi DM, Yang NS (1999) Synergistic inhibition of tumor growth in a murine mammary adenocarcinoma model by combinational gene therapy using IL-12, pro-IL-18, and IL-1 beta converting enzyme cDNA. Proc Natl Acad Sci U S A 96:13351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patil JB, Kim J, Jayaprakasha GK (2010) Berberine induces apoptosis in breast cancer cells (MCF-7) through mitochondrial-dependent pathway. Eur J Pharmacol 645:70–78

    Article  CAS  PubMed  Google Scholar 

  • Pawelec G, Solana R (1997) Immunosenescence. Trends Immunol 11:514

    Article  Google Scholar 

  • Pawelec G, Solana R, Remarque ED, Mariani E (1998) Impact of aging on innate immunity. J Leukoc Biol 64:703

    CAS  PubMed  Google Scholar 

  • Pawelec G (2001) Progress in vaccination against cancer. Trends Mol Med. 7:486–487.

    Article  CAS  PubMed  Google Scholar 

  • Peoples GE, Goedegebuure PS, Smith R, Linehan DC, Yoshino I, Eberlein TJ (1995) Breast and ovarian cancer-specific cytotoxic T lymphocytes recognize the same HER2/neu-derived peptide. Proc Natl Acad Sci U S A 92(2):432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pierpaoli E, Viola V, Pilolli F, Piroddi M, Galli F, Provinciali M (2010) Gamma- and delta-tocotrienols exert a more potent anticancer effect than alpha-tocopheryl succinate on breast cancer cell lines irrespective of HER-2/neu expression. Life Sci 86:668–675

    Article  CAS  PubMed  Google Scholar 

  • Pierpaoli E, Viola V, Barucca A, Orlando F, Galli F, Provinciali M (2013a) Effect of annatto-tocotrienols supplementation on the development of mammary tumors in HER-2/neu transgenic mice. Carcinogenesis 34(6):1352–1360

    Article  CAS  PubMed  Google Scholar 

  • Pierpaoli E, Arcamone AG, Buzzetti F, Lombardi P, Salvatore C, Provinciali M (2013b) Antitumor effect of novel berberine derivatives in breast cancer cells. Biofactors 39(6):672–679

    Article  CAS  PubMed  Google Scholar 

  • Pierpaoli E, Damiani E, Orlando F, Lucarini G, Bartozzi B, Lombardi P, Salvatore C, Geroni C, Donati A, Provinciali M (2015) Antiangiogenic and antitumor activities of berberine derivative NAX014 compound in a transgenic murine model of HER2/neu-positive mammary carcinoma. Carcinogenesis 36(10):1169–1179

    Article  CAS  PubMed  Google Scholar 

  • Pili R, Guo Y, Chang J, Nakanishi H, Martin GR, Passaniti A (1994) Altered angiogenesis underlying age-dependent changes in tumor growth. J Natl Cancer Inst 86:1303

    Article  CAS  PubMed  Google Scholar 

  • Provinciali M, Smorlesi A (2005) Immunoprevention and immunotherapy of cancer in aging. Cancer Immunol Immunother 54:93–106

    Article  PubMed  Google Scholar 

  • Provinciali M, Fabris N, Pieri C (1990a) Improvement of natural killer cell activity by in vitro active lipids (AL 721) administration in old mice. Mech Ageing Dev 52:245

    Article  CAS  PubMed  Google Scholar 

  • Provinciali M, Di Stefano G, Bernardi A, Fabris N (1990b) Role of pituitary-thyroid axis on basal and lymphokine-induced NK cell activity in ageing. Int J Neurosci 51:273

    Article  CAS  PubMed  Google Scholar 

  • Provinciali M, Muzzioli M, Di Stefano G, Fabris N (1991a) Recovery of spleen cell natural killer activity by thyroid hormone treatment in old mice. Nat Immun Cell Growth Regul 10:22

    Google Scholar 

  • Provinciali M, Pieri C, Fabris N (1991b) Reversibility of age associated NK defect by endocrinological and/or nutritional intervention. Ann Ist Super Sanità 27:61

    CAS  PubMed  Google Scholar 

  • Provinciali M, Di Stefano G, Bulian D, Stronati S, Fabris N (1997) Long-term melatonin supplementation does not recover the impairment of natural killer cell activity and lymphocyte proliferation in aging mice. Life Sci 67:857

    Article  Google Scholar 

  • Provinciali M, Argentati K, Tibaldi A (2000) Efficacy of cancer gene therapy in aging: adenocarcinoma cells engineered to release IL-2 are rejected but do not induce tumor specific immune memory in old mice. Gene Ther 7:624

    Article  CAS  PubMed  Google Scholar 

  • Provinciali M, Smorlesi A, Donnini A, Bartozzi B, Amici A (2003) Low effectiveness of DNA vaccination against HER-2/neu in ageing. Vaccine 21(9–10):843

    Article  CAS  PubMed  Google Scholar 

  • Provinciali M, Re F, Donnini A, Orlando F, Bartozzi B, Di Stasio G, Smorlesi A (2005) Effect of resveratrol on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Int J Cancer 115(1):36–45

    Article  CAS  PubMed  Google Scholar 

  • Provinciali M, Papalini F, Orlando F, Pierpaoli S, Donnini A, Morazzoni P, Riva A, Smorlesi A (2007) Effect of the silybin-phosphatidylcholine complex (IdB1016) on the development of mammary tumors in HER-2/neu transgenic mice. Cancer Res 67:2022–2029

    Article  CAS  PubMed  Google Scholar 

  • Provinciali M, Barucca A, Orlando F, Pierpaoli E (2017) Booster immunizations with DNA plasmids encoding HER-2/neu prevent spontaneous mammary cancer in HER-2/neu transgenic mice over life span. Sci Rep 7(1):3078

    Article  PubMed  PubMed Central  Google Scholar 

  • Quaglino E et al (2004) Electroporated DNA vaccine clears away multifocal mammary carcinomas in HER-2/neu transgenic mice. Cancer Res 64(8):2858–2864

    Article  CAS  PubMed  Google Scholar 

  • Racková L, Májeková M, Kost’álová D, Stefek M (2003) Antiradical and antioxidant activities of alkaloids isolated from Mahonia aquifolium. Structural aspects. Bioorg Med Chem 12:4709–4715

    Article  CAS  Google Scholar 

  • Rao VS, Garimella V, Hwang M, Drew PJ (2007) Management of early breast cancer in the elderly. Int J Cancer 120:1155–1160

    Article  CAS  PubMed  Google Scholar 

  • Renshaw M, Rockwell J, Engleman C, Gewirtz A, Katz J, Sambhara S (2002) Cutting edge: impaired Toll-like receptor expression and function in ageing. J Immunol 169:4697

    Article  CAS  PubMed  Google Scholar 

  • Reymond N, Fabre S, Lecocq E, Adelaide J, Dubreuil P, Lopez M (2001) Nectin-4/PRR4, a new afadin-associated member of the nectin family that trans-interacts with nectin1/PRR1 through V domain interaction. J Biol Chem 276:43205–43215

    Article  CAS  PubMed  Google Scholar 

  • Rink L, Cakman I, Kirchner H (1998) Altered cytokine production in the elderly. Mech Ageing Dev 102:199

    Article  CAS  PubMed  Google Scholar 

  • Roh H, Pippin J, Drebin JA (2000) Down-regulation of HER-2/neu expression induces apoptosis in human cancer cells that overexpress HER-2/neu. Cancer Res 60:560–565

    CAS  PubMed  Google Scholar 

  • Sadeghi HM, Schnelle JF, Thoma JK, Nishanian P, Fahey JL (1999) Phenotypic and functional characteristics of circulating monocytes of elderly persons. Exp Gerontol 34:959

    Article  CAS  PubMed  Google Scholar 

  • Saito H, Dubsky P, Dantin C, Finn OJ, Banchereau J, Palucka AK (2006) Cross-priming of cyclin B1, MUC-1 and survivin-specific CD8+ T cells by dendritic cells loaded ith killed allogeneic breast cancer cells. Breast Cancer Res 8:R65

    Article  PubMed  PubMed Central  Google Scholar 

  • Sansoni P, Cossarizza A, Brianti V, Fagnoni F, Snelli G, Monti D, Marcato A, Passeri G, Ortolani C, Forti E, et al. (1993) Lymphocyte subsets and natural killer cell activity in healthy old people and centenarians. Blood 82(9):2767–2773.

    CAS  PubMed  Google Scholar 

  • Seil I, Frei C, Sultmann H, Knauer SK, Engels K, Jager E, Zatloukal K, Pfreundschuh M, Knuth A, Tseng-Chen Y, Jungbluth AA, Stauber RH, Jager D (2007) The differentiation antigen NY-BR-1 is a potential target for antibody-based therapies in breast cancer. Int J Cancer 120:2635–2642

    Article  CAS  PubMed  Google Scholar 

  • Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88:593–602

    Article  CAS  PubMed  Google Scholar 

  • Seymour K, Pettit S, O’Flaherty E, Charnley RM, Kirby JA (1999) Selection of metastatic tumor phenotypes by host immune systems. Lancet 354:1989

    Article  CAS  PubMed  Google Scholar 

  • Sharma S, Dominguez AL, Lustgarten J (2006) High accumulation of T regulatory cells prevents the activation of immune responses in aged animals. J Immunol 177:8348–8355

    Article  CAS  PubMed  Google Scholar 

  • Shearer GM (1997) Th1/Th2 changes in aging. Mech Ageing Dev 94:1

    Article  CAS  PubMed  Google Scholar 

  • Silliman RA, Balducci L (1998) Breast cancer: a geriatric perspective. In: Balducci L, Lyman GH, Ershler WB (eds) Comprehensive geriatric oncology. Harwood Academic Publishers, Amsterdam, p 661

    Google Scholar 

  • Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244(4905):707

    Article  CAS  PubMed  Google Scholar 

  • Smorlesi A, Papalini F, Orlando F, Donnini A, Re F, Provinciali M (2005) Imiquimod and S-27609 as adjuvants of DNA vaccination in a transgenic murine model of HER2/neu-positive mammary carcinoma. Gene Ther 12:1324–1332

    Article  CAS  PubMed  Google Scholar 

  • Smorlesi A, Papalini F, Amici A, Orlando F, Pierpaoli S, Mancini C, Provinciali M (2006) Evaluation of different plasmid DNA delivery systems for immunization against HER2/neu in a transgenic murine model of mammary carcinoma. Vaccine 24:1766–1775

    Article  CAS  PubMed  Google Scholar 

  • Snyder LA, Goletz TJ, Gunn GR, Shi FF, Harris MC, Cochlin K, McCauley C, McCarthy SG, Branigan PJ, Knight DM (2006) A MUC1/IL18 DNA vaccine induces anti-tumor immunity and increased survival in MUC1 transgenic mice. Vaccine 24:3340–3352

    Article  CAS  PubMed  Google Scholar 

  • Sohn DM, Kim SY, Baek MJ, Lim CW, Lee MH, Cho MS, Kim TY (2006) Expression of survivin and clinical correlation in patients with breast cancer. Biomed Pharmacother 60:289–292

    Article  CAS  PubMed  Google Scholar 

  • Solana R, Pawelec G (1998) Molecular and cellular basis of immunosenescence. Mech Ageing Dev 102:115

    Article  CAS  PubMed  Google Scholar 

  • Stanley MA (2002) Imiquimod and the imidazoquinolines: mechanism of action and therapeutic potential. Clin Dermatol 27:571–577

    Article  CAS  Google Scholar 

  • Steger MM, Maczek C, Grubeck-Loebenstein B (1996) Morphologically and functionally intact dendritic cells can be derived from the peripheral blood of aged individuals. Clin Exp Immunol 105:544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stewart AK, Lassam NJ, Quirt IC, Bailey DJ, Rotstein LE, Krajden M, Dessureault S, Gallinger S, Cappe D, Wan Y, Addison CL, Moen RC, Gauldie J, Graham FL (1999) Adenovector-mediated gene delivery of interleukin-2 in metastatic breast cancer and melanoma: results of a phase 1 clinical trial. Gene Ther 6:350

    Article  CAS  PubMed  Google Scholar 

  • Suader DN (2000) Immunomodulatory and pharmacologic properties of Imiquimod. J Am Acad Dermatol 43:S6–S11

    Article  Google Scholar 

  • Sulli G, Di Micco R, d’Adda di Fagagna F (2012) Crosstalk between chromatin state and DNA damage response in cellular senescence and cancer. Nat Rev Cancer 12:709–720

    Article  CAS  PubMed  Google Scholar 

  • Tanaka Y, Koido S, Chen D, Gendler SJ, Kufe D, Gong J (2001) Vaccination with allogeneic dendritic cells fused to carcinoma cells induces antitumor immunity in MUC1 transgenic ice. Clin Immunol 101:192

    Article  CAS  PubMed  Google Scholar 

  • Theurillat JP et al (2007) NY-BR-1 protein expression in breast carcinoma: a mammary gland differentiation antigen as target for cancer immunotherapy. Cancer Immunol Immunother 56:1723. (Epub ahead of print)

    Article  CAS  PubMed  Google Scholar 

  • Thoman ML, Weigle WO (1989) The cellular and subcellular bases of immunosenescence. In: Dixon FJ (ed) Advances in immunology, vol 46. Academic, San Diego, p 221

    Google Scholar 

  • Vaux DL (1993) Toward an understanding of the molecular mechanisms of physiological cell death. Proc Natl Acad Sci U S A 90:786–789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Verschoor CP, Johnstone J, Millar J, Dorrington MG, Habibagahi M, Lelic A, Loeb M, Bramson JL, Bowdish DME (2013) Blood CD33(+)HLA-DR(−) myeloid-derived suppressor cells are increased with age and a history of cancer. J Leukoc Biol 93:633–637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wallace PK, Eisenstein TK, Meissler JJ Jr, Morahan PS (1995) Decreases in macrophage mediated antitumor activity with aging. Mech Ageing Dev 77:169

    Article  CAS  PubMed  Google Scholar 

  • Wanh X, Tsao S-W, Wong Y-C, Cheung LM (2003) Induction of senescent-like growth arrest as a new target in anticancer treatment. Curr Cancer Drug Targets 3:153–160

    Article  Google Scholar 

  • Watson MA, Fleming TP (1996) Mammaglobin, a mammary-specific member of the uteroglobin gene family, is overexpressed in human breast cancer. Cancer Res 56:860–865

    CAS  PubMed  Google Scholar 

  • Yie SM, Luo B, Ye NY, Xie K, Ye SR (2006) Detection of Suvivin-expressing circulating cancer cells in the peripheral blood of breast cancer patients by a RT-PCR ELISA. Clin Exp Metastasis 23:279–289

    Article  CAS  PubMed  Google Scholar 

  • Yin J, Gao Z, Liu D, Liu Z, Ye J (2008) Berberine improves glucose metabolism through induction of glycolysis. Am J Physiol Endocrinol Metab 294:E148–E156

    Article  CAS  PubMed  Google Scholar 

  • Zhou D, Chrest FJ, Adler W, Munster A, Winchurch RA (1993) Increased production of TGFbeta and IL-6 by aged spleen cells. Immunol Lett 36:7

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Advanced Technology Center for Aging Research, Scientific Technological Area, IRCCS-INRCA, Ancona, Italy

    Mauro Provinciali, Elisa Pierpaoli, Marco Malavolta, Alessia Donnini, Arianna Smorlesi & Cristina Gatti

Authors
  1. Mauro Provinciali
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elisa Pierpaoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marco Malavolta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alessia Donnini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arianna Smorlesi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cristina Gatti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mauro Provinciali .

Editor information

Editors and Affiliations

  1. Division of Geriatrics Research Center on Aging, University of Sherbrooke Dept. of Medicine, Sherbrooke, Québec, Canada

    Tamas Fulop

  2. Dept of Experimental Pathology, University of Bologna, Bologna, Italy

    Claudio Franceschi

  3. Institute for Health and Life Sciences, Tokyo, Japan

    Katsuiku Hirokawa

  4. Center for Medical Research, University of Tübingen, Tübingen, Germany

    Graham Pawelec

Section Editor information

  1. Research Center on Aging, Department of Medicine, Immunology Graduate Programme, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada

    Tamas Fulop

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Provinciali, M., Pierpaoli, E., Malavolta, M., Donnini, A., Smorlesi, A., Gatti, C. (2018). Breast Cancer and Immunosenescence. In: Fulop, T., Franceschi, C., Hirokawa, K., Pawelec, G. (eds) Handbook of Immunosenescence. Springer, Cham. https://doi.org/10.1007/978-3-319-64597-1_56-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-64597-1_56-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-64597-1

  • Online ISBN: 978-3-319-64597-1

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation