Hindawi Publishing Corporation Current Gerontology and Geriatrics Research Volume 2014, Article ID 478126, 11 pages http://dx.doi.org/10.1155/2014/478126 Review Article Senescent Remodeling of the Innate and Adaptive Immune System in the Elderly Men with Prostate Cancer GianluigiTaverna,1MauroSeveso,1GuidoGiusti,1RodolfoHurle,1PierpaoloGraziotti,1 SanjaŠtifter,2MaurizioChiriva-Internati,3andFabioGrizzi1 1HumanitasClinicalandResearchCenter,ViaManzoni56,Rozzano,Milan20089,Italy 2DepartmentofPathology,SchoolofMedicine,UniversityofRijeka,51000Rijeka,Croatia 3DivisionofOncologyandHematology,TexasTechUniversityHealthSciencesCenter,Lubbock,TX79409,USA CorrespondenceshouldbeaddressedtoFabioGrizzi;[email protected] Received31July2013;Revised26January2014;Accepted10February2014;Published19March2014 AcademicEditor:Moise´sEvandroBauer Copyright©2014GianluigiTavernaetal. This is an open access article distributed under the Creative Commons Attribution License,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperly cited. Despiteyearsofintensiveinvestigationthathasbeenmadeinunderstandingprostatecancer,itremainsamajorcauseofdeath inmenworldwide.Prostatecanceremergesfrommultiplealterationsthatinducechangesinexpressionpatternsofgenesand proteinsthatfunctioninnetworkscontrollingcriticalcellularevents.Basedontheexponentialagingofthepopulationandthe increasinglifeexpectancyinindustrializedWesterncountries,prostatecancerintheelderlymenisbecomingadiseaseofincreasing significance.Agingisaprogressivedegenerativeprocessstrictlyintegratedwithinflammation.Severaltheorieshavebeenproposed thatattempttodefinetheroleofchronicinflammationinagingincludingredoxstress,mitochondrialdamage,immunosenescence, andepigeneticmodifications.Here,wereviewtheinnateandadaptiveimmunesystemsandtheirsenescentremodelinginelderly menwithprostatecancer. 1.Introduction It has been ascertained that the human prostate is the site of origin for the two most prevalent diseases of elderly Prostate cancer is the most prevalent malignancy in men men:benignprostatichyperplasia(BPH)andprostatecancer worldwideandisaleadingcauseofcancerdeath[1,2].Several [13, 14]. Prostate cancer is a highly heterogeneous disease men with localized prostate cancer will never suffer any encompassing a wide variety of pathological entities and symptomsoradverseeffectsofthedisease,butbecauseofthe a range of very different clinical behaviors [15]. This is difficultiesinidentifyingthisgroupofpatientsthemajority underpinnedatmolecularlevelbyacomplexarrayofgenetic receive radical local treatment, which can mainly result in alterations that affect cell processes, thus determining the erectiledysfunctionandurinaryleakage[3,4].Thestillopen dynamical progression of the neoplastic disease and its questionforcliniciansisdecidingwhichmenhave“fastgrow- variable response to treatment (Figure1) [16, 17]. Genomic ing” cancers that need essential treatment and which men alterations with a potential involvement in prostate cancer have“slowgrowing”cancersthatwillnevertroublethem[5]. include somatic mutations, gene deletions or amplifica- Prognosticmarkersmayhelptoavoidunnecessarytreatment tions,andchromosomalrearrangements[17–21].Epigenetic and identify patients with poor outcomes who would be changes, more specifically DNA methylation, are the most candidates for trials of adjuvant treatment [6–9]. Based on common alterations in prostate cancer [22]. These changes the exponential aging of the population and the increasing areassociatedwithtranscriptionalsilencingofgenes,leading lifeexpectancyinindustrializedWesterncountries,prostate to an altered cellular behavior. In light of this, epigenetic cancer in elderly men is becoming a disease of increasing markers, especially the glutathione S-transferase pi gene significance[10–12]. (GSTP1),havebeenlargelyproposedaspotentialbiomarkers 2 CurrentGerontologyandGeriatricsResearch Proliferative Localized Natural Extracapsular inflammatory HGPIN confined Metastasis tissue invasion atrophy cancer t0 t1 t2 t3 tn−1 tn Figure1:Multistateprostatecarcinogenesisdeterminedbytheprogressionofdifferentqualitativestatesidentifiableinthedevelopment of cancer from normal tissue. The time parameter (𝑡0,𝑡1,...,𝑡𝑛−1,𝑡𝑛) depends on a large number of variables interconnected in many waysinanonlinearmanner.Thismakesitextremelydifficulttopredicttheexacttimeintervalbetweentwosuccessivestates.Although carcinogenesisisacontinuum,itsdifferentiationintosuccessivestatesisbasedondifferencesinhistologicalandclinicaldata.Proliferative inflammatory atrophy (PIA) is a frequently observed lesion in prostate biopsies and some investigators have postulated its involvement inprostatecarcinogenesis.PIAsharesgeneticalterationswithhigh-gradeprostaticintraepithelialneoplasia(HGPIN)andprostatecancer. HGPINiscurrentlyregardedastheprecursorlesiononthebasisofpathological,epidemiological,andcytogeneticevidence.HGPINlesions canbesubdividedintoatleastfourdifferentarchitecturalpatterns. for the evaluation of the probability of biochemical recur- shortly after prostatectomy (<1 year) and patients that did rence [23]. Other markers have a strong body of scientific not relapse in the first four years after prostatectomy and data supporting their role in prostate cancer diagnosis, identified 131 differentially expressed microarray probe sets most notably adenomatous polyposis coli (APC), retinoic between these two categories. They conclude that tumor- acid receptor beta (RARB), RAS association domain family adjacentprostatecancerstromacontainsnumerouschanges protein 1 (RASSF1), CDH1, CDKN2A (p16), and the O(6)- in gene expression at the time of diagnosis that correlate methylguanine-DNA methyltransferase (MGMT) [22, 24]. with the chance of relapse following prostatectomy [42]. It Prostate cancer clinical phenotypes range from indolent or is likely that the differences in RNA expression are often clinicallyinsignificanttolocallyaggressiveormetastatic[25– reflected in differences in chromatin modification, DNA 27]. A high number of gene expression profiling studies methylation, and protein levels, which could also serve as have been carried out to attempt the establishment of a stromal markers for progression [43]. Reinertsen et al. [44] “molecular”stagingsystem,buttheidentificationofgenetic showed that prostate fibroblast primaryculturesfrom areas markers that predict aggressive disease has not yet been withcancerandhyperplasiawithPC-3cellsseemtomakethe clinicallydemonstrated[28–33]. cancerousandhyperplasticfibroblastsmorelikeeachother, Molecular associations with prostate cancer phenotypes asthenumberofdifferentiallyexpressedgenesdecreases. continue to be fragmentary and, in some cases, have been Thecellsoftheimmunesystemthatarecommonlyfound − + poorlysubstantiatedbyfollow-upinvestigations.Histopatho- infiltratingprostatecancerincludeIL 17 macrophages[45, logical examination reveals that, like other solid tumors, 46],neutrophils[47],mastcells[48],naturalkillercells[49], prostatecancerisassociatedwithdiverseimmunecellinfil- andcellsassociatedwithanadaptiveimmuneresponse,that tratesandthat,inthecancercontext,epithelialcellscoexist is, T- and B-lymphocytes (Figure2) [50–54]. Although it is withextracellularmatrixcomponentsandnonneoplasticcell commonly thought that an immune response localized to types,includingfibroblastsandendothelialcells,whichcol- the tumor inhibits cancer growth, it is now clear that some lectivelyformthetumorstroma(Figure2)[34–36]. Several types of tumor-associated inflammation may also exert an lines of evidence support the concept that tumor stromal opposite action, at least at some point of prostate cancer cells are not merely a scaffold, but rather they influence naturalhistory[55].Here,wereviewtheinnateandadaptive growth, survival, and invasiveness of cancer cells, dynami- immune systems and their senescent remodeling in elderly callycontributingtothetumormicroenvironment,together menwithprostatecancer. with immune cells [35, 37–40]. It is known that interac- tions between epithelium and the surrounding stroma are 2.TheProstateCancerintheElderly required to maintain organ function and that these inter- actions provide proliferative and migratory restraints that Prostatecancer,whichismostoftendiagnosedinmenover define anatomical and positional information, mediated by the age of 65 years, still remains one of the most common severalgrowthfactorsandextracellularmatrixcomponents humancancers[11].Treatmentoptionsvarydependingonthe [41]. When cancer develops, transformed cells lose these stageandgradeofthecancer,aswellaspatientcomorbidity constraints while stroma adapts and coevolves to support and age. More than one-half of men aged younger than the “function” of the tumor [35]. The prostate represents 65 years are treated with radical prostatectomy [1]. Those an example of organ that relies on its surrounding stroma aged 65 years to 74 years commonly undergo radiation duringnormaldevelopmentandcancerprogression[35].Jia therapy (nearly, 40%). Data show similar survival rates for et al. [42] compared Affymetrix gene expression profiles in patientswithearlystagediseasewhoaretreatedwitheither stromaneartumorandidentifiedaset of115probesetsfor ofthesemethods.Activesurveillanceratherthanimmediate whichtheexpressionlevelsweresignificantlycorrelatedwith treatmentisacommonlyrecommendedapproach,especially time-to-relapse.Theauthorscomparedpatientsthatrelapsed foroldermenandthosewithlessaggressivetumorsand/or CurrentGerontologyandGeriatricsResearch 3 Innate immune cells Adaptive immune cells Fibroblasts Myofibroblasts Natural Prostate prostate Endothelial cells cancer tissue Adipocytes Pericytes Epithelial cells Extracellular matrix Cytokines-chemokines Time (t) Figure2:Histopathologicalexaminationrevealsthatprostatecancerisassociatedwithdiverseimmunecellinfiltratesandthat,inthecancer context,epithelialcellscoexistwithextracellularmatrixcomponentsandnonneoplasticcelltypes,includingfibroblastsandendothelialcells, whichcollectivelyformthetumourstroma.Evidencesupportstheconceptthattumourstromalcellsarenotmerelyascaffold,butratherthey influencegrowth,survival,andinvasivenessofcancercells,dynamicallycontributingtothetumourmicroenvironment.Theinteractions betweenepitheliumandthesurroundingstromaarerequiredtomaintainorganfunctionandprovideproliferativeandmigratoryrestraints that define anatomical and positional information, mediated by several growth factors, cytokines, chemokines, and extracellular matrix components.Whencancerdevelops,transformedcellslosetheseconstraintswhilestromaadaptsandcoevolvestosupportthe“function”of thetumour. moreseriouscomorbidconditions[1,56–59].Itisknownthat contributetoincreasedmorbidityandmortality.Ithasbeen overdiagnosisandovertreatmentarefrequentintheelderly ascertained that bidirectional interrelations of both sys- men.Competingmortalityrisksofmenolderthan75years tems are present in the young and in the elderly; that is, maysupersedetheriskofdyingfromprostatecancerseveral endocrinosenescence modulates the immune system and fold[10]. immunosenescence changes the endocrine system. Terms Itisnowacceptedthatagingisassociatedwithanincrease suchasalteration,deterioration,anddeclinedonotaccount in a wide range of age-related diseases, including cardio- for the complexity of immunosenescence [69]. Hence, the vascular dysfunction, metabolic disorders, neurodegenera- more appropriate term of “senescent immune remodeling” tion, and cancer [60]. Even in the absence of identifiable hasbeenproposed[70].Itisknownthatchronicinflamma- disease, the physiology of organs, tissues, and cells declines tion might contribute to general aging in several ways. The throughoutlife.Withinatissue,bothdifferentiatedcellsand perpetual presence of circulating proinflammatory factors adult stem cells are susceptible to intrinsic and extrinsic maykeeptheimmunesysteminastateof“chroniclow-level changesduringaging[61–64].Inadditiontothesedamages, activation.”Thischronicimmuneactivationmightdetermine cellularagingisalsoinfluencedbytheexposuretoextrinsic immunosenescence, caused primarily by an exhaustion of factors, including inflammatory cytokines [65–67]. It has the pool of na¨ıve T-cells, clonal expansion among T- and been accepted that mammalian aging is associated with B-lymphocytes,andtheconsequentshrinkageof“immuno- molecular, cellular, and physiological changes characterized logicalspace”;together,thesephenomenareducethebody’s by a deteriorating homeostatic balance associated with the ability to respond to new antigens [71, 72]. In addition to increasing prevalence of neoplasia and other chronic dis- causing immunosenescence, some proinflammatory factors eases [68]. Although the correlation between inflammatory (i.e., matrix metalloproteinase-3 (MMP-3)) may degrade pathwaysandagingisnowestablished,itremainsdifficultto the tissue microenvironment [73]. Several cytokines pro- demonstrateacausalconnection[65].Severaltheorieshave ducedbysenescentcells,includinginterleukin-6(IL-6)and beenproposedtodefinetheroleofchronicinflammationin interleukin-8(IL-8),areknownasattractorsandactivatorsof aging.Theyincludetheredoxstress,mitochondrialdamage, innateimmunecells,whichcandestroytissueenvironments immunosenescence, endocrinosenescence, epigenetic mod- by virtue of the oxidizing molecules they release [74]. It is ifications, and age-related diseases. Immunosenescence, a nowascertainedthatimmunosenescenceleadstoincreased stateofgradualdeteriorationoftheimmunesystembrought incidence of infectious diseases morbidity and mortality as on by natural aging, is felt to be a significant contributor wellasheightenedratesofotherimmunedisorderssuchas to this increased risk. Careful analyses of healthy people autoimmunity,cancer,andinflammatoryconditions[75]. ranginginagefromneonatestocentenarianssuggestthata Itisknownthat,afterpeakreproductiveage,thehistology complexandcontinuousremodelingoftheimmunesystem of the prostate begins to undergo age-related changes that occurs with age. In particular, deterioration of the immune continue throughout life. Additionally, it has been shown systemandtheendocrinesystemduringagingisthoughtto that the size of the prostate typically increases throughout 4 CurrentGerontologyandGeriatricsResearch a man’s lifetime and that different growth characteristics in increasedriskofaggressiveprostatecanceramongoldermen eachprostatezonemaycontributetodifferencesintheoverall andthatappropriateclinicaltrialsarecompulsorytodefine growthratewithage[76].Turkbeyetal.haverecentlyshown theroleoftestosteroneinthedevelopmentofprostatecancer that magnetic resonance imaging is able to document age- and insure the safety of testosterone-replacement therapy related changes in prostate zonal volumes [77]. Although [83]. key mechanisms are not yet completely understood, these changesmightbeattributedtoalteredandrogenactionand inflammatory processes that lead to either an unabated 3.TheInnateImmunityandProstateCancer trophiceffectontheglandand/orachronicinflammation.It ispossiblethatrepeatedepithelialinsultsustainedthrough- It has been widely demonstrated that the innate immune out the aging process results in a change of biology from systemisthefirstlineofdefenseagainstinfections.Although oneofdifferentiatedreproductivefunctiontooneofchronic itisgenerallyacceptedthatsomeaspectsofinnateimmunity woundrepair.Dasetal.[78]haveinvestigatedaging-related are well preserved in aging, several lines of evidence in changes in important cellular pathways, by systematically the last decade support the notion that immunosenescence determiningtheeffectsofgrowthanddevelopmentandaging affectsnotonlyadaptiveimmunitybutalsoinnateimmunity. on proteomic profiles in different lobes of the rat prostate. Aside from T- and B-lymphocytes, innate immune cells They found that proteins modulated during growth and orchestrateaninflammatoryenvironmentthatmayfunction developmentinthedorsolateral(DL)andventral(VL)lobes to either stimulate or inhibit cancer growth. Various innate areinvolvedinavarietyofbiologicalprocessesincludingcell immunitycellshavebeenimplicatedinprostatecanceronset, development,whereasproteinsmodulatedduringagingwere progression,andmetastasis.Amongthese,macrophagesare predominantlyrelatedtoantioxidantactivityandimmunity a primary source of secreted proinflammatory cytokines [78].Interestingly,theimportanceoftheGolgiapparatusin and are generally distinguished as type 1 (M1) or type cellular activities as a stress sensor, apoptosis trigger, lipid/ 2 (M2) [84, 85]. M1s generally have an interleukin (IL) protein modifier, mitotic checkpoint, and a mediator of 12lowIL-10highphenotype,showimpairedexpressionofreac- prostatemalignanttransformationhasbeenhighlighted[79]. tive nitrogen intermediates and poor antigen presentation, Richieetal.[80]comparedthelevelsofselenium,glutathione, andhavetumoricidalcapacity,whiletheyshowhighexpres- andprotein-boundglutathione(GSSP)inbloodandprostate sion of angiogenic factors (including vascular-endothelial tissues in young (4 months), mature (12 months), old (18 growthfactor(VEGF),epidermal-growthfactor(EGF),and months), and very old (24 months) male F344 rats. They semaphorin 4D), MMPs, and cathepsins as well as of the found that, after 12 months, an 85% reduction in selenium growth arrest-specific protein GAS6 [86–88]. Additionally, in the DL was observed, while levels in other lobes were M1 can support T-helper 1 (Th1) adaptive immunity [89]. unchanged.Inanimalsofallages,levelsofglutathionewere Conversely, M2s secrete immunosuppressive cytokines and thelowestintheVLthanintheDLandnosignificantchanges promote tumor growth [90]. It has been shown that cancer wereobservedinglutathionelevelsby18months.However, cells shape their interaction with macrophages by escaping GSSP,amarkerofoxidativestress,wasincreased90%after18 phagocytosis and by promoting an M2-like polarization monthsintheDLonly.Thesefindingsofage-relatedchanges throughout chemokines and polarizing cytokines including inGSSPandseleniumintheDLprostateareconsistentwith chemokine ligand 2 (CCL2), colony stimulating factor 1 the sensitivity of this lobe to carcinogenesis and, thus, may (CSF1), macrophage slowing factor (MSF), tumor necrosis be playing a mechanistic role. It is known that androgens factor-alpha(TNF-𝛼),IL-10,andtransforminggrowthfactor- areinvolvedineveryaspectofprostateembryogenesis,and beta (TGF-𝛽). Among the cells with M2 phenotype, the inagingmenwithprostatichyperplasia.Likewise,androgen tumor-associatedmacrophages(TAMs)havebeenshownto deprivationatanyphaseoflifecausesadecreaseinprostate becapableofsecretingproteasesthatenhanceinvasionand cell number and DNA content. The downstream control metastases,togetherwitharangeofcytokinesinhibitingan mechanisms by which hormonal signals are translated into adaptive tumor-specific immune response, and angiogenic differentiation, growth, and prostate function in elderly factors that increase neovascularity. It has been ascertained men are still unraveled [81, 82]. While many studies have that phagocytosis is also unimpaired in the elderly [91]. exploredtherelationshipbetweenprostatecancerandserum Although macrophages are usually found located around androgens, the association remains ill-defined and clinical necrotic areas of tumor and the advancing tumor margin, implications are difficult to recognize. Age remains one of theirroleinprostatecancerstillremainscontroversial.While the main factors that complicate the interaction between it was originally thought that the main function of TAMs prostate malignancy and serum hormone levels, mainly as was direct cytotoxic effects on tumoral cells, phagocytosis testosterone levels begin to decrease in the ageing man apoptotic/necroticcelldebris,andpresenttumor-associated coincidentally as the incidence of prostate cancer starts to antigens to T-lymphocytes, current evidence suggests that increase.Pierorazioetal.evaluatedtherelationshipbetween inflammation and TAMs can also promote tumor growth testosteronelevelsandthedevelopmentofhigh-riskprostate and metastasis. The density, size, and location of tumor cancerandfoundthathigherlevelsofserumfreetestosterone infiltratingmacrophagesinprostatecancerhavebeenshowed are associated with an increased risk of aggressive prostate as powerful predictors of patient outcome, and prostate cancer among older men [83]. They concluded that higher cancer specimens’ harbor increased positive cells express- levels of serum free testosterone are associated with an ing the macrophage specific marker CD68 compared to CurrentGerontologyandGeriatricsResearch 5 benign glands [92–94]. Additionally, it was demonstrated BPH, and prostatic cancer [103]. It has been observed that that expression of macrophage colony-stimulating factor PIA lesions are associated with chronic inflammation of (M-CSF)anditsreceptorcolony-stimulatingfactor-1recep- the prostate, and histological transitions have been noted tor (CSF-1R) are increased in primary tumors of patients betweenareasofPIAandhigh-gradeprostateintraepithelial exhibiting metastatic disease [95]. Shirotake et al. showed neoplasia (HGPIN) and between PIA and prostate cancer that both high monocyte chemoattractant protein-1 (MCP- [104].Theinflammatoryinfiltratesaremainlyrepresentedby + + 1) expression and high macrophage infiltration in prostate CD3 T-lymphocytes (70–80%, mostly CD4 lymphocytes) + + cancer specimens correlate with a high prostate-specific andCD19 orCD20 B-lymphocytes(nearly,10–15%)[105]. antigen(PSA)recurrencerateandthatAT1Rblockade(ARB) In the normal prostate, the infiltrates around the periglan- inhibits MCP-1 expression through the PI3K/Akt pathway dular area are mainly composed of T-lymphocytes (70% + and blocks macrophage infiltration in castration-resistant CD8 cells), while lymphoid aggregates are located in the prostatecancer[96].Nonomuraetal.[97]foundthatTAM fibromuscular stroma. These aggregates, mainly consisting infiltration was significantly correlated with serum PSA of B-lymphocytes follicles surrounded by parafollicular T- + level, Gleason score, and clinical stage. Shimura et al. [98] lymphocytes with CD4 cells, are two times more frequent + demonstratedtheassociationbetweenTAMinfiltrationand than CD8 cells. In the adult prostate, a different inflam- disease-free survival after radical prostatectomy. They also matory infiltrate pattern has been described in relation examinedtheassociationbetweenTAMinfiltrationandthe to the type and extension of inflammation. Robert et al. rateofdetectionofprostatecanceratarepeatbiopsyofthe [106] showed that, in 282 patients with BPH, there was an prostate in patients in whom the first biopsy was negative. inflammatory infiltrate constituted by T-lymphocytes (i.e., + They found no difference in TAM count between the cases CD3 cells) in the 80% of cases associated with 52% of + withorwithoutprostatecancer.Bycontrast,themacrophage antigen-presenting cells, including B-lymphocytes (CD20 scavengerreceptor-(MSR-)positiveinflammatorycellscount cells).Incontrast,asignificantdecreaseinthecountsofthese in patients with cancer was significantly lower than that in cellswasobservedinhigh-gradeprostaticcancercompared + patientswithoutcancerattherepeatbiopsy.Logisticregres- toBPH[105].TheincreaseddensityofCD3 T-lymphocytes sion analysis indicated that the MSR count at first biopsy inBPHsuggeststhattheinitialresponsetocellulardamageis is a significantly better predictive factor for positive repeat mediatedbycell-mediatedimmunity.Thedecreaseddensity biopsy than PSA velocity, interval between first and repeat of immune cells in high-grade prostatic cancer may reflect biopsies,orTAMcount.DecreasedinfiltrationofMSR-posi- immunosuppression. Recently, Fujii et al. found no signifi- tive inflammatory cells in negative first biopsy specimens cant difference in the number of infiltrating T-lymphocytes was correlated with positive findings in the repeat biopsy. betweenbenignandmalignanttumors;however,thenumber MSRcounthasbeen,therefore,proposedasavalidindexto of infiltrating B-lymphocytes was significantly reduced in avoidunnecessaryrepeatbiopsies[97].Gollapudietal.[99] malignantglands[107]. haverecentlyshownthatmeanTAMnumberwashigherin cancercoresversusprostaticintraepithelialneoplasia(PIN) and benign tissue and higher in high-grade prostate cancer 5.TheAntigen-PresentingMachineryin supporting the potential role of TAMs in prostate cancer ProstateCancer development.Inastudycomprising38prostatecancers,the + presence of CD1a Langerhans cells was associated mainly DefectsinHLAclassIantigen-processingmachinery(APM) with low-grade prostate carcinoma. Liu et al. [54] found a component expression often have a negative impact on the + significantcorrelationbetween lownumbersofCD1a cells clinicalcourseoftumorsandontheresponsetoT-cell-based and a high Gleason score and pathological stage pT3. The immunotherapy [108]. Aged neutrophils are also less able + numbers of CD1a cells were, however, very low in normal to respond to rescue from apoptosis, while aged dendritic andbenignprostatetissues[54].Otherstudieshave,however, cells (DCs) are less able to stimulate T- and B-lymphocytes demonstrated variable evidence for TAMs during prostate [109]. The altered T-lymphocyte stimulation is a result of cancerprogression. changesinhumanleukocyteantigenexpressionandcytokine production, and lower B-lymphocyte stimulation is a result of changes in DCs immune complex binding [109]. It is 4.TheAdaptiveImmunityinProstateCancer known that DCs are the most potent, professional antigen- presentingcellsoftheimmunesystem[110].Withtheirability Ageing is accompanied by alterations to T-lymphocyte tointeractwithB-andT-lymphocytesandtheirwidespread immunityandalsobyalow-gradechronicinflammatorystate localization, they are a pivotal component of the innate termed“inflammaging.”Immunecellinfiltrateisaconstant immunesystem.Therecentlydescribedpositiveoutcomeof featureinnormalprostate,BPH,andprostaticcancer[100]. aclinicaltrialwithT-lymphocyte-basedimmunotherapyin IthasbeenstatedthattheagedT-cellresponseischaracter- prostatecancerhasstimulatedinterestinthecharacterization izedbyincreasedproductionofproinflammatorycytokines, oftheAPMcomponentexpressioninprostatecancerlesions, which could significantly contribute to prostate carcino- sincethis“machinery”playsacrucialroleinthegeneration genesis through induction of key inflammation-mediated and expression of the trimeric HLA class I surface antigen prosurvivalfactors[101,102].Husseinetal.investigatedthe complex on tumor cells. Immunohistochemical staining of cells of the immune system present in normal prostate, a tissue microarray including 59 primary prostate cancers 6 CurrentGerontologyandGeriatricsResearch lesions and matched normal tissues has shown downregu- in prostate cancer, which will potentially be developed as lation of all the HLA class I APM components analyzed, a biomarker in prostate cancer. They also provide evidence although with a different frequency in tumor lesions when thatAKAP-4isapotentialtargetforprostatecanceradoptive comparedtonormalprostatetissues[108].Aprimaryfinding immunotherapy or antitumor vaccination [117]. Beginning wasthefrequentlossordownregulationofcalnexinand/or in the early 1990s, several tumor-associated antigen genes tapasin, which appears to be an independent prognostic including the cancer-testis antigens were identified that marker of tumor recurrence. In contrast, HLA class I HC exhibited tumor-specific expression. The cancer-testis anti- expression levels were less affected in primary prostate gens are a group of proteins that are typically restricted to cancers;thefrequencyofdownregulationdescribedbyBlades the testis in the normal adult but are aberrantly expressed et al. has been found markedly lower than that reported incancersofunrelatedhistologicorigin[118].Hudolinetal. by other authors [111] in a large number of prostate cancer observedMAGE-A1in10.8%ofcarcinomasamples,whereas lesions and that reported in other tumor types. In contrast, multi-MAGE-A and NY-ESO-1/LAGE-1 stained 85.9% and highfrequenciesoflossordownregulationoflowmolecular 84.8% of samples using immunohistochemistry, suggesting weightpolypeptides2(LMP2),transportersassociatedwith thatapanelofCTantigensratherthanindividualonesmaybe antigen processing 1 (TAP1), and tapasin as well as of 𝛽2- morevaluableasbiomarkers[119].Smithetal.suggestedthat microglobulin were demonstrated in prostate cancer when multiplesynovialsarcomaXchromosomebreakpoint(SSX) comparedtonormalprostatetissue.ThefrequencyofLMP2, proteinsareexpressedinmetastaticprostatecancers,which TAP1,andtapasindownregulationishigherthanthatfound areamenabletosimultaneoustargeting[120]. in lung, colorectal, hepatocellular, cervical, and renal cell Enzalutamide(i.e.,asecond-generationandrogenantag- carcinoma. In parallel to the findings in head and neck onist) has been recently approved for castration-resistant squamous cell carcinoma, cervical carcinoma, esophageal prostate cancer treatment. Ardiani et al. showed that enza- carcinoma, breast carcinoma, and melanoma, the impaired lutamidemediatedimmunogenicmodulationinTRAMP-C2 TAPexpressioninprostatecancerlesionsisassociatedwith cells.Invivo,enzalutamidemediatedreducedgenitourinary tumor grading, staging, and time to recurrence. Qiu et al. tissueweight,enlargementofthethymus,andincreasedlevels foundthat,invitro,theprostatecancercellPC-3infectedwith ofT-cellexcisioncircles.BecausenochangeswereseeninT- + LentivirusTAP1canefficientlyoverexpressTAP1andtapasin, lymphocytesfunction,asdeterminedbyCD4 T-lymphocyte andHLA-1wasalsoupregulatedonthesurfaceoftheinfected proliferation and Treg functional assays, enzalutamide was cells.TheLentivirusTAP1infectionincreasedtheapoptosis determined to be immune inactive [121]. The combination rateofPC-3cells.Inaddition,withthecoculturePC-3cells of enzalutamide and immunotherapy has been, therefore, + andlymphocytes,TAP1augmentedtheexpressionofCD3 suggested as a promising treatment strategy for castration- + + CD8 CD38 cells[112]. resistant prostate cancer. A renewed interest in prostatic acid phosphatase (i.e., a nonspecific phosphomonoesterase synthesized in prostate epithelial cells, whose level pro- 6.ImmunotherapyandProstateCancer portionally increases with prostate cancer progression) has been shown, because of its usefulness in prognosticating The goals of any cancer therapy are to improve disease intermediate to high-risk prostate cancers and its success control,palliatepain,andoverallsurvival[113].In2010,the in the immunotherapy of prostate cancer [122]. Based on American Food and Drug Administration (FDA) approved thegoodprognosticvalueofprostaticacidphosphataseand the first therapeutic cancer vaccine, called sipuleucel-T, for the potential usefulness of prostatic acid phosphatase as an the treatment of castration refractory prostate cancer [114, antigen,animmunotherapyemployingautologousprostatic 115]. Different from the currently adopted chemotherapy acid phosphatase-loaded dendritic cells was initiated [123]. drugs that produce widespread cytotoxicity to kill tumor Wada et al. used a well-described genetically engineered cells, anticancer vaccines and immunotherapies focus on mouse, autochronous prostate cancer model to explore empowering the immune system to overcome the tumor. It the relative sequencing and dosing of anti-cytotoxic T- hasbeenshownthatprostatecancerisanidealmodelforcan- lymphocyte-associated antigen-4 (CTLA-4) antibody when cer vaccine development. This is mainly due to its humoral combinedwithacell-based,granulocytemacrophagecolony- and cellular immunity to a range of cancer antigens, which stimulatingfactor-(GM-CSF-)secretingvaccine[124].These aregoodcandidatesforvaccinetherapytogeneratearobust experiments corroborate recent clinical data, which suggest antitumor response. Recently, Cheema et al. suggested the that the combination of CTLA-4 blockade and cell-based, potential application of BORIS (i.e., a cancer-testis antigen GM-CSF-secretingvaccinesmayhavesignificantantitumor normally present at high levels in the testis and aberrantly effectsinmenwithprostatecancer.Thesedataalsoindicate expressed in various tumors and cancer cell lines) as a that the “therapeutic window” of such an approach may biomarkerforprostatecancerdiagnosis,animmunotherapy be maximized through meticulous study of various dosing target, and, potentially, a prognostic marker of aggressive regimens.Additionally,futureclinicalstudiesmayfindthat prostate cancer [116]. The ability of BORIS to activate the theadditionofcyclophosphamidetothistreatmentstrategy androgen receptor gene suggests its involvement in the allowsforreductioninthedoseofanti-CTLA-4,potentially growth and development of prostate cancer [116]. Chiriva- limitingautoimmunetoxicity.InarecentphaseItrial,Perez Internati et al. first reported the aberrant expression of the etal.demonstratedthattheAE37vaccineissafeandinduces cancer-testis antigen A-kinase anchor protein-4 (AKAP-4) HER-2/neu-specificimmunityinaheterogeneouspopulation CurrentGerontologyandGeriatricsResearch 7 + of HER-2/neu prostate cancer patients [125]. Clusterin is etal.showedasignificantincreaseininfiltratinginflamma- a cytoprotective chaperone protein that is overexpressed torycellsincludingmacrophagesintheprostatesofagedmice in many tumor types and is upregulated in response to [38], reflecting the prominent role for immune cells during cellular stress caused by cancer treatments, including hor- theagingprocess,whichislinkedtoprostatecancerdevelop- monalmanipulation,radiation,andchemotherapy.Custirsen ment.Identifyingcontributingfactorsinthetumormicroen- is known as a second-generation antisense oligonucleotide vironment, which modulate this cleavage event on tumor that is complementary to clusterin mRNA and potently cells, is necessary for determining alternative therapeutic suppresses clusterin expression in preclinical models of targetsforamultimodalityapproachtoinhibittheinvasion prostate cancer as well as in clinical trials. The innova- stepsofmetastasis.Despitethetechnicaladvantagesoffered tive first-in-human phase I neoadjuvant trial demonstrated byroboticsystemsandothertechniques,thediagnosticpro- dose-dependent plasma and prostate tissue concentrations cessrequiresfurtherimprovement.Itisknownthatprostate of custirsen, which was well tolerated at all dose levels cancerconsistsofdistinctsubpopulationsofcancercells,each [126]. Results from the clinical trials (i.e., sipuleucel-T- withitsowncharacteristicsensitivitytoagiventherapeutic based vaccine, GVAX-prostate cancer, viral prostate cancer agent.Cancertherapiescanbeseenasfiltersthatremovethe vaccines,DNA-basedvaccines,andgene-mediatedcytotoxic sensitivesubpopulationsbutallowinsensitivesubpopulations immunotherapy) indicate that prostate cancer vaccines are to escape. The combined efforts of urologists, pathologists, generally safe and, encouragingly, capable of generating gerontologists, and biologists can contribute much towards tumor-specific T-lymphocyte responses. It is becoming evi- improving our understanding of the complexity of prostate dent that prostate cancer patients with early-stage disease cancer, and such a multidisciplinary approach will help to maybethosewhoobtainthemainbenefitsfromvaccines. clarifyexistingconcepts,categorizecurrentknowledge,and suggestalternativeapproachestothediscoveryofbiomarkers andpredictivevaluesthaturgentlyneedtobetranslatedinto 7.ConcludingRemarks clinicalpractice. The primary risk for prostate cancer is aging, often associ- ConflictofInterests ated with inflammation (Figure2). Inflammation results in a tissue microenvironment that alters the normal prostate The authors declare that there is no conflict of interests epithelialcelldifferentiationprogramandthatacceleratesthe regardingthepublicationofthispaper. initiation of prostate cancer with a basal cell origin [127]. Despite the continuous progress, prostate cancer is one of Authors’Contribution themaincancersthataffectmen,especiallyoldermen.This is largely due to the fact that the tumoral mass cannot be GianluigiTavernaandFabioGrizzicontributedequallytothe identifiedusingcurrentimagingtechniques.Prostatecancer paper. can only be diagnosed on the basis of increased PSA levels associatedwithalowaccuracyofthebiopsyfragmentsand References thewell-knownsubjectivityofapathologist’sinterpretation. Thishasledtomanypatientsbeingovertreated,undertreated, [1] R.Siegel,C.DeSantis,K.Virgoetal.,“Cancertreatmentand orsimplyinappropriatelytreatedandallowedtheprogression survivorshipstatistics,”CA.ACancerJournalforClinicians,vol. ofthedisease.Prostatecancerintheagingmalewillbecome 62,no.4,pp.220–241,2012. anincreasinglyimportantandcontroversialhealthcareissue. [2] M.F.LeitzmannandS.Rohrmann,“Riskfactorsfortheonset Because the median age of diagnosis for men with prostate of prostatic cancer: age, location, and behavioral correlates,” cancer is greater than 75 years, prostate cancer can be ClinicalEpidemiology,vol.4,no.1,pp.1–11,2012. considered a disease of the elderly. The aging population [3] T. Daly, B. E. Hickey, M. Lehman, D. P. Francis, and A. M. andloweringPSAthresholdto2.6ng/mLwillhavethemost See,“Adjuvantradiotherapyfollowingradicalprostatectomyfor significantimpactonestimatednewprostatecancercasesin prostatecancer,”CochraneDatabaseofSystematicReviews,no. 2021[128].Severaldisease-specificfactors(i.e.,stage,tumor 12,ArticleIDCD007234,2011. grade, and PSA level) and patient-specific factors (i.e., age, [4] D. J. Moskovic, B. J. Miles, L. I. Lipshultz, and M. Khera, “Emergingconceptsinerectilepreservationfollowingradical comorbidity, and functional status) need to be considered prostatectomy:aguideforclinicians,”InternationalJournalof in the decision-making process [129]. Rice et al. evaluated ImpotenceResearch,vol.23,no.5,pp.181–192,2011. the outcomes between a variety of treatments for low-risk [5] N.Lawrentschuk,G.Trottier,C.Kuk,andA.R.Zlotta,“Role prostate cancer in patients of 70 years of age and older of surgery in high-risk localized prostate cancer,” Current [130].Theyfoundthatpatientsmanagedonwatchfulwaiting Oncology,vol.17,supplement2,pp.S25–S32,2010. withoutsecondarytreatmenthadthepoorestoverallsurvival [6] H.MiyakeandM.Fujisawa,“Prognosticpredictionfollowing andthatwatchfulwaitingwithoutsecondarytreatmentrep- radicalprostatectomyforprostatecancerusingconventionalas resentsastatisticallysignificantpredictorofoverallmortality wellasmolecularbiologicalapproaches,”InternationalJournal [130]. Specific to prostate cancer, it has been identified that ofUrology,vol.20,no.3,pp.301–311,2012. macrophageinteractionswithtumorcellspromoteandrogen [7] N.Lumen,V.Fonteyne,G.deMeerleeretal.,“Screeningand resistance and increased prostate cancer invasion through early diagnosis of prostate cancer: an update,” Acta Clinica tissuefactorexpression[12,37].InvivostudiesbyParrinello Belgica,vol.67,no.4,pp.270–275,2012. 8 CurrentGerontologyandGeriatricsResearch [8] S.Carlsson,A.J.Vickers,M.Rooboletal.,“Prostatecancerscr- [25] T.J.Wilt,M.K.Brawer,K.M.Jonesetal.,“Radicalprostatec- eening: facts, statistics, and interpretation in response to the tomyversusobservationforlocalizedprostatecancer,”TheNew USPreventiveServicesTaskForceReview,”JournalofClinical EnglandJournalofMedicine,vol.367,no.3,pp.203–213,2012. Oncology,vol.30,no.21,pp.2581–2584,2012. [26] C. E. Barbieri, F. Demichelis, and M. A. Rubin, “Molecular [9] M.F.EylertandR.Persad,“Managementofprostatecancer,” genetics of prostate cancer: emerging appreciation of genetic BritishJournalof Hospital Medicine,vol.73,no.2,pp.95–99, complexity,”Histopathology,vol.60,no.1,pp.187–198,2012. 2012. [27] L.Cheng,R.Montironi,D.G.Bostwick,A.Lopez-Beltran,and [10] M.SpahnandK.Haeni,“Approachtoprostatecancerinmen D.M.Berney,“Stagingofprostatecancer,”Histopathology,vol. olderthan75years:activeorpassive?”UrologeA,vol.51,no.10, 60,no.1,pp.87–117,2012. pp.1368–1374,2012. [28] J. Luo, N. L. Solimini, and S. J. Elledge, “Principles of cancer therapy:oncogeneandnon-oncogeneaddiction,”Cell,vol.136, [11] E.R.KesslerandT.W.Flaig,“Optimalmanagementofrecurrent no.5,pp.823–837,2009. prostatecancerinolderpatients,”DrugsAging,vol.29,no.11,pp. [29] J.Sun,A.Turner,J.Xu,H.Gro¨nberg,andW.Isaacs,“Genetic 871–883,2012. variabilityininflammationpathwaysandprostatecancerrisk,” [12] G.Albrand,N.Mottet,A.Ruffionetal.,“Prostatecancerineld- UrologicOncology:SeminarsandOriginalInvestigations,vol.25, erlysubjects:howdiagnosisshouldbemade,whyandhowgeri- no.3,pp.250–259,2007. atricassessmentshouldbeimplemented,”Progre`senUrologie, [30] A. Foye and P. G. Febbo, “Cancer gene profiling in prostate vol.22,supplement2,pp.S55–S63,2012. cancer,” Methods in Molecular Biology, vol. 576, pp. 293–326, [13] C.H.Lee,O.Akin-Olugbade,andA.Kirschenbaum,“Overview 2010. of prostate anatomy, histology, and pathology,” Endocrinology [31] C. Golias, A. Charalabopoulos, D. Stagikas et al., “Molecular andMetabolismClinicsofNorthAmerica,vol.40,no.3,pp.565– profilingandgenomicmicroarraysinprostatecancer,”Exper- 575,2011. imentalOncology,vol.29,no.2,pp.82–84,2007. [14] D. D. Orsted and S. E. Bojesen, “The link between benign [32] N.Konishi,K.Shimada,E.Ishida,andM.Nakamura,“Molec- prostatic hyperplasia and prostate cancer,” Nature Reviews ularpathologyofprostatecancer,”PathologyInternational,vol. Urology,vol.10,no.1,pp.49–54,2012. 55,no.9,pp.531–539,2005. [15] A.C.Mackinnon,B.C.Yan,L.J.Joseph,andH.A.Al-Ahmadie, [33] M.A.Reynolds,“Molecularalterationsinprostatecancer,”Can- “Molecular biology underlying the clinical heterogeneity of cerLetters,vol.271,no.1,pp.13–24,2008. prostatecancer:anupdate,”ArchivesofPathologyandLabora- [34] C.Yates,“Prostatetumorcellplasticity:aconsequenceofthe toryMedicine,vol.133,no.7,pp.1033–1040,2009. microenvironment,” Advances in Experimental Medicine and [16] W.Liu,S.Laitinen,S.Khanetal.,“Copynumberanalysisindi- Biology,vol.720,pp.81–90,2011. cates monoclonal origin of lethal metastatic prostate cancer,” [35] O.E.FrancoandS.W.Hayward,“Targetingthetumorstroma NatureMedicine,vol.15,no.5,pp.559–565,2009. asanoveltherapeuticapproachforprostatecancer,”Advances [17] A. M. Aschelter, S. Giacinti, P. Caporello, and P. Marchetti, inPharmacology,vol.65,pp.267–313,2012. “Genomicandepigenomicalterationsinprostatecancer,”Fron- [36] D.A.BarronandD.R.Rowley,“Thereactivestromamicroen- tiersinEndocrinology,vol.3,article128,2012. vironmentandprostatecancerprogression,”Endocrine-Related [18] I.N.Holcomb,J.M.Young,I.M.Colemanetal.,“Comparative Cancer,vol.19,no.6,pp.R187–R204,2012. analyses of chromosome alterations in soft-tissue metastases [37] F. Iacopino, C. Angelucci, and G. Sica, “Interactions between within and across patients with castration-resistant prostate normalhumanfibroblastsandhumanprostatecancercellsina cancer,”CancerResearch,vol.69,no.19,pp.7793–7802,2009. co-culturesystem,”AnticancerResearch,vol.32,no.5,pp.1579– 1588,2012. [19] S.A.Tomlins,D.R.Rhodes,S.Perneretal.,“Recurrentfusion [38] S.Parrinello,J.Coppe,A.Krtolica,andJ.Campisi,“Stromal- of TMPRSS2 and ETS transcription factor genes in prostate epithelialinteractionsinagingandcancer:senescentfibroblasts cancer,”Science,vol.310,no.5748,pp.644–648,2005. alterepithelialcelldifferentiation,”JournalofCellScience,vol. [20] H.Nakagawa,S.Akamatsu,R.Takata,A.Takahashi,M.Kubo, 118,part3,pp.485–496,2005. andY.Nakamura,“Prostatecancergenomics,biology,andrisk [39] A.S.GoldsteinandO.N.Witte,“Doesthemicroenvironment assessmentthroughgenome-wideassociationstudies,”Cancer influencethecelltypesoforiginforprostatecancer?”Genesand Science,vol.103,no.4,pp.607–613,2012. Development,vol.27,no.14,pp.1539–1544,2013. [21] L.H.Cazares,R.R.Drake,A.Esquela-Kirscher,R.S.Lance,O. [40] M. Gharaee-Kermani, S. Kasina, B. B. Moore, D. Thomas, R. J.Semmes,andD.A.Troyer,“Molecularpathologyofprostate Mehra, and J. A. Macoska, “CXC-type chemokines promote cancer,”CancerBiomarkers,vol.9,no.1–6,pp.441–459,2010. myofibroblast phenoconversion and prostatic fibrosis,” PLoS [22] L.vanNeste,J.G.Herman,G.Otto,J.W.Bigley,J.I.Epstein,and ONE,vol.7,no.11,ArticleIDe49278,2012. W.vanCriekinge,“Theepigeneticpromiseforprostatecancer [41] E. Singer, J. Linehan, G. Babilonia et al., “Stromal response diagnosis,”TheProstate,vol.72,no.11,pp.1248–1261,2012. to prostate cancer: nanotechnology-based detection of thior- [23] R. Chen, S. Ren, T. Meng, J. Aguilar, and Y. Sun, “Impact of edoxin-interactingproteinpartnersdistinguishesprostatecan- glutathione-S-transferases (GST) polymorphisms and hyper- cerassociatedstromafromthatofbenignprostatichyperplasia,” methylation of relevant genes on risk of prostate cancer bio- PLoSONE,vol.8,no.6,ArticleIDe60562,2013. chemicalrecurrence:ameta-analysis,”PLoSONE,vol.8,no.9, [42] Z.Jia,F.B.Rahmatpanah,X.Chenetal.,“Expressionchangesin ArticleIDe74775,2013. thestromaofprostatecancerpredictsubsequentrelapse,”PLoS [24] L.Richiardi,V.Fiano,C.Grassoetal.,“MethylationofAPCand ONE,vol.7,no.8,ArticleIDe41371,2012. GSTP1innon-neoplastictissueadjacenttoprostatetumourand [43] Z.Jia,Y.Wang,A.Sawyersetal.,“Diagnosisofprostatecancer mortalityfromprostateCcncer,”PLoSONE,vol.8,no.7,Article usingdifferentiallyexpressedgenesinstroma,”CancerResearch, IDe68162,2013. vol.71,no.7,pp.2476–2487,2011. CurrentGerontologyandGeriatricsResearch 9 [44] T.Reinertsen,J.Halgunset,T.Viset,A.Flatberg,L.L.Haugs- [61] R.C.TaylorandA.Dillin,“Agingasaneventofproteostasis moen,andH.Skogseth,“Geneexpressionalchangesinprostate collapse,”ColdSpringHarborperspectivesinbiology,vol.3,no. fibroblasts fromcancerous tissue,” APMIS,vol.120,no.7, pp. 5,2011. 558–571,2012. [62] T.Nystrom,J.Yang,andM.Molin,“Peroxiredoxins,geronto- [45] E.V.Vykhovanets,G.T.MacLennan,O.V.Vykhovanets,and geneslinkingagingtogenomeinstabilityandcancer,”Genesand S.Gupta,“IL-17expressionbymacrophagesisassociatedwith Development,vol.26,no.18,pp.2001–2008,2012. proliferative inflammatory atrophy lesions in prostate cancer [63] E. Sahin and R. A. Depinho, “Linking functional decline of patients,” International Journal of Clinical and Experimental telomeres,mitochondriaandstemcellsduringageing,”Nature, Pathology,vol.4,no.6,pp.552–565,2011. vol.464,no.7288,pp.520–528,2010. [46] L.Y.Fang,K.Izumi,K.P.Laietal.,“Infiltratingmacrophages [64] A.Y.Seo,A.Joseph,D.Dutta,J.C.Y.Hwang,J.P.Aris,and promote prostate tumorigenesis via modulating androgen C.Leeuwenburgh,“Newinsightsintotheroleofmitochondria receptor-mediated CCL4-STAT3 signaling,” Cancer Research, in aging: mitochondrial dynamics and more,” Journal of Cell vol.73,no.18,pp.5633–5646,2013. Science,vol.123,no.15,pp.2533–2542,2010. [47] K.Okada,M.Kojima,Y.Nayaetal.,“Correlationofhistological [65] A. Freund, A. V. Orjalo, P. Desprez, and J. Campisi, “Inflam- inflammationinneedlebiopsyspecimenswithserumprostate- matorynetworksduringcellularsenescence:causesandconse- specificantigenlevelsinmenwithnegativebiopsyforprostate quences,”TrendsinMolecularMedicine,vol.16,no.5,pp.238– cancer,”Urology,vol.55,no.6,pp.892–898,2000. 246,2010. [48] P. Pittoni and M. P. Colombo, “The dark side of mast cell- [66] R.Benelli,S.Stigliani,S.Minghelli,S.Carlone,andN.Ferrari, targetedtherapyinprostatecancer,”Cancer Research,vol.72, “ImpactofCXCL1overexpressionongrowthandinvasionof no.4,pp.831–835,2012. prostate cancer cell,” The Prostate, vol. 73, no. 9, pp. 941–951, [49] T. L. Frankel, W. Burns, J. Riley et al., “Identification and 2013. + − characterizationofatumorinfiltratingCD56 /CD16 NKcell [67] R.Bonecchi,M.Locati,andA.Mantovani,“Chemokinesand subset with specificity for pancreatic and prostate cancer cell cancer:afatalattraction,”CancerCell,vol.19,no.4,pp.434– lines,”CancerImmunology,Immunotherapy,vol.59,no.12,pp. 435,2011. 1757–1769,2010. [68] D.Bianchi-Frias,F.Vakar-Lopez,I.M.Coleman,S.R.Plymate, [50] O.N.Kryvenko,M.Jankowski,D.A.Chitaleetal.,“Inflamma- M.J.Reed,andP.S.Nelson,“Theeffectsofagingonthemolecu- tionandpreneoplasticlesionsinbenignprostateasriskfactors larandcellularcompositionoftheprostatemicroenvironment,” forprostatecancer,”ModernPathology,vol.25,no.7,pp.1023– PLoSONE,vol.5,no.9,ArticleIDe12501,2010. 1032,2012. [69] R. H. Straub, L. E. Miller, J. Scho¨lmerich, and B. Zietz, [51] K.S.SfanosandA.M.deMarzo,“Prostatecancerandinflam- “Cytokines and hormones as possiblelinks between endocri- mation:theevidence,”Histopathology,vol.60,no.1,pp.199–215, nosenescence and immunosenescence,” Journal of Neuroim- 2012. munology,vol.109,no.1,pp.10–15,2000. [52] A. Flammiger, F. Bayer, A. Cirugeda-Kuhnert et al., “Intratu- [70] P.O.Lang,S.Govind,andR.Aspinall,“ReversingTcellimm- moralTbutnotBlymphocytesarerelatedtoclinicaloutcome unosenescence:why,who,andhow,”Age,vol.35,no.3,pp.609– inprostatecancer,”APMIS,vol.120,no.11,pp.901–908,2012. 620,2012. [53] K.L.McDowell,L.A.Begley,N.Mor-Vaknin,D.M.Markovitz, [71] C.Franceschi,M.Bonafe`,S.Valensinetal.,“Inflamm-aging.An andJ.A.Macoska,“Leukocyticpromotionofprostatecellular evolutionaryperspectiveonimmunosenescence,”Annalsofthe proliferation,”TheProstate,vol.70,no.4,pp.377–389,2010. NewYorkAcademyofSciences,vol.908,pp.244–254,2000. [54] Y. Liu, T. Saeter, L. Vlatkovic et al., “Dendritic and lympho- [72] J. E. McElhaney and R. B. Effros, “Immunosenescence: what cytic cell infiltration in prostate carcinoma,” Histology and does it mean to health outcomes in older adults?” Current Histopathology,vol.28,no.12,pp.1621–1628,2013. OpinioninImmunology,vol.21,no.4,pp.418–424,2009. [55] B.LakshmiNarendra,K.EshvendarReddy,S.Shantikumar,and [73] J.Campisi,“Senescentcells,tumorsuppression,andorganismal S. Ramakrishna, “Immune system: a double-edged sword in aging:goodcitizens,badneighbors,”Cell,vol.120,no.4,pp.513– cancer,”InflammationResearch,vol.62,no.9,pp.823–834,2013. 522,2005. [56] P.C.Albertsen,J.A.Hanley,andJ.Fine,“20-yearoutcomesfol- [74] J.J.GoronzyandC.M.Weyand,“Immuneagingandautoim- lowingconservativemanagementofclinicallylocalizedprostate munity,”CellularandMolecularLifeSciences,vol.69,no.10,pp. cancer,”JournaloftheAmericanMedicalAssociation,vol.293, 1615–1623,2012. no.17,pp.2095–2101,2005. [75] L. Malaguarnera, E. Cristaldi, and M. Malaguarnera, “The [57] G.L.Lu-Yao,P.C.Albertsen,D.F.Mooreetal.,“Outcomesof roleofimmunityinelderlycancer,”CriticalReviewsinOncol- localizedprostatecancerfollowingconservativemanagement,” ogy/Hematology,vol.74,no.1,pp.40–60,2010. JournaloftheAmericanMedicalAssociation,vol.302,no.11,pp. [76] S.J.Zhang,H.N.Qian,Y.Zhaoetal.,“Relationshipbetween 1202–1209,2009. ageandprostatesize,”AsianJournalofAndrology,vol.15,no.1, [58] W.V.ShappleyIII,S.A.Kenfield,J.L.Kasperzyketal.,“Prospec- pp.116–120,2013. tivestudyofdeterminantsandoutcomesofdeferredtreatment [77] B.Turkbey,R.Huang,S.Vourgantietal.,“Age-relatedchanges or watchful waiting among men with prostate cancer in a in prostate zonal volumes as measured by high-resolution nationwidecohort,”JournalofClinicalOncology,vol.27,no.30, magneticresonanceimaging(MRI):across-sectionalstudyin pp.4980–4985,2009. over500patients,”BJUInternational,vol.110,no.11,pp.1642– [59] M. Froehner and M. P. Wirth, “Locally advanced prostate 1647,2012. cancer:optimaltherapyinolderpatients,”DrugsAging,vol.30, [78] A. Das, J. D. Bortner Jr., C. A. Aliaga et al., “Changes in no.12,pp.959–967,2013. proteomic profiles in different prostate lobes of male rats [60] N. S. Jenny, “Inflammation in aging: cause, effect, or both?” throughoutgrowthanddevelopmentandagingstagesofthelife DiscoveryMedicine,vol.13,no.73,pp.451–460,2012. span,”TheProstate,vol.73,no.4,pp.363–375,2012. 10 CurrentGerontologyandGeriatricsResearch [79] T.MigitaandS.Inoue,“ImplicationsoftheGolgiapparatusin [96] S.Shirotake,A.Miyajima,T.Kosakaetal.,“Regulationofmono- prostatecancer,”TheInternationalJournalofBiochemistryand cyte chemoattractant protein-1 through angiotensin II type 1 CellBiology,vol.44,no.11,pp.1872–1876,2012. receptorinprostatecancer,”TheAmericanJournalofPathology, [80] J.P.RichieJr.,A.Das,A.M.Calcagnotto,C.A.Aliaga,andK. vol.180,no.3,pp.1008–1016,2012. El-Bayoumy,“Agerelatedchangesinseleniumandglutathione [97] N.Nonomura,H.Takayama,A.Kawashimaetal.,“Decreased levels in different lobes of the rat prostate,” Experimental infiltrationofmacrophagescavengerreceptor-positivecellsin Gerontology,vol.47,no.3,pp.223–228,2012. initial negative biopsy specimens is correlated with positive repeatbiopsiesoftheprostate,”CancerScience,vol.101,no.6, [81] J.D.Wilson,“Thecriticalroleofandrogensinprostatedevelop- pp.1570–1573,2010. ment,”EndocrinologyandMetabolismClinicsofNorthAmerica, vol.40,no.3,pp.577–590,2011. [98] S.Shimura,G.Yang,S.Ebara,T.M.Wheeler,A.Frolov,andT.C. Thompson, “Reduced infiltration of tumor-associated macro- [82] F. Montico, A. C. Hetzl, E. M. Caˆndido, W. J. Fa´varo, and V. phages in human prostate cancer: association with cancer H.A.Cagnon,“Hormonaltherapyinthesenescence:prostatic progression,” Cancer Research, vol. 60, no. 20, pp. 5857–5861, microenvironmentstructureandadhesionmolecules,”Micron, 2000. vol.42,no.6,pp.642–655,2011. [99] K.Gollapudi,C.Galet,T.Groganetal.,“Associationbetween [83] P. M. Pierorazio, L. Ferrucci, A. Kettermann, D. L. Longo, E. tumor-associatedmacrophageinfiltration,highgradeprostate J. Metter, and H. B. Carter, “Serum testosterone is associated cancer,andbiochemicalrecurrenceafterradicalprostatectomy,” withaggressiveprostatecancerinoldermen:resultsfromthe AmericanJournalofCancerResearch,vol.3,no.5,pp.523–529, BaltimoreLongitudinalStudyofAging,”BJUInternational,vol. 2013. 105,no.6,pp.824–829,2010. [100] A.M.deMarzo,E.A.Platz,S.Sutcliffeetal.,“Inflammation [84] T.A.Wynn,A.Chawla,andJ.W.Pollard,“Macrophagebiology inprostatecarcinogenesis,”NatureReviewsCancer,vol.7,no.4, indevelopment,homeostasisanddisease,”Nature,vol.496,no. pp.256–269,2007. 7446,pp.445–455,2013. [101] A. F. Olumi, “Commentary on, “Age-related alterations in T- [85] S.K.Biswas,P.Allavena,andA.Mantovani,“Tumor-associated lymphocytesmodulatekeypathwaysinprostatetumorigenesis”, macrophages: functional diversity, clinical significance, and A. de Angulo, R. Faris, D. Cavazos, C. Jolly, B. Daniel, L. openquestions,”SeminarsinImmunopathology,vol.35,no.5, DeGraffenried,DepartmentofNutritionalSciences,DellPedi- pp.585–600,2013. atricResearchInstitute,UniversityofTexas,Austin,TX,USA.: [86] S. K. Biswas and A. Mantovani, “Macrophage plasticity and Prostate,vol.73,no.8,pp.855–864,2013,”UrologicOncology, interaction with lymphocyte subsets: cancer as a paradigm,” vol.32,no.2,pp.212–213,2014. NatureImmunology,vol.11,no.10,pp.889–896,2010. [102] A. de Angulo, R. Faris, D. Cavazos, C. Jolly, B. Daniel, and [87] A.MantovaniandA.Sica,“Macrophages,innateimmunityand L. DeGraffenried, “Age-related alterations in T-lymphocytes cancer: balance, tolerance, and diversity,” Current Opinion in modulatekeypathwaysinprostatetumorigenesis,”TheProstate, Immunology,vol.22,no.2,pp.231–237,2010. vol.73,no.8,pp.855–864,2013. [88] A.Sica,P.Larghi,A.Mancinoetal.,“Macrophagepolarization [103] M.A.Hussein,M.AL-Assiri,andA.O.Musalam,“Phenotypic intumourprogression,”SeminarsinCancerBiology,vol.18,no. characterization of the infiltrating immune cells in normal 5,pp.349–355,2008. prostate, benign nodular prostatic hyperplasia and prostatic adenocarcinoma,”ExperimentalandMolecularPathology,vol. [89] A.Mantovani,A.Sica,andM.Locati,“Newvistasonmacro- 86,no.2,pp.108–113,2009. phage differentiation and activation,” European Journal of [104] A. Celma, P. Servian, J. Planas et al., “Clinical significance of Immunology,vol.37,no.1,pp.14–16,2007. proliferative inflammatory atrophy in prostate biopsy,” Actas [90] A.Rigo,M.Gottardi,A.Zamo` etal.,“Macrophagesmaypro- UrologicasEspanolas,vol.38,no.2,pp.122–126,2013. motecancergrowthviaaGM-CSF/HB-EGFparacrineloopthat [105] C. de Nunzio, G. Kramer, M. Marberger et al., “The contro- isenhancedbyCXCL12,”MolecularCancer,vol.9,article273, versialrelationshipbetweenbenignprostatichyperplasiaand 2010. prostatecancer:theroleofinflammation,”European Urology, [91] W.Li,“Phagocytedysfunction,tissueaginganddegeneration,” vol.60,no.1,pp.106–117,2011. AgeingResearchReviews,vol.12,no.4,pp.1005–1012,2013. [106] G.Robert,A.Descazeaud,N.Nicola¨ıewetal.,“Inflammationin [92] I. C. Sroka, C. P. Sandoval, H. Chopra, J. M. C. Gard, S. C. benign prostatic hyperplasia: a 282 patients’ immunohisto- Pawar, and A. E. Cress, “Macrophage-dependent cleavage of chemicalanalysis,”TheProstate,vol.69,no.16,pp.1774–1780, thelamininreceptor𝛼6𝛽1inprostatecancer,”MolecularCancer 2009. Research,vol.9,no.10,pp.1319–1328,2011. [107] T. Fujii, K. Shimada, O. Asai et al., “Immunohistochemical [93] I.F.Lissbrant,P.Stattin,P.Wikstrom,J.E.Damber,L.Egevad, analysis of inflammatory cells in benign and precancerous and A. Bergh, “Tumor associated macrophages in human lesionsandcarcinomaoftheprostate,”PathoBiology,vol.80,no. prostate cancer: relation to clinicopathological variables and 3,pp.119–126,2013. survival,” International Journal of Oncology, vol. 17, no. 3, pp. [108] B.Seliger,R.Stoehr,D.Handkeetal.,“AssociationofHLAclassi 445–451,2000. antigenabnormalitieswithdiseaseprogressionandearlyrecur- [94] P. F. Lindholm, Y. Lu, B. P. Adley et al., “Role of monocyte- renceinprostatecancer,”CancerImmunology,Immunotherapy, lineage cells in prostate cancer cell invasion and tissue factor vol.59,no.4,pp.529–540,2010. expression,”TheProstate,vol.70,no.15,pp.1672–1682,2010. [109] T.P.Plackett,E.D.Boehmer,D.E.Faunce,andE.J.Kovacs, [95] E. Richardsen, R. D. Uglehus, J. Due, C. Busch, and L.-T. R. “Agingandinnateimmunecells,”JournalofLeukocyteBiology, Busund, “The prognostic impact of M-CSF, CSF-1 receptor, vol.76,no.2,pp.291–299,2004. CD68andCD3inprostaticcarcinoma,”Histopathology,vol.53, [110] J.Li,B.Schuler-Thurner,G.Schuler,C.Huber,andB.Seliger, no.1,pp.30–38,2008. “Bipartite regulation of different components of the MHC