Часть 2 (1121000), страница 66
Текст из файла (страница 66)
This instability can take variousforms. Some cancer cells are unable to repair certain types of DNA damage or tocorrect replication errors of various kinds. These cells tend to accumulate morepoint mutations or other DNA sequence changes than do normal cells. Othercancer cells fail to maintain either the number or the integrity of their chromosomes, and they consequently accumulate gross abnormalities in their karyotype that are visible at mitosis (Figure 20-f 3).
The genetic instability is furtheramplified when some of the DNA changes alter epigenetic control mechanismsin ways that produce extra heterochromatin and DNA methylation. And epigenetic changes by themselves, arising accidentally and independently of priorgenetic changes,may also lead-in principle at least-to destabilization of normal patterns of cellular inheritance by facilitating other changes either at thegenetic or the epigenetic level. From an evolutionary perspective, none of thisshould be a surprise: anything that increasesthe probability of random changesin gene function that are heritable from one cell generation to the next is likelyto speed the evolution of a clone of cells toward malignancy.Although the epigenetic changes in cancer cells have not been so thoroughly analyzed, a great deal is now knor,rmabout the genetic changes. Different tumors-even those from the same tissues-can show different kinds ofgenetic instability, caused by heritable alterations in any one of a large numberof so-called DNA maintenance genesinvolved in propagating DNA or chromosomes.
It is rare for a person to inherit a mutation in one of these genes, butthose people that do so have a raised incidence of cancer, confirming that a lossof genetic stability can cause cancer. Generally, such destabilizing mutationsCANCERASA MICROEVOLUTIONARYPROCESS, .r , .. l,r :, :. . ,. .i , , , .
1 2 | 5from aFigure20-13 Chromosomesbreasttumor displayingabnormalitiesinstructureand number,Chromosomeswere preparedfrom a breasttumor cell inspreadon a glassslide,andmetaphase,stainedwith (A)a generalDNAstainor(B)a combinationof fluorescentstainsthat coloreachnormalhumanchromosomedifferently.The staining(displayedin falsecolor)showsmultipleincludinga doublytranslocations,translocatedchromosome(whitearrow)madeup of two piecesof chromosome8(brown)and a pieceof chromosome17(purple).Thekaryotypealsocontains48 chromosomes,insteadof the normal46. (Courtesyof JoanneDavidsonandPaulEdwards.)(A)(B)are not inherited but arise de nouo in the clone of cells in which a tumor develops, helping the cancer cell to accumulate mutations much more rapidly thanits neighbors.
Recent analysesshow that the cells in a variety of human cancersexperience single nucleotide substitutions at a rate that is 10-20 times higherthan the rate observed in normal cells.As a result, the sequencing of more than10,000 genes in a set of breast and colorectal cancers reveals that cancer cellshave accumulated enough mutations to cause an amino acid change in the proteins of roughly 100 genes.Most are random changes that affect different genesin different individual tumors. But a subset of genes are found to be repeatedlymutated in a particular t!?e of cancer, suggestingthat alterations in as many as20 genes are needed to drive tumor progression.Genetic instability does not in itself give a cell a selectiveadvantage.It seemsthat there is some optimum level of genetic instability for the development ofcance! making a cell mutable enough to evolve rapidly, but not so mutable thatit accumulates too many harmful changes and dies.
To be favored by selection,a genetically unstable cell must acquire properties that confer some competitiveadvantage.CancerousGrowthOften Dependson DefectiveControlof CellDeath,CellDifferentiation,or BothJust as an increased mutation rate per cell can raise the probability of cancer, socan any circumstance that increasesthe number of proliferating cells availablefor mutating. People who are clinically obese, for example, have a stronglyincreased risk of many types of cancer,compared with people of normal weight;and this is presumably due, in part at least, to an increase in both the number ofcells in the body and the rate at which these cells divide when overnourished oroverstimulated by growth factors.The same principle applies to both cancer initiation and cancer progression: the bigger the clone of altered cells resultingfrom an early inherited change, the greater the chance that at least one ofthesecells will undergo an additional mutation or epigenetic change that will allowthe cancer to progress.Thus, at every stage in the development of cancer, anycondition that helps the altered cells to increase in number favors the progression of the tumor.An early mutation or epigenetic change can have this effect by increasingthe rate at which a clone of cells proliferates, as we discuss in detail later.
Suchchanges,howeve! are not the only-or necessarilythe most important-mechanism for increasing cell number. In normal adult tissues,especiallythose at riskof cancer, cells may proliferate continually; but their numbers remain steadybecause cell production is balanced by cell loss, as part of the body's homeostatic control mechanisms. Programmed cell death by apoptosis'ttsually plays anessential part in this balance, as we discuss in Chapters 18 and 23.
If too many12",6 Chapter20:CancerHOMEOSTASISa!cllcells are generated,the rate of apoptosis increasesto dispose of the surplus. oneof the most important properties of many types of cancer cells is that they fail toundergo apoptosis when a normal cell would do so. This greatly contributes tothe growth of a tumor (Figure 20-14).Inherited changes can also increase the size of a clone of mutant cells byaitering their ability to differentiate, as illustrated by the situation in the uterinecervix, discussedearlier.\A/hena stem cell in the basal layer divides, each daughter cell has a choice-it can either remain a stem cell or commit to a pathwayIeading to differentiation; the committed cells initially proliferate and then stopdividing and terminally differentiate (the committed, proliferating cells arecalled transit amplfuing cells).If the differentiation program is blocked at somestage,proliferating cells accumulate, contributing to the progression from lowgrade intraepithelial neoplasia of the cervix to high-grade intraepithelial neoplasia and malignant cancer (see Figure 20-9).
Similar considerations apply tothe development of cancer in other tissues that rely on stem cells, such as theskin, the lining of the gut, and the hemopoietic system. Several forms ofleukemia, for example, seem to arise from a disruption of the normal program ofdifferentiation, such that a committed progenitor of a particular type of bloodcell eventually becomes able to divide indefinitely, instead of undergoing terminal differentiation in the normal way and dying after a limited number of celldivisions (as discussedin Chapter 23).Thus, the accumulation of mutations and epigenetic changes that lead todefects in the normal controls of cell division, apoptosis, and differentiation canall contribute to the development and progression of cancers.CancerCellsAre UsuallyAlteredin TheirResponsesto DNADamageand OtherFormsof StressAs just discussed,many normal cells permanently stop dividing when they differentiate into specialized cells.
Differentiation, however, is not the only reasonthat proliferating cells stop dividing; they can also do so in responseto stressorto damage to their DNA. As described in chapter 17,normal cells contain a set ofcheckpoint control mechanisms. These arrest the cell cycle temporarily whensomething goes a\,'ly, providing time to correct the problem. Chromosomebreakage and other types of damage to DNA generate intracellular signals thatactivate these checkpoint mechanisms, causing a normal cell to halt its cycle,andthereby giving it a chance to repair the damage before it attempts to progressthrough the cycle and divide. And if the damage is irreparable, a normal cell,rather than forge ahead and generate daughters with a damaged genome, willeither permanently withdraw from the cell cycle or commit suicide by apoptosis.cancer cells usually acquire mutations and epigenetic changes that inactivate such responsesto DNA damage.
From the selfish standpoint of the cancerFigure20-14 Both increasedcelldivisionand decreasedapoptosiscancontributeto tumorigenesis.In normaltissues,apoptosisbalancescelldivisiontomaintainhomeostasis.<GCCC>Duringthe developmentof cancer,eitheranincreasein celldivisionor an inhibitionofapoptosiscan leadto the increasedcellnumbersimportantfor tumorigenesis.Cellsfatedto undergoapoptosisareshown in gray.LLZL[q a8eauUaq] urp]urgul sllaouels aq;'afleauq aqlJo f,l]slre]Jereqosllec pezIeIJ-ads aqt olur elprluaJaJJlp^[pnluala pup dlarnsuaga a]eIeJIToJd]eql (silel fiuI-.!ldrue lrsueJt eqt) sllal ecnpoJd sllec uels 8utpptp,,i.pto1s 'arer :t(qcreralq E sBpazueSro.{pcrd,,i1 ere sllac eqt 'e8eeull IIeo f,l}slodouaq eqt s€ qons telouJnlilac ]lnpE IeuJou e ul'EZ reldBqJ uI ssnsslp e1!\svIIaJ lEl]uelsqns qll^ a3eau11slle) uals re)ue) ro uollelndodlleus vsulelulPWsrounl (ue1q1'do1spporvr sllaf,IeruJou ueqm suolllpuof,'pasn d8alerlsJapun aleragqord ol anulluoc slleJ Jeoueo eql leql sl lpsal eqleql Jo ssalpre8ag 'spue auosotuoJqJ Supe8uola JoJ sluslueqoeru e]€uJelleeAIoAaslles JaJueJ Jaqlo ]a 'peuauol{s seJeluolal lleql se JoJ pelseles eJeMleql sa8upl{f,crleuaSldaro JIleuaBJo Unsal e se &nnce aq} parrnbce a^Bq sllef,alqercardde lnoqll^a sllal uI paleu€tro JaJuBcJatueJ aq] dlp1IlJBaspJa111oleleql q8noqtle 'sas€oreqlo u1 ,fiprpce slql a^eq leql slleo ruels uI paleur8rro rac-uec aql asnecaqr(1pulJgaseJeluolelule]ule1ll,{.eu s11acJeJUEJeql 'sasPoeluos'a1era;t1ordu1 'paddecun eruoJaq ro ueuoqs ]ou op saJeruolal Jlaql leql os'aJueJseuesa^lleJlldeJLaql se ,fiyrpce eseJeuolal ulelurcul uago sllal Jecuef,'slleJ JaJuuf, uI uouledgf,se ol ,{$e}erls Jaq}oue sV ^ olaq ssnlslp IIBqs e1vrsE-uroo ^Je^ eJBpup tJeJJesrql aneq ,{ertqled ggd aqt alelllJeul luql suouetnlN'paddecun eruoJeq saJeruolalueq^ uala alcdc o1 enulluo3 sllef, aql teql os IoJl-uoc lurod4caqs er{l alqesrp 13q} sesueqJ cuauaSrda pue cqauaS arnbce ,taq}'lsrtC 's.,{e^Vrolli\l ul ecua3seuas1ac annuotldeJ plo^e sllal JeJuEc uEunH'uorssarSordJolunl JoJsaqrunpoddo snoruJoue apnord eslmJaqlo p1nolvruedsa;q 3uo1 dlarrrleredluoodlaq of eJuecseuas1ac altlecqdeJ peau suglunqJno asneJaq JelueJluanard'JaIrrBqslqlteq] pasodord uaaq sEq 1I{3el aroJeraqlpue atereJllord,'(aqrsP saJe-ruolel IBruJoupue l1nuce eseJeluola]uleluleru 'lserluof, [q 's1ac ]uepor aruos'sJorun] a3re1ruro; ol JaIJJeq sq] ar1;ocJalo Jo plole rr,roqaruoslsnu sflec Jef,-ueJ ueunH '[poq aqt uI sllef,;o sadr! eq] Jo ]soru roJ uol]ereJllord 1ac o] ]FrIIpcrSolorsr(qde slas peqrJJseptsnf luslueq]aur 3ut]unoc-uolstlrtp-lleJ eqJ,'lseJJea1cl.c-1acluaueluJed e Je33u] spue euosoluoJqo paJel[Baqr ,i1p-nlualg 'elpJorrelap SdpJ a1rlJelord rtaq] pug (uoIsIAIp zfua,raqlyvr ueUoqs SaJe-uolel JIaq] 'aseJeruola]ut ]ueIJIJapeJE (slleJ luals lou lnq) slleJ uerunq Suqe-raylord.{ueru asneceg 'spue auosoruoJqf, aq} }Ja}oJd }eql seJn}cnJlsdEJ ulel-ord 3o uorteuroJ aq] salouoJd pue acuanbas y5q JrJeuolal prcads eql sulBlroJ 'slselqorqlJueunq roJ 09-gZ) s8ullqnop uopepdodJo reqrunu uleuec e raguSupptlp do1s.{puaueurred daql :arnllnc ur e}eraJlloJd ol pete1nrups uaqm apIAIpuec rtaq] saurlJo Jequnu aql ol lltu1 ul-fllnq e aleq slleJ uelunq purrou r(ueyquollelelllordlle) ol l!ul!'lu!-ll!n8e ade)sl slla) ro)ue) uerunHaql aleln8ar dlaq teqr sruslueqJeruloJluol lutod>1caqcJeqlo uI e^lpeJep uegoosle ale sllac Jecuef,aql dcueu$rpu ralearfi ol uorssarSordaql ualsuq dqaraqluec pue uollepdod IIaJ Joruru aq] uI elelntunf,Je suouulnlu qJIqM ]e aleJ'VNCI pa8eruep qllm ue^e.{ldn1nru o} anupeqt salpreleJJe slql 'aur1tatues eq] 1V-uoc ol rueqt SumollB ,a8plue^pBue sJaJuoJsluleJlseJ esaql Jo ssol aq] 'sllecv sv ul)NVfssr)oudAUVNollnlo^lou)ltN('sa)uatfSjo Iuepety leuotteNurorj uorssluuadqllM t00Z '9gl_LgLil}l'V'S'n' pS'pDV llDN'tot4'e5ey'tpue rqrn6o1a5 'opuo)paldepv)rloll1f'slla) a>npo.rd plno)slla)ds-uouloudSaql'slla)ds-uoupue ds qloq patnpordslla)dSaqf sealoqMla^oalow 'sjot!nluuoJpup (;enrsuelxaalela;r1ordplno) slla)uollelndodaprseq1I;uo lpql paMoqsslla)6urureuelaqt qrlmslla)(dS)uollelndodaprsasaql6uueduor sluaulladx3'uo11alut pale)tput ,pautetsse,{11q6;1,{1uooloJareqtare pue aIp aqrtno dund slla)aql,o o/ot'glnoqv .6ur1ros1;ar{q pez{;eueuaql pue (Zt€€€lsq)eoH)auelqulauteurse;daql qbnolqrssedue>]eql a^p e qllm pateoll aramloutnl euor;6ler e ulolJpautplqoautllla) paqstlqelsaue ur slla)oql ,alduexasrqlul .slla)1o uorle;ndodapls llpuls e u! slla) uolsro)ue) sleanal6u1yos;;a1 g 1-gg a.rn6r1+uolsslrlaparrq611co@fo3fveql'[ec SuldJrldr.uelrsupr] E se qJns 'peleuuereJJrp ero{u sl }eq} IIaJ Surlera;11orde ur a8ueqJ e q8norq] sr asrJe uef, IIoc tuels JeJueJ e leql ^e^a puoJes eqlraJuBO e olur dolanap ol parmbeJ suorlelnru JoJeqrunu eq] elelnrunJou ol q8noua Suol JoJ elpJeJrloJdpue Lpoq eq] ut urcrueJsilec uals,{1uo 'sanssrleseq} q 'Ja^ourn} IIaJ ler}ue}sqnso8Jepun }eql puaq}rdeur dolanap,{.aq}asnecaq 'sllaf,ure}sruoqesrJpz(lqeqordsJaJuEcueunqIBruJoufueru 'esrala{r'I 'JeJuec srq]JrlsrJa}JeJeqcuorlecolsueneq} q}lm ,eurosJo-oruoJqc pqdlepplrqd aql upluo3 Lueru 'sluerled asaq]Jo ^ oJreru euoq aqlruorJ pegrrnd are (gglt 'd aasl sllac ruals Jperodouraq ppuelodpFru eqt uaqm,snql 'asrre serua{nel snoueSola.{ruJruoJqc ,r(emaq}.,(pmgac}sorup sr s}uene'aldr.uexaroC 'JaJuEJeqlJo Jor Er{eqJo ecuanbes slqtIprooseaq} JoJalqrsuodsarsa8ueqc ollaue8rde pue suopplntu aql selelnrunJJe dlenpe.r8 qcrq^\ ,llaJuals anssr]IeuJou e ur saluurSuoJe3uE3eql leqt sJorunl etuos JoJJpelf,sl u'saSueqccrlauaB tuoq upqt JeqlpJ cqaua8rdaruo4 llnseJ lsnru sacue'saur1-JeJJIpesaq]Jo ,{ueurilec JacuEJpeJnllnc qllm paqrJcsep}sn[ slpsal eqlruoJCaq] ur silecdlrrofeuraql ruo4 sruJe] Jelnoeloru ur 1r saqsm8uqiJaf,uecJo-slp lPqm puE 'llec ruels recupJ aqlJo eJnlBu aq] sr ler.I A iasrJEsllsc uals eseqlop ^aoH 'suorlsenb Sum8ulur Jo Jaq{.unup sasreJlI pup ,}r Sunean JoJ pu€ JeJ-ueJ SulpuetsJepun JoJqloq 'suorlecrldrul lupuodurr flaruarlxe seq sllal ruelsracuec 3o uo4epdod leurs e Lq paurelureru aJesrecupc dueru leql Surpug aqlslle) uals la)ue) oc MoHeasrJv'slInseJJelrurs uanrB aneq Jacuef, aqlur8uoanssr] eql ut sllec ruels pruJou ezruJoJo,serpnlsreqlo uI-3ocar lpql sepoqpue puolcouour SursnsuoqpuorloeqIIof,'s11acSururcureJeq]Jo seJnllnJur dolanapsaopuouppdodeprsesEaJer{Mltlalrugapurpeure}umrulousr pupp ,eJnllnosreaddeardlprder uoqelndodaprspeuJrualolsraurlraJuEJpilptusIIaoqf,ns ruo{ pa}Elosruorlepdod aprs aq} ueq^ teloeJol4tr'(gI-02arntl$tou saop'aurl eq] ur slleo aql,uoqepdodluelseJongJo dluoferu ]sBAeqt sepnlJur qJIqM[UBlq Surureurareq] (uor]e]upldsuerl reUB sJounl srurogLppeal seurl eseq] JoqJEaJouorlepdod aprsaql sBeJeqM:arnllncur srear(d1rrq]ueql eJorurog pale8e-dorduaaqa^eq leqt saurl ilec Jacuet eruos JoJasef, eql osle sr qql flqelJeurag'eJrruluerorJapounru{ur o}ur uor}e}ueldsuerl regp sJeJuEJ ,tteu Sunuro; goalqedec s[a] eq] Jo 'lle ]ou Jr 'lsotu ureluoc ol punoJ sr rapodsuerf l11V uE q]pruorlelndod eprs IIEtus e 'Ierr erues eql ur paz,{pue eJe sJeJuEf,eruos ueqlt'lleJ eqtJo 1no azi.paqt sdund z(1alr1celEql auEJqruaru eruseld rraqtur (11 raldeq3 ur passnf,srp)ragodsueJl :)gV uB alpq rtaql asnecaq luaosaJongi(qeaa,r,,tpo ere sllar ruels aqJ 'slleJ tueosarong Lgeam; o uopn1ndod aprc lleluuLsB ur peqorrua ,{.1q8q eq o} punoJ uauo are enssr} aq} Jo slleJ ruets eql furvr slqlur pauos ueql pue a,{p aqi o1pasodxa sr enssq prurou B ruo4 peredard uorsuad-sns IIaJ p uar11\'(7-g arn8rg aas) JeuosIIef, pele^r]f,e-eouecseJonge pue a.{plua3seJonu alqearurad-1lece sasn sJecuEJeruos ur sllec Iuels JeJuEJa,rrlduns'uorleBedord rournl loJ papaau-a.rdgo uoqepdodileurs eqt qcuua o1dem augfiradord prcads aql e^eq uraql Jo lesqns IIErusE Lluo pue ,snoaueSoralaqaJesllal Jacupc eql esneJeqsr srql 'sesec,{ueruur .lpql u aoqs e^Bq sllec Suqros ro;sa€o1ouqca1^aaN 'esnoru luerJrJepounruurruE olul ll Supueldrur dq ,aldurexaroJ-os op ot drgqe slr roJ petsel ueqm Jounl ^aeu E aleraua8 01 elqe eq IIIzr,rJeJUEJp ruo4 IIaJ IBnphrpur uesoqt ztluopuer p leq]-o6l u€ql ssel qcnur dle-nsn-acuuqf,llerus e Lpo sr eJaq] ]eql srea,{ 0t JeAoJoJrr,lrroDlueeq seq }I'sJaJuEJ,{ueur ur sllal ar{l ,fi1roferulse^ aq] dn a>1eruppJo-uatod qpror8 palFull e qllm slleo aseql leql pazruSocar dlapur aurocaq fpuacar,r(po seq 1I 'lemauer-JIasroJ dlrcedec petg4l e eABq]Bq] slleJ 8up,{SrrdureIISuEJ}3upp1p fprder ol asrr an€ osp daql rnq ,IB^ auaJ-Jlasetugepur Jo alqedec areslleJ ruels eseqJ 'Jorun] e ur slleJ;o uorlupdod aqt Surumlureru JoJalqrsuodsarz{qcrerarq eql Jo dol eqt }e sIIeJ ruels JecrrBJ eJeJqllm dea,rpcrqcrerarq arueseql q pazrue8ro ele sJacuecdueur leql acueprna Sursearcursr eraqJ.uollep-ueJaJJrpo1 Surpeay,{ea,rqlede ol }rurruoc leql sraq}o Surcnpord el,[rllv',Qamaual-fias palet ssacorde) sllaf,ruels ureruer upJ leql slac ralq8nep aruos Burcnpordra)up):97 raldeq39LZL'saltradordlla)uratsuraqla^r6leql sa6upq))tloua6tdaro suorlelnulauoolapuna^eqleql slla)palPlluaraJJ!paroul ruo4 ro isnole)ue)ureqleleur ol suotlelnulpautelsnsa^eLl]Pq]slla)urelsleuilouLllorlasueue) slla)ulatsra)uel slla)6ut^,tldrueltsueJlseq)ns slla))rua6llounl-uoualelaua6aulttauJesaql le pue'slla)uats ]ueu6tleulalnpolo ol Mauar-,lasleuorlrppeue) lPr]lslla)la)ue) asoqlse pauuaparesllal uals ja)ue)'slla) uals Ja)ue)urorJasue{eu slarue; 9 1-97 arn611'luaq]ilpl o] puE sllal uals racuec aq] ]e8JElots^emJaueq purJ ot I€rJnJJ,{lJealcsl U 'sreJuecoJnc oJ 'r(deraqto} asuodsal IeIlIuIJrlerueJpe Jaue JnJaJfluouuroJ sJeJuPf,.{qmuosear Jo[Elu P aq deur sIqI'JaJ'palpJrpeJe-uEJeJeslleoIualseql'fuanLaqieqleleJeua8alz(1a>11louJI11t,u'sllac reqtoilr{'slle3 uels JaJ]Bq] slualulEarl .,{ueruol }uelsrsal dlunsnun ueq} e{elu plnoJ }I'@I-EZ-ueoarnBrgaes)ii.ernsrqlulseuosoluoJqJJleqlroJesBJeqlospsrsrqlJI'sllac ruels ,(po pue 'sllec urelslpql;o uorle8ar8es aq] eteurpJooopeepur UEJ]sa88ns sluarurradxa ]uaJag ;lleJ urels p urerueJIIr^ lerll 1ac ralq8nep auo aqlolur pale8ar8asaq o] aruosoruoJqcqJEe ur pueJls aluldrua] VNCI plo aql smolle'uorlucrldarleq] usrueqcau prcads e azrlln IIec tuals e Jo uorsrlrp qcea plnooy1qq Surrnp esrre suorlelnu .{ueur arurs 'relnrrlred u1 'suorlelnu Suqelnur-ncoe ruo4 sllac ruals lcalord ]uql susrueqoeu JoJ pelJelas e^eq pFo^ uoqnl-ola leql pasodord sem lr 's0Z6I eql ul lenoerohl 'sluauleeJ] eseql ol elrlrsuesssayaq,r{eur,{aqt'{1.uoysaJolu qJnr.uaprnrpdlensn slleJ lue}s Jacuer eqt esneJeg'rorun] E ur sllef, recueJ Superagrlord,{lprder}soru eq} 1q z(lppuarayard o1 z(1a4tare s8nrp cxololdc pue uorlerper se qJns sarderaqt Jaoupc luaJJnJ lsol I'(gI-02 arnS;g; qloq ro 'a8ueqc cpaua8rda 'uortetnurq8norqt p^ auer-Jlespaurelsns ro; dlrcedec aq] parmbce spq leql IIaJ p ruo4esrresreqlo 'llal ruels e [uo4 eslJesJeJuEJuErunq ]solu alrqA\'teql ,{1a>91srueas'snqJ'llef, ruels papruruoJun ue ur ueql JeqleJ 'lleJ JosJnJerdal,boqdrudl glIpallnutuoc e ur paleur8rJoJaJuEl aq] ]Eql SurlsaSSns'(gZ Jeldeq3 ur pessncsrp)saua8 .{poqr}ue raql ur sluaura8uerJeerf,r}aua8 arues aq} ur€luoc erua{nal eqons ur sllal aql Jo 11y,{erursrql ur asrJeol ruaas 'aldurexe JoJ 'serluelnal a$coqd-udl g auos 'llal Jacuer rrmolq-1pge eruoJeq 01pepeeu sa8ueqocqaua8rdapuesuorlelnru reqto eql alplnrunJJe ol erup eq] e^eq IIIM IIaJ peJelle aqr 'uaql .{popue 'uaqJ 'lemauar-Jlaspa8uoyord ro; dlrcedec eq] pue ,{poq aql ur paure}araq o1 ^,!rpqe aq] :seuradord 1ac-rua1s pnnJl o^ l aql JaJuoJ lsnur sa8ueqcJOUrnll l a ) u r a l sJ a ) u e )tIFtterFiIqyriror6penutluo:I-\llal ualsra)u e)tueuEtteulemauoJ'--.iIs a 6 u e q rr r l a u e 6 r d ap u e s u o r l e l n u rlla) urals leuiJou6tzL1rsue.r111a:6urr{1r;du.resst)oud UVNoTIn-loA3ouftwv sv ul)NV)poolq E ]JeJ]]e sJorunl 'senssp IBruJou a{q 'ezrs urEual E puo^eq qnoJS Jolun}JoJpeJrnbar sr 'slessel poolq Ai\auJo uorleruJoJ eql3lsauaSotBun 'snq1'sluelJlnupue ua8z{xotuarJlgns sta8 }r }pql eJnsue o1 .{1ddns pooyq alenbepe uE }lnJf,eJlsnu Jorunl e 'a8re1,uor8 ol 'paquJsep lsn[ sluaruarrnbar aq] IIB o] uoqlppe ule)npuls,rounlstseua60t6uv'ap$1p pue anor8o1slleoJeqlo uror; spu8rs uo luapuadep ssel oslp are daq;'auroq radord rraql ruor;Surdecsa rege aArAJns,tppuar eroru uec aJoJaJeqlpue sllal IBruJou qlyrr pared-uroc srsoldode o] ]uelsrsal uego eJEsrselselaur;o alqedec sllef,JaJueJ'(BI ral-deq3 ur passnJsrp)srsoldode o8rapun pue draurqceru qtpep iler Jleql alelllJe[aq] 'qeu8rs aseqt Jo paarrdap uaqrt lluaruuoJllue IeIuJou Jleql uI luepunqe^,(1anr1u1areJE]pq] spu8rs IeArAJnsJplnlleJeJlxe uo puadap sllec pIxJoN ']uIEJlseJleuorlrppe ue aq o1 l(1a>11sr saqilqedeJ IeAInJns ptcads JoJ paau eqJ'srselseleruorJlru E Sururog Je{e uela 'uoupzluoloo eAIeqJEsllef,ana;os,(qm urc1dxappoan slleJ ruels JacuecJo dllrer aq1 ']ualuuoJllue uellp ue uIelt,uns pue aplas or irIIqE aql pue ']1u41]noqlul ap4lp ol uaql alqeue illv\ ]PqlJel3eJeqf,IlaJ-ruals aq] qloq aner1JaJueJ lelldril p uI sflec aql Jo uopepdod leursd-rane Lluo leql aq Leur ]l 'sI lEqI'papaau sauradord plcads aq] e^pq leqt slleo Jo,!per aq1 slJager uollpzruoloJ Jo eleJ llrol aqt f1a41 aro61 ztla4lun sruaas slql 'ellsuerp ue ur Suunor8 pue 'Surplas '3urnn:ns Jo ecueqo ,tup arues aql arreq lq8luIueerlspoolq aqt Surratua IIe3 raf,uer qrea lBql aldtcurrd ut alqtssod $ lI apq \'palorual sr Jorun] drerurrd eql paJnr aq uuc pue seluoloJ Jllplspleru punoJJIo1 pa8eueru a,,reqdaql eroJaq peJe^oJSIp eJe sJacuBOdue141'saselspleruoJJlruueq] erotu Surqltue uJoJ ot aAIAJns 'suotlltru uI euo sdeqrad 'spues-noql uI auo upql JaMaJ'eseql yo uotlrodord dun e dpo leql Moqs slueurradxatanaanoll 'slassal poolq ro crluqdrur(1olur adecsaol a8eueur Jorunl B uI sllal eq]leql aJnlPInosPAeql;o,,(uuur ler{l suees rr pue !(1ee1sr sJolun} olut srvr,or8'luetuuoJllue irlreuaqt'(LI-OZ arn81g) uorlpzruoloo sB u^ ou{ ssecordl1nlUJIp eur,{yanrsuaryaaleragqordpue eArAJns}eq} sllec ecnpord }snu seselseleluoJf,Ituasaql Jo aruos 'sseJo.rd crlelseleru eql alayduoc oJ 'slsulseleruoJJlrue sB rrr!\oDl slleJ Jo durnlo llElus e lsJrJ lE Sunuro; 'alIS ^\au eq] q ,rnor3puefpoq aqt ur araq ^asla Iassel p uorJ ]rxe 'qdrudl Jo poolq eql Jelue ot sE os Ias-saleql3uru11prtaqlopua eql pue euruel Ieseq aql SurssorcLq lassarrcpeqdJo'l.pgssaccns ezlselselatu UPOlI-uL1 e roIassal poolq E alerleuad lsnu IIef, eaJoJag'll aAarqJEsllac .t,reJluorlerado ]ueIcIJJauIpue 'lr,rols'xalduroc e sr-sue8rotuplsrp ur saruoloc Jo ]uauqslqelsa eqt-slselselaru ut dals ]xau eqJ'(Zi-Of arn8rg ees)tueur-dolanapprtaqttda atuos uI sJn3Jo qtlqm '(JWn uoqtssenssllSurrnpIEruJou-unt11arufu4tuasara-ol-Ior1aqudaaql salqueser a8ueqc slql 'seIuouIJJeJJoJtelelssnosrp a,r,rsV'xrJleru Jelnllaf,EJxa eql ol pue sroqq8rau radord Jleql ol peJeqlalslac daal fletuJou leq] srusrueqJeru allseqpp aq];o uoqdnrsrp e sarrnbar L1urc1-Jac]sorule sseuelrselur 'poolsrepun ilala lou are sa8ueqcrepcalou 8urflrapunaqr q8noqrly '16-67 arn8rg 'aldruexa JoJ 'aes) anssq SutpunoJJnseql olul suols-ualxe qlrm 'sJapJoq pa38er pue qutor8 go uralled paztue8rostp B ^ ot{s qJIWV\'senssp'sJorun]lueu8rpur;o saqredord Sururgapeq] Jo auo snql sl ssaueAISuAuISurroqq8rauSurpenurtuo4 luaql luanard pue saceldradord Jleqt uI sllal I€ruJoudaa>1leqr slurprlsuoc Jo eaq )eaJq lsnu ]t 'azlsptselelu ol [ec t""y:;;i:i,""aJepallolur srusrupqceruJplncalorueqlJo ]soru pue 'xaldruoc TIeslL,rlar rl.r",r"eseq] Jo qJEg 'salrs luelsrp ]e saluoloc Jelnllec r\/Ieuqsqqelsa ueq] puE 'slesse^eql aleal 'uorlelnJJrc aq1 q8norql elotu 'slassal puu senssll Iesol epelul o] eluq'uoueIpPJJIpezlleJolslleJ Jef,ueoaql :ssacord dalst]pru e JIeslI sI sISElseleIAIro dra8rns raqlra ,tq elullppre o1 alqtssodrul lsourp seruoJeq raJuec u ,(poqaql lnoq8norq] Surpeards,rtg'sqleap paluloosse-JeJueoJo %06 JoJ alqtsuodsarSuraq tacuec 3o lcadse-poolsJapun tseal pue-dlpeap lsoru eql sl slselselel trluouruoilAul u6larol e u! alelar!loldpue a^r^rnslsnw slla) ra)ue) lueu6llew 'ezlselselewoIro)ue3:97taldeqlOZZL'JalEI ssnssrp e^asE 'ddeJeq] SnJp JoJ1e3J4 snor^qo euoeJp sJorunl otut peloeJlle are ]Bql slessal leruJouqe eql pue ,{1ddnspoolq alenb-ape up uo serlal q$\oJB Jorunl telemoq ,{laruu4tln 'lueuBqeru aroru are daq}leq] sueaurLllensn qlrqm'suorlrpuoo lryssaJlspup qsreq aseql q eAIAJnsol elqere1eq eft leql slleo JeJupJ luelnru JoJ slJeles 'uJnl ul 'exod[11 '(8I-02 arn8;g)erxoddq go suor8ar puoqrppe elearr o1Surdlaq 'rorunl eq] ul{tl,rlr ^aog poolq rEIn-3au ol peel 'sepcelou Surpu8rs Jo aJuelpq lerurouqp uB r.uo4 llnsar dlqeqordqrlr{ivr 'sarlqeurJouqe aseql 'spue peep qlrm seqcuerq ,(ueru aneq daqt pue '.{4ea1pue 'Jaleruerp ur snoeueSoralaq 'snonpol eJe slassel peJnpu aql talel oH'azrsplselaru ol slleo sll JoJelnoJ adecsa ue apnord oslplnq'ua8dxo pue sluerJtnu qlp\ rounr aql ^lddns dlaq dpo rou slessal eqJ ' (vE-tZ an-3rg aas; slasse^ poolq ,lreu qprorB aqt aleFrurls prre slleJ lelleq]opua ]Jer]]eJo'Utgnnlcnt qimoJ8 luryaqiopua JDInJSDIleql sulalord pelarcas ere eseqJsB qons 'sJolceJcruaSor8ue-ord apocue leql saua8 go uorldrrcsupJl eql selelrloe'uJnJur 'uralord srql ltz raldeq3 ur paqrJcsepuralord drolep8ar aua8 e'(nt-ilH)nt -toilol alqtcnpul atxodfg Jo la^al aqt ur esearrur uu Surxonord ,i.qd.yddnspooyqaql aseaJrur ol?4JflmsJrua&o1&unup selpllloe exodrtq eqJ 'JalarrrelpuI oml Jo Ja]-eurTlrur e puodaq sa8relua Jounl eql sE slleo eql peJJp o1 su€aq qJIqM'exoddqol asuodsar ur pacnpo.rd are spu8rs asaql 'spu8rs eruaSor8ueSurlarcas,{.q,,{.1ddns'alrsMau e rournl alqelralap e arnpo.rdol se os onssrlMou e azruolo)lpllrir,tueorlspoolq aLllralua ]eql slla)townl 1ueu6r;er.upuesnoql{ra^a ur auo ueql roma}reJIllerrdft leql Moqssleurueur sarpn}S'sase}se}au-rapou-qdu{1ol asu 6urnr6'IeMoql 6uo;esapouqdur(;u; padde.rluauo lassan>rleqduI;er-uo>eqP paraluaa^eqteLltslla)rounf 'Luearlspoolqaql olu! (qdu^l) sluoluo)s1rsa6.reqrsrp,(lalPur]ln]eqleql 6ursson{q 'sdeqrad,(;uor.uuorarou 10 'araqperuruer6erpse 'lassanpoolq e;essenrtteqdu,(1e lo 1;ernoql raluo{eru s;;arrownl'ia^rl aql ol rappelqaql se qxs uebro,o lleMaqr 6utssorlIq ^lparlp urearlspoolque ulolJlorun] e;o peardsaql salerlsnllre;dwexasrLll'slselselaur1ossaroldaql u1sdet541.-ggarn6r3srselselauruMolq-lln]6 u r u r .
![](https://s.studizba.com/z.php?f=/templates/si/i/noavatar.png&w=100&h=100&t=1"){kind=avatar}
