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lVhen specimens of cervical epithelium from different women areexamined, however, it is not unusual to find patches in which this organizationis disturbed in a way that suggeststhe beginnings of a cancerous transformation. Pathologists describe these changes as intraepithelial neoplasia, and classify them as low-grade (mild) or high-grade (moderate to severe).In the low-grade lesions, the undifferentiated dividing cells are no longerconfined to the basal layer but occupy other layers in the lower third of theepithelium; although differentiation proceeds in the upper epithelial layers, itis somewhat disordered (Figure 20-98).
Left alone, most of these mild lesionswill spontaneously regress, but about t0% progress to become high-gradelesions, in which most or all of the epithelial layers are occupied by undifferentiated dividing cells, which are usually highly variable in size and shape.Abnormal mitotic structures are frequently seen, and the karyotype (the display of thefull set of chromosomes) is usually abnormal. But the aberrant cells are stillconfined to the epithelial side of the basal lamina (Figure 20-9C). At this stage,it is still easy to cure the condition by destroying or surgically removing theabnormal tissue. Fortunately, the presence of such lesions can be detected by1212Chapter20:Cancerji.lF;.#+il*t&*try.3*;#*n-A(A)(B).1-#Figure20-10 Photographsof cellscollectedby scrapingthe surfaceoftheuterinecervix(the Papanicolaouor"Papsmear"technique).(A)Normal:the cellsarelargeand well differentiated,withhighlycondensednuclei.(B)Precancerouslesion:differentiationand proliferationareabnormalbut the lesionis not yet invasive;the cellsarein variousstagesofdifferentiation,somequite immature.(C)lnvasivecarcinoma:the cellsall appearwith scantycytoplasmundifferentiated,and a relativelylargenucleus.Forall threepanels,debrisin the backgroundincludessomewhite bloodcells.(CourtesyofWinifredGray.)(c)10LLmscraping off a sample of cells from the surface of the cervix and viewing it underthe microscope (the "Pap smear" technique-Figure 20-10), thereby savingmany lives.Without treatment, the abnormal patch of tissue may simply persist andprogress no further or may even regress spontaneously.
In at least 30-40% ofcases,however, progression will occur, giving rise, over a period of severalyears,to a frank invasive carcinoma (see Figure 20-9D): the cancer cells cross ordestroy the basal lamina, invade the underlying tissue, and may metastasizetolocal lymph nodes via lymphatic vessels.Surgical cure becomes progressivelymore difficult as the invasive growth spreads.TumorProgressionInvolvesSuccessiveRoundsof RandomInheritedChangeFollowedby NaturalSelectionFrom all the evidence,it seemsthat cancers arise by a process in which an initialpopulation of slightly abnormal cells, descendants of a single abnormal ancestor, evolve from bad to worse through successivecycles of random inheritedchange followed by natural selection.
At each stage, one cell acquires an additional mutation or epigenetic change that gives it a selective advantage over itsneighbors, making it better able to thrive in its environment-an environmentthat, inside a tumor, may be harsh, with low levels of oxygen, scarce nutrients,and the natural barriers to growth presented by the surrounding normal tissues.The offspring of the best-adapted cell continue to divide, eventually taking overthe tumor and becoming the dominant clone in the developing lesion (Figure20-f f). Tumors grow in fits and starts, as additional advantageous inheritedchanges arise and the cells bearing them flourish. Tumor progression involves alarge element of chance and usually takes many years, which is why the majority of us will die of causesother than cancer.\A/hy are so many changes needed? Clearly, large animals have had to evolvea very complex set of regulatory mechanisms to keep their cells in check.Withoutmultiple controls, inevitable errors in the maintenance of DNA sequenceswouldFigure20-1 1 Clonalevolution.In this schematicdiagram,a rumordevelopsthroughrepeatedroundsof mutationand proliferation,givingriseeventuallyto a cloneof fully malignantcancercells.At eachstep,asinglecellundergoesa mutationthat eitherenhancescellproliferationordecreasescelldeath,so that its progenybecomethe dominantclonein thetumor.Proliferationof eachclonehastensthe occurrenceof the next steoof tumor progressionby increasingthe sizeof the cellpopulationat riskofundergoingan additionalmutation.Thefinalstepdepictedhereis invasionthroughthe basementmembrane,an initialstepin metastasis.In reality,therearemorethan the threestepsshownhere,and a combinationofgeneticand epigeneticchangesareinvolved.a c c i d e n t apl r o d u c t i o nof mutantcelle p i t h e l i a cl e l l sg r o w t n go nbasal aminaII c E L LP R O L T F E R A T T O Ntc e l l w i t h2 m u t a t i o n s: | :,.,:'..
"s. . I ! : : :':,1.,!.,:,*o,-,rr*o'o,f.rr,-I DANGERoUScELLPROLTFERATTON+CANCERAS A MICROEVOLUTIONARYPROCESSproduce numerous tumors early in life and quickly destroy any large multicellular organism. Thus, we should not be surprised that cells employ multiple regulatory mechanisms to help them maintain tight and precise control over theirbehavior, and that many different regulatory systems have to be disrupted beforea cell can throw off its normal restraints and behave as an asocial cancer cell. Therestraints are of many types, and tumor cells meet new barriers to further expansion at each stage of their evolution.
Oxygen and nutrients, for example, do notbecome limiting until a tumor is one or two millimeters in diameter, at whichpoint the cells in the tumor interior may not have adequate accessto these necessaryresources.Cellsmust acquire additional mutations, epigenetic changes(orboth) to overcome each new barrier, whether physical or physiological.In general, the rate of evolution in any population of organisms on Earthwould be expected to depend mainly on four parameters: (l) the mutation rate,that is, the probability per gene per unit time that any given member of the population will undergo genetic change; (2) the number of reproducing indiuidualsin the population; (3) the rate of reproduction, that is, the average number ofgenerations of progeny produced per unit time; and (4) the selectiueaduantageenjoyed by successfulmutant individuals, that is, the ratio of the number of surviving fertile progeny they produce per unit time to the number of surviving fertile progeny produced by nonmutant individuals.
The same tlpes of factors arealso crucial for the evolution of cancer cells in a multicellular organism, exceptthat both genetic and epigenetic changes help drive the evolutionary process.TheEpigeneticChangesThatAccumulatein CancerCellsInvolveInheritedChromatinStructuresand DNAMethylationAs just stated, the progression toward cancer differs from normal biological evolution in one important respect: epigenetic changes also occur that give the cells aselective advantage.For many years, pathologists have used an abnormal appearance of the cellnucleus to identify and classifycancer cells in tumor biopsies. For example, cancer cells sometimes contain an unusually large amount of heterochromatin-acondensed form of interphase chromatin that silences genes (see p. 238). Wenow understand some of the molecular mechanisms involved in forming thischromatin, and it is possible to associatenew heterochromatin formation withthe epigenetic silencing of specific genesthat would otherwise block tumor progression.Heterochromatin formation and maintenance involve specific covalentmodifications of histones; these in turn attract complexes of chromatin-bindingproteins that are stably maintained following DNA replication (discussed inChapter 4).
In this way, genes can be turned off in a cell-to-cell inherited manner without any change in the DNA sequence.This epigenetic form of gene regulation plays a major role in driving the orderly pattern of cell specializationsthat occur during embryonic development (discussedin Chapter 22). Errors thatoccur in this process are potentially dangerous becausethey can be transmittedto the progeny of the cell in which the original change occurred.We now know that many of the mutations that make a cell cancerous alterthe proteins that determine chromatin structures.
These include not onlyenzymes that modify the histones in nucleosomes,but also proteins in the "codereader-writer" complexes that interpret the histone code (see Figure 4-43).These findings provide strong evidence for the importance of chromatin-basedepigeneticchangesin lumor progression.During normal developmental processes, an inherited pattern of DNAmethylation reinforces many of the gene silencing events caused by the packaging of genes into heterochromatin (see p. 467).
Analyses reveal that a largeamount of DNA methylation also occurs on selected genes during tumor progression. In summary, although recognized relatively recently, it now appearsthat the abnormal epigenetic silencing of genesis no less important than mutations in DNA sequencesfor the development of most cancers (Figure 20-12).12131214C h a p t e r2 0 :C a n c e rg e n e t i cg e n e i n a c t i v a t i o ng e n exIepigeneticgene inactivationepigeneticgene inactivationg e n eX" "' "'" DNAa c c i d e n t acl h a n g ein nucleotides e q u e n c ei n D N Ag e n eXI a c c i d e n ct a u s e sD N AI p a c k a g i n gi n t oV heterochromatinI a c c i d e n ct a u s e sI m e t h y l a t i o no fV C nucleotidesJC E L LD I V I S I O N SXxttDrvrsroNs-???????????t???t-???????????t???t-????????????????aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaawM A N Y C E L LWS ITHINACTIVATEDGENEXM A N Y C E L LWS ITHI N A C T I V A T EGDE N EXaaaaaaaaaaaaaaaaM A N Y C E L LWS ITHI N A C T I V A T EGDE N EXFigure20- l2 Comparisonof the geneticand epigeneticchangesobservedin tumors.A mutationresultsfrom anirreversiblechangein DNAsequence.In contrastto suchgeneticchanges,epigeneticchangesare basedon alterationsthat,while heritablefrom cellto cell,can be reversedeitherby site-specificchangesin histonemodification(heterochromatinpathway)or by site-specific(methylationpathway).BecauseDNAdemethylationthe epigeneticmarksongenesaregenerallyreversedduringthe formationof eggsand sperm,they arenot inheritedbetweengenerationsandthereforehavenot beenextensivelystudiedby geneticists.As discussedin Chapter7, it is thoughtthat DNAmethylation(aninheritedpatternof methylationof C nucleotidesin CpGsequences)is a mechanismthat is usedto more permanentlysilencegenesthat havealreadybeenturnedoff,and DNAmethylationseemsto be a silencingmechanismthat normallyfollowsthe formationof heterochromatin.Butthemisregulationthat arisesduringtumor progressionmay be ableto producegenesilencingindependentlyofheterochromatinization,as schematicallvillustratedhere.HumanCancerCellsAreGeneticallyUnstableMost human cancer cells accumulate genetic changes at an abnormally rapidrate and are said to be genetically unstable.
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