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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5186_Библиотеки_им_академика_М_И_Перельмана.pdf
Amplification of some oncogenes results in multiple copies of a gene with resultant
overexpression of the corresponding protein. HER-2/neu amplification in a subset of
breastcancersisanexampleofatumordrivenbyamplificationofasinglegenethatcanbe
therapeutically targeted using an anti-HER-2/neu antibody,trastuzumab. Other oncogenes,
such as KIT in gastrointestinal stromal tumors (GISTs), may become overactive when
affected by point mutations at codons that change a single amino acid leading to gain of
function.Finally,oncogenesmaybetranslocatedfromonechromosomallocationtoanother
andthencomeundertheinfluenceofpromotersequencesthatcause overexpressionof the
gene.Thislattermechanismfrequentlyoccursinleukemiasandlymphomas(e.g.,theBCR-
ABL translocation in chronic myelogenous leukemia), but is relatively uncommon in
gynecologic and other solid tumors. For tumorigenesis that is driven by activation of
individualoncogenes,targetingtheoncogenecanbeausefultherapeuticapproach.
Many genes that are involved in normal growth regulatory pathways can elicit
transformation when altered to overactive forms via amplification, mutation, or
translocation(explained in detail in Chapter1). Onthisbasis,a large numberof genes
havebeenclassifiedasoncogenes.Studiesinhumancancershavesuggestedthattheactual
spectrumofgenesalteredinthedevelopmentofhumancancersismorelimited.Anumberof
genesthatelicittransformationwhenactivatedinvitrohavenotbeendocumentedtoundergo
alterationsinhumancancers.
TumorSuppressorGenes
Lossoftumorsuppressorgenefunctionplaysaroleinthedevelopmentofmostcancers
(seeChapter1).Thisusuallyinvolvesatwo-stepprocessinwhichbothcopiesofatumor
suppressorgeneareinactivated.Inmostcases,thereisamutationofonecopyofatumor
suppressor–encodinggene.Thelossoftheothercopyiscausedbydeletionofasegmentof
thechromosomewherethegeneresides.Sometumorsuppressorgenesmaybeinactivated
becauseofmethylationofthepromoterregionofthegene(7). The promoteris an area
proximaltothecodingsequencethatregulateswhetherthegeneistranscribedfromDNAto
RNA.Whenthepromoterismethylated,itisresistanttoactivationandthegeneisessentially
silenceddespiteremainingstructurallyintact.
Beyond simply inhibiting proliferation, normal p53 is thought to play a role in
preventing cancer by stimulating apoptosis of cells that have undergone excessive
geneticdamage.Inthisregard,p53hasbeendescribedasthe“guardianofthegenome”
becauseitdelaysentryintoSphaseuntilthegenomehasbeencleansedofmutations.If
DNA repair is inadequate, then p53 may initiate apoptosis, thereby eliminating cells with
geneticdamage.Likewise,othergenesthatrepairdamagetotheDNAnucleotidesequenceor
strandbreakagesometimesareclassifiedastumorsuppressors.
DNARepair
Gene variants of the OGG1 (8-oxoguanine DNA glycosylase) and NEIL2 (nei like DNA
glycosylase 2) base excision repair (BER) glycosylases were proposed to contribute to an
enhancedriskofovariancancerinpatientswithmutationsinBRCA1andBRCA2(8).OGG1
variantsandBRCA1germlinemutationsaredetectedin63%ofwomenwithovariancancer
(9). Upregulated POLB (DNA polymerase beta), APE1 and XRCC1 (x-ray repair cross
complementing1)proteinlevelscorrelatewithhigh-gradeserousovariancancer,higherrates
of platinum resistance, and poor overall survival (10,11). XRCC1 polymorphisms are
associatedwithovarianandcervicalcancer(12,13),andthey arealsoinvolved inrepairof
single-strand breaks during BER (14) and nucleotide excision repair (NER) (15). XRCC1deficientcells are sensitivetoDNAdamaging agentsand accumulate chromosomalbreaks
(16).Therefore,lossofXRCC1expressionissignificantlyassociated withpoor survivalof
breast cancer patients, presumably due to genome instability and a hypermutational
phenotype(17).
Remarkably, inhibition of double-strand break repair with synthetic inhibitors in
XRCC1-deficientcellsresultsinaccumulationofdouble-strandbreaks,arrestofG2–M
cell-cycle progression, and induction of cell death (17). Defective double-strand break
repairandBERareriskfactorsforgynecologiccancerdevelopment.MonitoringNHEJand
BERproteinexpression aswell asdetectionof genevariants andmutationsinhomologous
repair(HR),NHEJandBERgenesmaybeusedaspredictivebiomarkersfortheoutcomeof
chemotherapy.SinceBERandHRrepairDNAdamagecausedbyirradiationandalkylating
agents,selective inhibition ofBER and HR during treatmentmayincrease effectivenessof
cancertherapy,andcautionisrequiredtonotoverdosethepatient.
DNADamageResponseDefectsandSyntheticLethalityto
EnhanceEfficacyofCancerTherapy
GenotoxicinsulttoinflictcytotoxicDNAdamageandinducecelldeathisanimportant
strategy in cancer treatment. Ionizing radiation and/or cisplatin can generate DNA
cytotoxicdouble-strandbreaks, intrastrand and interstrand DNAcross-links and have been
proventobesuccessfulinthetreatmentofavarietyofcancers.Yet,theeffectivenessofthese
strategiesislimitedbythedevelopmentofresistance.Thelatteroriginatesfromreduceddrug
uptake,increaseddrugexport,andincreaseddamagerepairortolerancebyupregulationof
DNAdamageresponse(DDR)components(18).Anotherproblemissecondarymalignancies
which can be caused by DNA damaging agents because of potential mutagenesis and
carcinogenesis following treatment of cancer cells with reduced DNA repair activity.
Therefore, improved strategies for cancer therapy using more selective approaches for
overcomingtumorresistanceareneeded.TargetingDNArepairsystemshasemergedasa
potentialapproachtoadjuvanttherapiesforimprovingthetherapeutic indexof DNA
damage–inducingagentsincancertherapy.
ThesyntheticlethalinteractionofPoly-ADP-Ribose-Polymerase(PARP)inhibitionand
BRCA1 or BRCA2 mutation emerged as a novel strategy for treating patients with
BRCA-mutant tumors. Synthetic lethality is a genetic term used to describe a situation
where a defect in each of two pathways individually has no effect, but a defect in both
pathways together results in cell death (19). This concept of synthetic lethality was
successfullyusedbyinhibitingPARP1activityinBRCA-mutatedtumorcells.BRCA-mutated
cellsaresensitivetoPARPinhibitionandgointoapoptosis,whereasBRCAwild-typecells
arelargelyunaffected(20).Themechanismunderlyingthesyntheticlethalinteractionof
PARP1inhibitionand BRCA1 orBRCA2mutationcanbeexplainedby the ability of
PARPinhibitors(rucaparib,olaparib,niraparib,talazoparib)toblockauto-PARylationand
PARP1dissociationfromthesingle-strandbreaks(21).
In BRCA1- or BRCA2-mutated cells, these double-strand breaks are not repaired,
ultimatelycausingsyntheticlethality.Theexample ofPARPinhibition demonstratesthat
targeting key DNA repair factors in DDR-reduced cancer cells represents a promising
treatment option for patients with gynecologic malignancies. Importantly, the approach to
induce synthetic lethality is not limited to HR but may be achieved by targeting other
alternative DNA repair pathways and enhanced in combination with DNA-damaging
chemotherapeutics(22).
CellDeathPathways
Inadditiontobeingdrivenbyincreasedproliferation,cancergrowthmaybeattributableto
cellularlethal resistance. Atleastthree distincttypesof cell deathpathwayshave been
characterized,includingapoptosis,necrosis,andautophagy(23).Allthreepathwaysmay
beongoingsimultaneouslywithinatumor.
Autophagy
Autophagyisapotentiallyreversibleprocessinwhichacellthatisstressed“eats”itself.
Awiderangeofstressfactorshavebeenidentifiedthatmayelicitautophagy(someofwhich
mayalsoelicitapoptosis),includinggrowthfactordeprivationandaccumulationofreactive
oxygen species. Unlike necrosis and apoptosis—in which the loss of integrity of the
cytoplasmicand nuclear membranes are the defining events—autophagyischaracterized
by the formation of cytoplasmic autophagic vesicles, into which cellularproteinsand
organellesaresequestered.Thismayallowforcellsurvivalifdamagedorganellescanbe
repaired.Conversely,theprocessmayleadtocelldeathifthesevesiclesfusewithlysosomes
with resultant degradation of their contents. Several cancer therapeutic agents have been
shown to induce autophagy, while targeted disruption of genes such as ATG5 that are
involvedinautophagycaninhibitcelldeath(24).
Apoptosis
ThetermapoptosisisderivedfromGreekandalludestoaprocessakintoleavesdyingand
fallingoffatree.Apoptosisisanactive,energy-dependentprocessthatinvolvescleavage
of the DNAor proteins by endonucleases and proteases called caspases, respectively.
Morphologically, apoptosis is characterized by the condensation of chromatin, nuclear and
cytoplasmicblebbing, andcellular shrinkage.The molecularevents thataffectapoptosisin
responsetovariousstimuliarecomplexandhavebeenonlypartiallyelucidated(25).Several
reliable markers of apoptosis have been discovered including annexin V, caspase-3
activation,andDNAfragmentation(24).
External stimuli such as the tumor necrosis factor and related apoptosis-inducing
ligands,fattyacidsynthase(FAS),aswellasotherdeathligandsthatinteractwithcell
surface receptors can induce activation of caspases and lead to apoptosis via an
extrinsicpathway(Fig.2.2).Incontrast,theintrinsicpathwayisactivatedinresponsetoa
widerangeofstressfactors includingDNAdamageanddeprivationofgrowthfactors.The
intrinsicapoptosis pathwayisregulated by acomplex interaction ofpro-and antiapoptotic
proteins in the mitochondria that affect its membrane permeability. Proteins that increase
permeability allow the release of cytochrome c, which initiates the apoptosome complex
leadingto theactivation ofcaspases andconsequentlycell apoptosis.Conversely,proteins
thatstabilizemitochondrialmembraneshavebeendescribedthatinhibitapoptosis.
Figure2.2Thepotential mechanism ofERRαinenergymetabolism:thePGC-1α/ERRα
axis,asthekeypointofenergymetabolismincancercells,isinvolvedinmediatingthe
metabolismoflipids,glycolysis,andglutaminethroughtranscriptionfactorsthataffect
the bioenergetics of cancer cells, and then changes the behavior of invasion,
metastasis,anddrugresistanceofcancercells.ERRα,estrogen-relatedreceptorα;PPAR
γ, peroxisome-proliferator activated receptorγ; FASN,fatty acid synthase;TCA, tricarboxylic
acidcycle;ROS,reactiveoxygenspecies.FromLiuG,SunP,DongB,etal.Keyregulatorof
cellularmetabolism,estrogen-relatedreceptorα,anewtherapeutictargetinendocrine-related
gynecologicaltumor.CancerManagRes2018;10:6887–6895.
The first major insight into the understanding of the intrinsic apoptotic pathway was the
findingthatanactivatingtranslocationofthe BCL-2genein B-celllymphomas resulted in
essentially a complete inhibition of apoptosis (26). Subsequent studies have demonstrated
that the antiapoptotic effect of BCL-2 is attributable to stabilization of the mitochondrial
membrane.AdditionalgenesrelatedtoBCL-2(e.g., BADand BCL-XL)block apoptosisby
inhibiting membrane permeability. Other genes in the BCL family (e.g., BAX and BAK)
increasemembranepermeabilityandareproapoptotic.Anincreasedunderstandingofthe
complexsystemof molecularchecksandbalancesinvolvedin regulationofapoptosis
provides opportunities for targeted cancer therapies; several strategies are under
development(27).
Inadditionto restrainingthenumberof cells in apopulation,apoptosis serves as an
importantroleinpreventingmalignanttransformation byallowingthe eliminationof
cells that have undergone genetic damage. Following exposure of cells to mutagenic
stimuli, including radiation or carcinogenic agents, the cell cycle is arrested so that DNA
damagemayberepaired.Here,apoptosisusuallyoccursifDNArepairisnotsufficient.This
servesasananticancersurveillancemechanismbywhichmutatedcellsareeliminatedbefore
theybecomefullytransformed.Inthisregard,theTP53tumorsuppressorgeneisacritical
regulator of cell cycle arrest and apoptosis in response to DNA damage, and the
frequencyof TP53 mutations in human cancers reflects its critical role in preventing
tumorigenesis.
Necrosis
Necrosisisa typeof celldeaththatisdistinctfromapoptosis,and itis theresultofa
bioenergeticcompromise.Morphologicchangesincludeswollenorganellesandrupture of
thecellmembrane,leadingtolossofosmoregulationandcellularfragmentation.Necrosisis
alesswell-regulatedprocessthatleadstospillageofproteincontents,andthismayincitea
brisk immune response. This is in contrast to the silent elimination of cells by apoptosis,
whichtypicallyelicitsaminimalimmuneresponse.Thereisevidencethatsomedrugsmay
enhance necrotic death in tumors, and this may stimulate a beneficial antitumor immune
response(24).
CancerStemCells
Cancerstemcells(CSCs)areconsideredtobeasmallsubpopulationoftumorcellsthat
havepropertiesoftumorigenesis,potentialformultilineagedifferentiation,self-renewal,
andslowcyclingcapacity(28).CSCsarethoughttobethestartingpointforcarcinogenesis
and to play critical roles in cancer relapse and metastasis. They are promising targets for
cancertreatment(29).TumorsconsistofamixtureofCSCsandtheirdiverselydifferentiated
progeny, which contributes to the significant phenotypic and functional heterogeneity of
CSCsandeventuallytotheheterogeneityofcancers(28,29).
Cervical cancer has a causal relationship with specific human papillomavirus (HPV)
strains. A current view proposes that HPV-associated cervical carcinoma arises from the
HPV-infected cells in the squamocolumnar junction area, the transition area between the
endocervixandectocervix,whichmayactastheCSCniche(30). Endometrialcancer may
alsoderivefrom normal endometrial epithelial stemcellsresiding in glandular tissue even
after shedding in each menstrual period. They are thought to be easily susceptible to
transformingmutations,andtheirclonalexpansionultimatelyresultsinclonaloccupationof
wholeglands.Thissupportsthe“stem-cell–hit”theoryofendometrialcarcinogenesisandthe
ideathatsuchaglandisoccupiedbydescendantsofastemcellthathadsufferedagenetic
“hit”(31,32).
Ovariancancerstem cells(OCSCs)havebeendescribedformorethanadecade (33).
ThemanydifferentkindsofOCSCsmayaccountforthevarietyofovariancancersubtypes
and/or the heterogeneity within a tumor in addition to the various proteins described as
potentialCSCmarkers.Consequently,manymarkersofOCSCshavebeensuggested,some
ofwhichhavebeenconsideredastargetsforimmunotherapy.Ovariancancerseemstobea
prototypicalexampleofCSC-drivendiseaseasinitiation,primarytumorgrowth,metastasis,
relapse,resistance totherapy,andeven epithelial-to-mesenchymaltransition (EMT) canbe
explainedbyOCSCexistence.ThenichesforOCSCcanbethesameasforthesomaticstem
cellswithintheovaryandthetubes,buttheperitonealdisseminationimpliestheexistenceof
multiple types of niches to support the function of OCSC in different anatomical sites.
Interestingly,cellswithOCSCtraitsarefoundinascites,aperitonealfluidcommonlypresent
in patients with advanced OC (34,35).Elimination of OCSC by an immunotherapeutic
approach, for instance by CAR T-cellular immunotherapy,indeed appears attractive
andiscurrentlybeingconsidered(35).
CellularSenescence
Normal cells are capable of undergoing division only a finite number of times before
becoming senescent. Cellular senescence is regulated by a biologic clock related to
progressive shortening of repetitive DNA sequences (TTAGGG) called telomeres that
captheendsofeachchromosome.Telomeresarethoughttobeinvolvedinchromosomal
stabilization and in preventing recombination during mitosis. At birth, chromosomes
havelong telomeric sequences(150,000 bases) thatbecomeprogressively shorter by50 to
200baseseachtimeacelldivides.Telomericshorteningisthemolecularclockthattriggers
senescence.Malignantcells oftenavoidsenescencebyturning onexpressionoftelomerase
activitytopreventtelomericshortening(36).Telomerase isa ribonucleoproteincomplex.
The RNA component serves as a template for telomeric extension, and the protein
subunitcatalyzesthesynthesisofnewtelomericrepeats.
Telomerase activity can be detected in a high proportion of gynecologic cancers,
including ovarian (37), cervical (38,39), and endometrial (40). Thus, detection of
telomerasehasbeensuggestedasusefulforearlydiagnosisofcancer,butthelackofcancer
specificity is a significant issue. In this regard, endometrium is one of the normal adult
tissuesinwhichtelomeraseexpressionismostcommon(41).Perhapsthisrelatestotheneed
foralargenumberoflifetimecelldivisionsbecauseoftherapidgrowthandsheddingofthis
tissue each month during the reproductive years. Therapeutic approaches to inhibiting
telomeraseareunderdevelopment,focusingonreversingtheimmortalizedstateofcancer
cellstomakethemsusceptibleonceagaintonormalreplicativesenescence(36).
CellMetabolism
Normal tissues generate energy (in the form of ATP) using mitochondrial oxidative
phosphorylationandswitchtoglycolysisonlytoderiveenergyintheabsenceofoxygen,
which leads to the accumulation of lactate. Cancer cells, in contrast, as they grow
rapidlyrequireincreasedamountsofglucosetosatisfytheirmetabolicdemandsanduse
glycolysis even in the presence of oxygen, a phenomenon called “aerobic glycolysis.”
Thisisreferredtoasthe“Warburgeffect”(42,43).Cancercellsnotonlyrequiresufficient
energy, they also must maintain pools of metabolic intermediates for building up the
macromoleculesneededforproliferationincludingtheDNA,proteins,andlipids.
Thesetasksareaccomplishedbymetabolicreprogramming,thatis,theadaptationofthe
metabolismtothecancercells’requirements.Theseincludeincreasedaerobic glycolysisto
produce energy, increased consumption of glutamine to supply the nitrogen for nucleotide
and amino acid synthesis, and elevated availability of fatty acids for the lipid synthesis
needed for membrane synthesis for cell division. Likewise, cancer cells need sufficient
oxygentocounteract thehypoxic microenvironmentoftenseen intumors.Thisisachieved
by the induction of HIF-a (hypoxia-inducible factor 1-alpha), a transcription factor which
promotestranscriptionofpro-angiogenesisgenesandofthoseinvolvedinglucosetransport
andglycolysis.
The mechanisms behind the metabolic reprogramming are diverse and include
oncogenicactivation,therepressionoftumorsuppressorsignaling,epigeneticmodifications,
andmutationsinmetabolicenzymesthemselves.OneexampleistheactivationofthemTOR
pathway which plays a key role in intracellular metabolism (glycolysis, glutamine uptake,
and protein translation) and hence governs processes related to proliferation, growth,
survival,motility,andproteintranslation(44,45).
As the metabolic profiles of tumor cells distinguish them from normal cells and are
criticalfortheirgrowth and survival, the metabolic signaling pathways have become
desirable targets for therapeutic intervention in cancer patients (46). It has been
establishedthat,understressfulconditions,transformedcellscanrapidlyadaptmetabolismto
usealternativestoglucosefuelsources,includinglactate,ketonebodies,andacetate.Some
of these metabolites are waste products of glycolysis and they can alter the tumor
environment via acidification, and suppress the immune system. They can also drive the
remodelingoftheextracellularmatrix,stimulatecellmigrationandangiogenesis,andpermit
thetranscriptionalactivationofoncogenes,eventuallyfurtherpromotingcancerprogression
and metastasis. These aspects of cancer cell metabolism have stimulated interest in
developingnovelanticancertherapiesthattargetenergyandmetabolicpathways(47).
HormoneMetabolism
Imbalance of female hormone levels is closely associated with the initiation and
development of malignant carcinomas, particularly endometrial and ovarian cancers.
Estrogen is the most prominent hormone and its receptor ER (estrogen receptor)
perhapsthebestdescribedtherapeutictarget(Fig.2.3)(48).ER-alphahasakeyfunction
intheinitiationanddevelopmentoftheseendocrine-relatedgynecologictumors.Itgoverns
themetabolicprogramthatsubsequentlypromotestumorcellgrowth,division,proliferation,
angiogenesis, migration, metastasis, and drug resistance. The application of selective
estrogen receptor antagonists (selective ER modulators, SERMs), which targetthe ER has
produced varying clinical results. While therapeutic benefits have been achieved in breast
cancer,theseagentshavebothanticancerandcarcinogeniceffectsinendometrialcarcinoma,
buthavebeenlesseffective.Theeffectofendocrinetherapyinthemaintenancesettingand
inspecificsubtypesofovariancancer(low-gradeserousovariancancer)isyettobedefined
andtrialsareongoing(49–51).
Post-translationalModifications
By definition, post-translational modification (PTM) refers to the covalent and
generally enzymatic modification of proteins following protein biosynthesis, thereby
increasing the functional diversity of the proteome by the covalent addition of functional
groups or proteins, proteolytic cleavage of regulatory subunits, or degradation of entire
proteins. These modifications include phosphorylation, glycosylation, ubiquitination,
nitrosylation, methylation, acetylation, lipidation, and proteolysis and they influence
almostallaspectsofnormalcellbiologyandpathogenesis.Aberrantphosphorylationand
glycosylationarethemostfrequentPTMsincancer.
AnexampleforaberrantphosphorylationistheAKTpathway,whichisoneofthemost
frequently hyperactivated signaling pathways in human cancer (52). Stimulated by
growthfactors,hormones,and released cytokines through serial phosphorylation events or
lossofPTEN,AKTsignalingregulatescriticalcellularprocessesincludingcellsurvivaland
proliferation,glucosemetabolism,cellmigration,cancerprogression,andmetastasisthrough
phosphorylationofavarietyofdownstreamtargets.
Lessthan 2%ofproteins oftheentireproteomeareexpressedina cell/tissue-specific
manner.Thus,glycosylation,aformofpost-translationalmodification,definesthefunction
for each eukaryotic cell. Along with nucleic acids, proteins, and lipids, glycans
(carbohydratesorsugars) areone ofthefourfundamentalclasses ofmoleculesinvolvedin
almostallbiologicprocesses.Glycosylationofproteinsandlipidshasbeenlinkedtovarious
human diseases including pathogenic infections, inflammation, and cancer. Aberrant
glycosylationisoftenahallmarkofmalignanttransformationand tumorprogression.
This may include loss or overexpression of certain glycan structures, the persistence of
truncatedstructures,andtheemergenceofnovelstructures(53).Tumorcellsdisplayawide
range of aberrant glycosylations compared to their nontransformed counter cells. These
includeglycoconjugatessuchasN-glycansandO-glycansonglycoproteins,glycolipids,and
glycosaminoglycans.
Glycosylationofproteinsoccursinonlyasmall fractionofknownglycoproteins, however,
thereisclear evidence that glycosylation ofproteinsresults in enhanced cancer specificity
andnot just thespecificityof theglycanor peptide moietyalone. Aberrantglycosylation
represents a hallmark of cancer and reflects cancer-specific changes in glycan
biosynthetic pathways such as the altered expression of glycosyltransferases and
glycosidases. Aberrant abundance of glycan structures, occurrence of truncated structures
and novel structures of glycans present on biomolecules such as proteins and lipids are
believedtoaffectthefunctionofthebiomoleculesandtheligand–receptorinteractions,and
thus interfere with the regulation of cell adhesion, migration, and proliferation (54). As
glycosylationofproteinsandofotherbiomoleculescandifferbetweencancerand“healthy”
cells,glycobiologyalso represents a promising field for potential biomarker identification,
eventually contributing to earliest possible disease detection and to improvement of
diagnostic and prognostic accuracy (55–58). Interestingly, antiglycan antibodies present in
serumand ascitesof ovariancancer patientshavebeen proposed as tumor markers due to
theirdiscriminatorydiagnosticpower(59,60).