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Figure2.3 Thepotentialroleofepithelial-to-mesenchymal(EMT)plasticityduringhighgradeserous(HGS)ovariancancerprogression.A:The colorofthecells representstheir
EMT-state(blue = epithelial, purple = spectrum of epithelial/mesenchymal differentiation,and
red=mesenchymal).TGFβpresentinfollicularfluid,whichis released during ovulation, can
induceEMTinthenormalfallopiantubeepithelium(FTE).Thiscanleadtothedevelopmentof
serous tubal intraepithelial carcinoma (STIC) lesions. Activin A, another component of the
follicular fluid, stimulates migration of the STIC cells to the ovary, where they undergo
mesenchymal-to-epithelial transition (MET) and form a primary tumor.In a later stage, cells
exfoliatefromtheprimarytumorandsurviveassinglecellsorspheroidsintheascites.Finally,
they invade the mesothelium and again undergo MET to form macroscopic peritoneal or
omentalmetastases.B:EMTplasticitywithEMTandMETalternatelytakingplaceduringHGS
ovariancancerprogression.FromLoretN,DenysH,TummersP,etal.Theroleofepithelial-
to-mesenchymal plasticity in ovarian cancer progression and therapy resistance. Cancers
2019;11:E838.
Ubiquitinationphysiologicallyservesasadegradationmechanismofproteinsbut the
dysregulatedexpressionofubiquitinationregulatoryproteinsincludingE2s,E3ligases,
anddeubiquitinasescontributestothesignalingofvariousoncogenes,leadingtocancer
progression and metastasis (61). Aberrant ubiquitination of NOTCH3 and TWIST was
found in ovarian cancer (62,63) and ubiquitination degradation-associated FBXW7 was
foundmutatedincervicalcarcinoma(64)andendometrialcancer(65).
NonproductionanddysregulationofS-nitrosylationhavebeenproposedascriticaleventsin
oncogenesis (66). Dysregulated S-nitrosylation, however, affects intracellular trafficking
processes, protein phosphorylation, and protein–protein interactions, and was reported in
prostateandovariancancer(67).
Acetylationofp53enhancesitsfunction by two principal mechanisms. Firstly,C-terminal
acetylation induces a conformational change, opening up the C-terminal DNA-binding
domain, thereby increasing DNA binding and transcriptional activity (68). Secondly,
acetylation of central lysine (K120) specifically induces cell cycle arrest and apoptosis by
activatingp21(69).
CellInvasionandMetastasis
Metastasisisaprocessbywhichsinglecancercellsorcancercellclustersspreadfrom
theprimarytumortodistantsites(70).Cancermetastasiscanproceedonlyifaseriesof
sequential steps are completed, including proliferation, angiogenesis, invasion,
embolizationorcirculation,transportation,adherenceatdistantorgansorvesselwalls,
andextravasationintothesiteofmetastasis.
Most types of cancer have an organ-specific pattern of metastasis. The propensity of
varioustypes of cancer to formmetastasesin specific organswas first proposed byPaget,
whohypothesizedthatthesepatternsresultedfromthe“dependenceoftheseed(cancercell)
on the soil (the metastatic site)” (71). This hypothesis was suggested by the nonrandom
patternofmetastasis.Pagetconcludedthatmetastasesformedonlywhenthe“seedandsoil”
werecompatible.Itisnowappreciatedatamolecularlevelthatmetastasisisdependent
onabalancebetweenstimulatingfactorsversusinhibitoryfactorsfromboththetumor
andhostcells.
A metastasisusually requiresthebalance weightedtowardthe stimulatorysignals. Cancer
progressionisaproductofanevolvingcrosstalkbetweendifferentcelltypeswithinthe
tumorandthesurroundingstroma(72).Thetumorstromacontainsspecificextracellular
matrixas wellascellular componentssuch as fibroblasts,immune andinflammatorycells,
andbloodvesselcells.Theinteractivesignalingbetweentumorandstromacontributestothe
formationofacomplexmulticellularorgan.
The cellular microenvironment can markedly change the gene-expression patterns of
cancercellsandthereforetheirbehaviorandgrowthpotential.Recentstudiesregarding
chemokinesandtheirreceptorsprovideimportantcluesregardingthereasonssomecancers
metastasizetospecificorgans.Invasionthroughthebasementmembraneisacriticalfirst
stepinmetastasisandtheprimaryfeaturethatdefines malignancy. Invasionrequiresthe
interplay between cancer cells and a permissive underlying stroma (73). Invasion of
malignant cells through the basement membrane and endothelial cell migration for
angiogenesisrequiredegradationoftheextracellularmatrix.Thisprocessisfacilitatedbya
groupof enzymes calledmatrixmetalloproteinases(MMPs), which are a family of zincdependent endopeptidases that digest collagen and other extracellular matrix components.
TheyalsostimulateproliferationandinducereleaseofVEGF.Ovariantumorsoverexpress
MMP-2andMMP-9,and this increased expressioncorrelates with aggressiveclinical
behavior(74).
Tumor cell adhesion to the extracellular matrix within tissues greatly influences the
abilityof amalignant celltoinvade andmetastasize (75).Given theshedding natureof
ovariancancer,adhesionmoleculessuchasfocaladhesionkinase,integrins,andE-cadherin
havebeenevaluatedfortheirroleinperitonealmetastasis(76).
The proteins of the extracellular matrix include type I and IV collagens, laminins,
heparinsulfateproteoglycan,fibronectin,andothernoncollagenousglycoproteins(77).
Cell adhesion to these proteins is mediated in part by a group of heterodimeric
transmembraneproteinscalledintegrins,whicharecomposedofanoncovalentlyassociated
alpha-andbeta-subunitthatdefinetheintegrin–ligandspecificity(78,79).
Cadherins are another group of cell–cell adhesion molecules that are involved in
development and maintenance of solid tissues. E-cadherins are the subgroup
predominantlyfoundinepithelialcells(80).Thesetransmembraneproteinsmediatecell–
cell adhesion. E-cadherin is uniformly expressed in ovarian cancer, in low–malignantpotentialtumors,inbenignneoplasms,and—notably—ininclusioncystsofnormalovaries,
butnotinthenormalsurfaceepithelium(81).Cadherindysfunctionisassociatedwithlossof
cell–cell cohesion, altered cellular motility, and increased invasiveness and metastatic
potential.Changesin thecompositionofthecadherin–catenin complex,phosphorylationof
components in the complex, and alterations in the interactions with the actin cytoskeleton
have all been suggested as playing a role in regulating adhesion. Disruption of adhesion
molecules seems to be an early marker of ovarian cancer development and targets like
Claudin-3/4,EpCAMandothersareunderbiomarkerevaluation(82).
Epithelial-to-MesenchymalTransition
Epithelial-to-mesenchymal transition (EMT) as well as its reverse, mesenchymal-toepithelialtransition(MET),arephysiologicprocessesinwhichepithelialcellslosetheir
cell–cell contacts and adopt a mesenchymal-like property that features cytoskeleton
remodelingandmigratoryactivity.Thisisimportant forembryonic developmentand
tissuerepair(83).EMTplaysanessentialroleinmetastaticdiseaseofvariouscancertypes
andisconsideredtobeamajorcontributortothepoorprognosisofgynecologiccancers.By
understanding the EMT-inducing factors in individual tumors, new therapeutic strategies
such as specific small-molecule inhibitors, epigenetically acting agents, or use of miRNA
maybedeveloped.Theaimwouldbetoreversetheprocessandre-induceanepithelialstate
wherethecanceriseasiertotreat(84,85).
EMTplaysaparticularlycrucialrole,particularlyinepithelialovariancancer.Already
early in development, so-called tumor-initiating cells, which are believed to drive ovarian
cancer initiation, show mesenchymal features. There is strong evidence that EMT is a
major contributor to ovarian cancer metastasis and a more aggressive phenotype.
Growing evidence indicates that cells in a partial or “hybrid” EMT-state are even more
aggressivethancellswithacompletemesenchymalphenotype,suggestingthatpartialEMT
maydriveascitesformationandthedevelopmentofperitonealmetastasesinovariancancer.
ThismayalsomeanthatitistheplasticityofEMT,forexample,theabilityofcancercellsto
alternately undergo EMT and MET at different stages, which drives high-grade serous
ovariancancerprogressionanddissemination(Fig.2.3)(86).
Recently,glycosphingolipidshavebeendescribedasaclassofbiomoleculeswhichregulate
EMT in ovarian cancer cells via E-cadherin (87). In endometrial cancer, EMT has been
described as an estrogen driven process which involved various PI3K/AKT-mediated
signalingpathwayssuch as Ras/Raf/MEK/ERK and WNT(88). HPV-derived oncoproteins
canalsoinduceEMTandcontributetocervicalcarcinogenesis(89).
TumorMicroenvironment
Withinthetumormicroenvironment,othercelltypesalsoplayacriticalroleintumorgrowth
and progression. For example, certain types of inflammatory cells including
macrophages, neutrophils, and mast cells and their associated cytokines, may confer
protumorfunctions, an unfavorable prognosis, and increased tumor growth. Tumorassociatedmacrophages(TAMs)andtumor-associatedneutrophilscanenhancetumor
cell invasion and metastasis, angiogenesis, immune suppression, extracellular matrix
remodeling,anddrugresistance,whileinhibitingtheantitumoralimmunesurveillance
(90–93). For example, TAMs, a class of immune cells present in high numbers in the
microenvironmentofsolidtumors,areinvolvedincancer-relatedinflammationandsupport
diseaseprogressionbyprovidingmalignantcellswithtrophicandnutritionalsupport.Their
composition seems to depend on the tumor type, stage, size, and location. They promote
angiogenesis by secreting pro-angiogenic factors like VEGF and suppress the T-cell–
mediatedantitumorimmuneresponses.
Conversely,thepresenceofanadaptiveimmuneresponsecharacterizedbycytotoxicT
cells or tumor-infiltrating lymphocytes (TILs) is associated with improved clinical
outcome as shown in multiple studies across diverse patient cohorts, including
gynecologiccancers(94).Inhigh-gradeserousovariancancer,theextentofCD8+andTILs
is prognostic regardless of the extent of residual disease after cytoreduction and first-line
chemotherapy.ProgressivelygreaterTILcountscorrelatewithabetterprognosis,except
inpatientswithBRCA2mutations.InclusionofTILcountsinthepathologicreportmight
be required in the future. In POLE-mutated endometrial cancers, TILs correlate with
outcome,particularlyinrelationtoresponsetoplatinum-basedchemotherapy(95).
Cancercellsmayevadeimmunerecognitionanddestructionbyvariousmeans,suchasFas
ligandproductionto inducelymphocyticapoptosisandHLA-G secretiontoinhibitnaturalkiller cell activity (96). Cytokine production by cancer cells promotes growth and inhibits
apoptosis.However,themechanistic interactionsbetween themicroenvironmentandtumor
growthremainonlypartiallyunderstood.
ImmuneCheckpoints
Immune checkpoints, crucial for maintaining immune self-tolerance and preventing
autoimmune diseases, can be exploited by tumors to allow them to avoid immune
surveillance (see Chapter 3) (97). There are multiple costimulatory and inhibitory
interactions that regulate T-cell responses. Cytotoxic T-lymphocyte–associated antigen 4
(CTLA4) is expressed exclusively on activated T cells including regulatory T cells and
downregulates T-cell activation. CTLA4-blocking antibodies, such as ipilimumab,
increaseT-cell proliferation and activation, leading to improved antitumorresponses.
Ipilimumabisusedinthetreatmentofmalignantmelanomaandisunderevaluationfor
thetreatmentingynecologiccancers.
Programmeddeath-1 (PD-1) is a heavily glycosylated protein of the immunoglobulin
superfamilyandisinvolvedsimilarlytoCTLAinblockingtheimmuneresponsetosilence
the immune system and thus maintaining physiologic homeostasis. PD-1 is broadly
expressedonactivatedTcellsandbindstotwoligands,PD-L1andPD-L2.Exhaustion
oftumor-infiltratinglymphocytes(TILs)correlatedwithexpressionofPD-1ligandsintumor
cells(98).Despitetheirdifferencesinregulatoryroles,dualblockade,orPD-L1andCTLA4, has shown a synergisticeffect in activating CD8+ and CD4+ effector T cells, reducing
immune-inhibitorycytokinesincludingTGFβandIL-10,andultimatelyimprovinglong-term
survivalrates(99).Variousphase-3trialstargetingthePD-1andPD-L1areongoingin
allgynecologiccancers(seeChapter3).However,reliablepredictivebiomarkersarestillnot
available.
Angiogenesis
All cells require oxygen and other nutrients for survival and growth, and cells must
reside within 100 μm of a capillary in order to receive oxygen (100). Therefore,
angiogenesisisrequiredforsustainedmalignantgrowthbeyondapproximately1mmin
diameter.Angiogenesisoccursasaresultofashiftinbalancetowardproangiogenicfactors
withinthetumormicroenvironmentalongwithdownregulationofantiangiogenicinfluences.
Oneoftheprimary mediatorsof angiogenesisisvascularendothelial growthfactorA
(VEGF-A) (101), which increases vascular permeability, stimulates endothelial cell
proliferationandmigration,andpromotesendothelialcellsurvival(102).Othermediatorsof
angiogenesisincludetumor-derivedfactorsandhoststromal factorsincludingIL-8,alpha-v
beta-3 integrin, the tyrosine kinase receptor EphA2, and matrix metalloproteinases (103).
Patient-specifictumormicroenvironmentalcharacteristicsmay influence the response
toantiangiogenictherapy(104).
Therapeutic strategies have targeted angiogenesis using VEGF-A neutralizing
antibodies (bevacizumab) and multikinase inhibitors that target the VEGF-receptors
alongwithotherkinases.Bevacizumabisthebest-establishedantiangiogenicdrugandis
widely used in the treatment of endometrial, ovarian, and cervical cancers, despite
producingonlymodestprolongationofprogression-freesurvival(PFS)andnoincrease
inoverallsurvival.Multitargetedantiangiogenictyrosinekinaseinhibitorssuchascediranib
andpazopanibhaveshownsomeimprovementinpatientswithplatinum-sensitive,aswellas
platinum-resistantovariancancer.
Most promising, however, seems to be the early observation of improvements in PFS in
patientswithrecurrentovariancancerwiththecombinationofcediranibandPARPinhibition
(105). However, it seems apparent that only a combination of various approaches with
tolerabletoxicitywillleadtoanimprovementinoutcome.Therefore,attemptsareongoingto
combine(i)deficientsingle-strandDNArepairusingPARPinhibitorswith(ii)tumorhypoxia
usingVEGF antagonists, which inturndownregulate genes that areespecially involved in
double-strand DNA repair. Failing both single-strand and double-strand DNA repair may
resultincytosolicDNA.Thelattermayactivatethestimulatorofinterferongenes(STING)
pathway, or may result in cell death with enhancement of local antigen release. Both
mechanisms may improve the efficacy of immune checkpoint blockade. The first trial has
shownacceptabletoxicityofsuchatripletreatmentapproachcombiningolaparib,cediranib,
anddurvalumab(106).
Biomarkers
According to the National Institutes of Health (NIH) Definition Working Group, a
biomarker is a characteristic objectively measured and evaluated as an indicator of
normal biologic processes, pathogenic processes, or pharmacologic responses to a
therapeuticintervention(107).ThisWorkingGroup further separated markers into those
thatwereamarkerofthenaturalhistoryofadiseaseandcorrelatelongitudinallywith
known clinical indices (Type 0 markers) and those that capture the effects of a
therapeuticinterventioninaccordancewithitsmechanismofaction(Type1markers).
Ingeneral,validated biomarkers may have utility at allpointsinthe management of
cancer,namelyas:
Predispositionmarkers:usedtoidentifythoseatincreasedriskofdevelopingcancer,for
example,patientswithinheritedmutationsinBRCA1-2andDNAmismatchrepair(MMR)
genes;
Screeningmarkers:usedinearlydetectionsuchasprostate-specificantigen(PSA)inthe
earlydetectionofprostatecancer;
Diagnosticmarkers: used to define the type, stage, or grade of a tumor, for example,
immunohistochemicalassaysofhistologicsamples;
Prognosticmarkers:usedtoidentifythelikelydiseasecourse.Thesemarkersmaydirect
therapy with low-risk groups avoiding therapy and high-risk groups receiving
intensificationoftherapy;
Predictive markers: used to identify those more (positive predictive marker) or less
likely(negativepredictivemarker)tobenefitfromtreatment,forexample,ER,PR,HER-2
expression.
Biomarkersarealsousefulindrugdevelopment,becausetheymaybeusedasendpoints
and act as surrogate markers of outcome, thus allowing earlier read out of efficacy,
therebysupportingfurtherdevelopment.Pharmacokineticmarkersgiveinformationabout
drug levels, distribution, and elimination kinetics. They can be used to assess proof of
mechanism, namely whether or not a therapy is hitting its target, and proof of concept,
namelywhetherornotitishavingitsdesiredeffectonthetumorbiology.Thisinformationis
vital in interpreting the results of early phase trials. Biomarkers may also be useful for
gaininganunderstandingofthemechanismsunderlyingthevarious clinicalresponses, and
for gaining crucial knowledge from negative as well as positive trials. Therapies may fail
becausetheycannotbedeliveredattherapeuticdoses,theydonothavethedesiredeffecton
theproposedtarget,thehypothesisandproposedmechanismofactionwaswrong,thewrong
populationwastestedorresistancemechanismswerepresentorunderdevelopment.Without
appropriatemarkers,itisnotpossibletounderstandwhyatrialisnegative.Biomarkersmay
thus accelerate drug development and help prevent active therapies from being discarded
(108,109).
A good biomarker is an objectively measured and reproducible characteristic that
describes a normal or abnormal biologic state in an organism by analyzing
biomolecules such as DNA, RNA, protein, peptide, and biomolecular chemical
modifications. If it is to be used in clinical practice, it must be practical and costeffective(110,111).Theaccuracyandthusdiagnosticperformanceof abiomarkertest
canbeexpressedintermsofitssensitivity,forexample,itsabilitytodetectdiseasewhen
diseaseistrulypresent(truepositives)anditsspecificity(itsabilitytodetectabsenceof
disease;truenegatives).Thereisoftenatrade-offbetweenthetwoandtheextenttowhich
thisisacceptablewilldependontheclinicalcircumstances.
Biomarkerdevelopmentrequiresrigorousinvestigationandvalidation.Numerouschallenges
exist, including tumor heterogeneity, their sensitivity to variations in sample handling,
processing and storage, as well as the validity of the assay. Therefore, all potential
biomarkers need to be extensively validated. In order to improve the development of
biomarkers, Cancer Research UK has developed roadmaps for screening, diagnostic,
prognostic/predictive,pharmacologic,andimagingbiomarkers.TheNCRI,NCI,andEORTC
have created a working group to examine the risks and challenges of incorporating
biomarkersintoclinicaltrials.Theyhavedevelopedarisk-assessmentframeworkandalist
ofusefulresourcestohelpprincipalinvestigatorswhendevelopingprotocolsforbiomarkerdriventrials(112).
TumorMarkers
Tumormarkersassumeincreasingrolesinallaspectsofcancercare,coveringscreening
to follow-up after treatment, and they become even more significant in the era of
precisionmedicine (113,114). There are more than 20 tumor markers used in oncology,
whereasthere isno universalcarcinomatumor marker. Tumormarkersareidentifiedby
means of genome, transcriptome, and proteome analyses, and consist of DNA
mutations/deletions, increased/decreased mRNA or protein levels, or protein
modifications.Secretedproteinsareparticularlyusefulbecausetheycanbedetectedin
blood. Nevertheless, tumor markers are only of restricted use, given that almost every
healthypersonhas smallamounts oftumormarkersintheir blood,and anincreaseusually
onlyoccursafterextensivetumorinvolvement,whilesomepatientswithcancerneverexhibit
increasedtumormarkervaluesatall.Theoptimaldetectionrangeforpatientswithcancer
isintheirrangeoflatentgrowth,whichisfarbelowtheclinicallydetectabletumorsize
(numberoftumorcells:103–109).However,thecurrentdetectionlimitofusabletumor
markersis109,whichisclosetotheclinicaldetectionsizeof1012cells.
Personalized medicine represents a major goal in oncology, and now the concept of a
biomarker no longer just corresponds to biologic characteristics measured ex vivo. It also
includes their complex physiologic characteristics that can be measured by different
technologies. A single biomarker may not be sufficient; a combination of several
biomarkerswill probably berequiredtoincreasethe sensitivity and specificitytothe
required level. In addition to advanced imaging technologies like positron emission
tomography (PET), an integrated approach incorporating noninvasive technologies will be
necessarytocharacterizeinvivotumorheterogeneity(115).
“Liquid biopsies” for early detection and real-time monitoring of cancer progression
are assuming increasing importance. These techniques include measurements of
circulatingtumor cells(CTC),circulatingtumor DNA(ctDNA),longnoncodingRNA
(lnRNA), circulating RNA (circRNA), and tumor-derived exosome, which are all
currently under intense evaluation as potential tumor markers (116–119). Also, the
microbiomecompositionmayserveasbiomarkerfortheefficiencyofcheckpointinhibitorbasedimmunetherapy(120).
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