Cell and tissue interactions in carcinogenesis and metastasis and their clinical significance.docx
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Cell and tissue interactions in carcinogenesis and metastasis and their clinical significance.docx
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Cellandtissueinteractionsincarcinogenesisandmetastasisandtheirclinicalsignificance
Review
Cellandtissueinteractionsincarcinogenesisandmetastasisandtheirclinicalsignificance
DavidTarin
a,
aDepartmentofPathologyandMooresComprehensiveCancerCenter,UniversityofCalifornia,SanDiego,3855HealthSciencesDrive,MC0803,LaJolla92093,UnitedStates
Availableonline13December2010.
Abstract
Thisreviewdescribesanewvisionforfuturedirectionsinthestudyofmetastaticcancerbiologyandpathology.Itisbaseduponclinicalandexperimentalobservationsontheconstituentcelllineageswithinaneoplasmandontumour-hostinteractions.Thevisionincorporatesinformationfromstudiesinpopulationbiology,developmentalbiologyandexperimentalpathologyaswellasinvestigationsuponhumanmalignantdisease.Theassembledinformationrevealsthatinvasionandmetastasisaresupra-cellularmanifestationsof“emergentbehavior”amongcombinationsofnormalandmalignantcelllineagesinvivo.Emergentbehaviorisacombinatorialinteractiveprocessinwhichapopulationdisplaysnewtraitswhichcannotbeachievedbyindividualsactingseparatelyandwhichsubsidewhenthespecificpopulationmixdisaggregates.Disruptionofsuchpathologicalinteractionsinthefieldofadevelopingprimaryorsecondarytumouris,therefore,requiredtodisablethemalignantpopulationandarrestprogressionwithouttissuedestruction.Theseconclusionsoriginate,inpart,fromprincipleswhichgovernthesociobiologyandgroupbehaviorofbees,ants,fish,birdsandhumansocieties.Inallthesesocialorganisms,externalfactorscandisruptsignalingmechanismsandinduceexpandingself-perpetuatingroguebehavior,leadingtosocialdisintegration.Theseprinciplesalsoapplytocellularsocietiescomposinghigheranimals,whichlikewiseneedintrinsicrulestomaintainsocialorderandavoidanarchy,andrecognitionofthisisessentialforadvancingfutureresearchonthemechanismsinvolvedincarcinogenesisandmetastasis.Summarisedevidenceispresentedheretosupporttheconclusionthatmiscommunicationsbetweencellsandtissuesintheregionofthedevelopingtumouranditsmetastasesarethemaindirectperpetratorsofmalignantdisease.Geneticlesions(mutations,deletions,translocations,reduplications,etc.),commonlyseenincancers,cansignificantlydisruptimportantmolecularpathwaysinthenetworksofcommunicationsneededtosustainorderlytissue/organstructureandfunction.However,geneticlesionscanalso,themselves,beinducedbyabnormalcellinteractionsinitiatedbyextrinsiccarcinogenicagentssuchaschemicals,viruses,hormonesandradiation.Theevidenceshowsthat,irrespectiveoftheinitiatingcause,itisthismiscommunicationintheregionofadevelopingtumouranditsmetastasesthatisultimatelyresponsiblefortheemergenceandprogressionofthedisease.Thearticledescribeshowthisinformationcollectively,providesaframeworkfordesigningspecificnoveltherapeuticapproachestargetingthecellandtissueinteractionsdrivingtumourmetastasisanditsmanifoldeffectsonthewholebody.
Keywords:
Pathology;Pathogenesis;Emergentbehavior;Superorganism;Regression;Progression;Para-neoplasticSyndromes;Inappropriategeneexpression;Evolution;Neoplasia;Cancer;Malignancy;Tumour
ArticleOutline
1.
Introduction
2.
Currentstateofknowledgeaboutthebiologyandpathologyofcancermetastasis
2.1.Ismetastasisrestrictedtotumours?
2.2.Cellandtissueinteractionsinmetastasis
2.3.Metastasisasanintrinsicpropertyoftumourcells
2.4.Originofthemetastaticdrive:
evolutionarybiology
2.5.Metastasisasanexampleofinappropriategeneexpression
2.6.Carcinogenesis/neoplasia:
theparentofthemetastaticprocess
3.
Anewanddifferentexplanationofcarcinogenesisandmetastasis
4.
Biologicalandclinicalimplicationsofthisnewparadigm
5.
Conclusion
Conflictofinterest
Acknowledgements
References
1.Introduction
Sincethedawnofunderstandingaboutthecancerprocesssome5000yearsago,inthetimeofImhotep,physiciantotheearlyPharaohDjoser,medicalsciencehasbeenmystifiedbytherelentlessgrowthandlocallyinfiltrativenatureoftheprimarytumourandhumbledbyitsdebilitating,frequentlyfatal,effectsuponthehost[1].Subsequentphysicians,includingHippocrates(
400 BC)andGalen(
150 BC)wereawareofthepoorprognosisofcancerpatients,butsofaraswecandetermine,thereisnorecordofarecognitionofthemetastaticbehaviourofmalignanttumoursforover4000yearsofearlycancerhistory.Sometimeinthelate16thcenturyandthe17thcentury,FrenchandItaliansurgeonsincludingFabriciusHaldanus(1560–1634),MarcusAureliusSeverinus(1580–1656),JeanLouisPetit(1658–1725)andFrancoisleDran(1685–1770),begantorecognisethetendencyoflocallydestructiveprimarycancerouslesionstocausehardexpansivenodulesinthevicinityandtheyrecordedthatsimultaneousexcisionofthesesatelliteswasagrimnecessitytogivethepatientevenalowprobabilityofsurvival.However,itwasnotuntil200yearslaterthataFrenchgynaecologist,J-CRecamier[2],recognisedthataspace-occupyinglesioninthebraincausingneurologicalsymptomsinapatientwithbreastcancerwasasecondarytumourseededfromthebreastlesionandnamedtheprocesscancermetastasis.HealsorealisedthatthetumourmightspreadalongbloodvesselseventhoughhehadnomicroscopesandthecellularcompositionofthebodyandoftumourswasyettoberecognisedbySchwann[3]andbyVirchow[4]respectively.DespitethisremarkableleapofinductivereasoningbyRecamier[2],itwasnotuntilthepainstakingmicroscopicalstudiesofThiersch[5]thatitwasestablishedthatcarcinomasarisefromepitheliumandnotfromtheconnectivetissueofanorgan.Thislaidthefoundationforthelaterrealisationthattumoursarenotjustballsofcancercellsbutcomplexmaladjustedlivingentitiescomposedofinterwovennon-neoplasticandneoplasticcomponents.Aquarterofacenturylater,Pagetin1889[6]studiedautopsyrecordsof735womenwithbreastcancerandmadehislandmarkdiscoverythatmetastasesarenotrandomlydistributedinthebody,buttendtocolonisecertainspecificorganswheretheconditionsarefavourable.This,togetherwithSchmitt'smicroscopicdemonstrationoftumourcellsinbloodvessels(1904),finallyconfirmedthatthevasculardisseminationofcancercellsleadstotheformationofsecondarycancers,innon-randompatterns,relatedtothesiteoforiginoftheprimarygrowth.
Evenaftertheadventofmethodstoinducecancersatwill,initiatedbyYamagiwaandIchikawa'ssuccessfulcausation,in1914,ofcancerinrabbitsearspaintedwithcoaltar[7],progressintumourmetastasisresearchwasglaciallyslowuntiltheisolationofrodentand,later,humancancercelllines.
Insteadofbecomingclearerinthetimesincethen,theprocessofmetastasishasbecomeevenmoreinscrutable,asmoreinformationhasbeengathered.Mostofwhatisstatedbelowisobtainedfromdirectpersonalobservationonhumanautopsiesandanimalexperimentsandremainsastruetoday,aswhentheobservationsandfindingswerefirstnoted.
2.Currentstateofknowledgeaboutthebiologyandpathologyofcancermetastasis
Ifwestarttheanalysisoftheprocessofmetastasis,unconventionally,atitsendratherthanitsbeginningwefindthat:
(i)Metastasescangrowmuchlargerthantheoriginalprimarytumourandcanvaryfromeachotherinsizeeveninthesameorgan.
(ii)Thesesecondarycoloniesarenotrandomlydistributedinthebody.
(iii)Theorgandistributionpatternsrelatetothesiteandhistopathologicaltypeoftheprimarytumour.ThiswasfirstreportedbyPaget
[6]andhasbeenconfirmedbymanyarticlesdescribinghumanautopsyseriesandbyexperimentsinanimalsandinhumansreferencedbelow.
(iv)Inindividualpatients,occasionalmetastasescansometimesbefoundoutsidethecommondistributionpatternforthattypeofcancer.
(v)Thehistopathologicalstructureofthemetastasesisverysimilar,whenviewedunderamicroscope,tothatseenintheprimarytumour(
Fig.1a–c)andthisisoftenclinicallyhelpfulinfindinganoccultprimary.Thissimilarityindicatesthatthedisseminatingcellscarrywiththemtheblueprintsforreassemblingtheoriginalhistologicalpatternfromlocallyavailablecellsandtissues.ThustheydoNOTtransformintoothercelltypes(lineages)characteristicofthenewlocation.Forexampleabreastcancermetastasisinthebrainhistopathologicallyresemblestheoriginalbreastcancernotabraincancer.
Full-sizeimage(265K)
Fig.1.
(a)Histologyofinfiltratinglobularcarcinomaofthebreast(E:
epithelialcells;SStromalcells;C:
Intercellularcollagen)(200×).(b)Histologyoflymphnodemetastasisfromprimarytumourshownin(a).Notethesimilarityinthepatternoforganizationtotheprimarytumourandtheresiduallymphocytes(L)whicharetheonlyremnantsofthenode(200×).(c)Normalwellorganizedbreasttissue(100×).(d)CarcinomastainedwithantibodyKi67tomitoticprotein.Notefrequencyofmitoticcellsinnon-neoplasticstroma(thinarrows)equalsthatinthecarcinomatousepithelium(thickarrows)ofamalignantgland(200×).(e)Non-neoplasticgreenhoststromalcells(S)andbloodvessels(V),labeledwithgreenfluorescentproteininfiltratingamongredcarcinomacells,labeledwithredfluorescentproteininaprimarycarcinoma(200×).(f)Hoststromalcellsandbloodvesselsenteringametastaticcarcinomadepositseededfromthetumourshownin(e)(400×).(g)Yewtreewithtumourofthetrunk(1/250×).(h)Anotherviewshowi
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