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Gastric Cancer in History: A Perspective Interdisciplinary Study

Authors:
  • University of Campania “L. Vanvitelli”

Abstract and Figures

Background: Gastric adenocarcinoma is the fourth most common type of cancer and the second leading cause of cancer death in the world. Despite abundant traces of an ancient history, the comprehension of its pathogenic mechanisms is rather recent and continuously updated. Methods: We investigated about how the ancient civilizations tried to understand the exactly physiopathology of gastric cancer, from the time when they could not examine deeply the histological and pathophysiologic aspects of the disease, but they just based their knowledge on a visual analysis of the signs and consequences of such disease. We examined the historical evolving knowledge of the disease along the centuries on the gastroenterological, pharmacological, and surgical fields, defining how gastric cancer became an increasingly curable disease. Results: Cancer was known in the ancient world. Ancient people did not know exactly the causes but the climatic, hygienic, and food conditions were the first to be considered over time, also taking into consideration supernatural negative influences. During the Renaissance, a tumultuous time of scientific discoveries started, thanks to an increasing number of autopsies made on cadavers and to the progressions in visual analysis of the stomach mucosa throughout endoscopy. From the first gastric surgery in 1879, many steps forward have been made and, today, gastric cancer is regarded as a more curable disease; one important discovery in this field has been the revelation of the role of Helicobacter pylori in the peptic ulcer disease (PUD) and in some forms of gastric lymphoma. Conclusions: Gastric cancer has the fourth highest incidence of various cancers worldwide and is ranked second as a cause of cancer-related death. It exists from the antiquity and a lot of hypotheses have been developed about its etiology during the centuries, influencing its therapy. During the 20th century, thanks to the scientific and technological progresses the causes of the cancer have been discovered and the role of the bacterium Helicobacter pylori has been demonstrated, and new perspective research are currently trying to investigate the role of other microorganisms in gastric physiopathology, as well as its possible modulation by probiotics.
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Cancers2020,12,264;doi:10.3390/cancers12020264www.mdpi.com/journal/cancers
Article
GastricCancerinHistory:APerspective
InterdisciplinaryStudy
SkenderTopi
1,2,†
,LuigiSantacroce
3,4,
*
,†
,LucreziaBottalico
4
,AndreaBallini
5,6
,
AlessioDaniloInchingolo
7
,GiannaDipalma
7
,IoannisAlexandrosCharitos
8,‡

andFrancescoInchingolo
7,‡
1
DepartmentofClinicalDisciplines,SchoolofTechnicalMedicalSciences,UniversityofElbasan
A.Xhuvani”,3001Elbasan,Albania;skender.topi@uniel.edu.al
2
Surgery,RegionalHospital“X.Kongoli”,3001Elbasan,Albania
3
IonianDepartment(DJSGEM),MicrobiologyandVirologyLab.,UniversityofBari“A.Moro”,
70124Bari,Italy
4
PolyphenoAcademicSpinOff,UniversityofBari“A.Moro”,70124Bari,Italy;bottalico.lu@gmail.com
5
DepartmentofBiosciences,BiotechnologiesandBiopharmaceutics,UniversityofBari“AldoMoro”,
70124Bari,Italy;andrea.ballini@uniba.it
6
DepartmentofPrecisionMedicine,UniversityofCampania“LuigiVanvitelli”,S.AndreadelleDame—
ViaL.DeCrecchio,7—80138Naples,Italy
7
DepartmentofInterdisciplinaryMedicine,UniversityofBari,GeneralHospital,Bari,Italy;
aleinki10@hotmail.it(A.D.I.);info@francescoinchingolo.it(G.D.);francesco.inchingolo@uniba.it(F.I.)
8
PoisoningNationalCenter,EmergencyandUrgencyService,RiunitiUniversityHospitalofFoggia,
71122Foggia,Italy;alexanestesia@hotmail.com
*Correspondence:luigi.santacroce@uniba.it;Tel.:+390805478486
Sharedfirstauthor.
Sharedlastauthor.
Received:24December2019;Accepted:20January2020;Published:22January2020
Abstract:Background:Gastricadenocarcinomaisthefourthmostcommontypeofcancerandthe
secondleadingcauseofcancerdeathintheworld.Despiteabundanttracesofanancienthistory,
thecomprehensionofitspathogenicmechanismsisratherrecentandcontinuouslyupdated.
Methods:Weinvestigatedabouthowtheancientcivilizationstriedtounderstandtheexactly
physiopathologyofgastriccancer,fromthetimewhentheycouldnotexaminedeeplythe
histologicalandpathophysiologicaspectsofthedisease,buttheyjustbasedtheirknowledgeona
visualanalysisofthesignsandconsequencesofsuchdisease.Weexaminedthehistoricalevolving
knowledgeofthediseasealongthecenturiesonthegastroenterological,pharmacological,and
surgicalfields,defininghowgastriccancerbecameanincreasinglycurabledisease.Results:Cancer
wasknownintheancientworld.Ancientpeopledidnotknowexactlythecausesbuttheclimatic,
hygienic,andfoodconditionswerethefirsttobeconsideredovertime,alsotakinginto
considerationsupernaturalnegativeinfluences.DuringtheRenaissance,atumultuoustimeof
scientificdiscoveriesstarted,thankstoanincreasingnumberofautopsiesmadeoncadaversandto
theprogressionsinvisualanalysisofthestomachmucosathroughoutendoscopy.Fromthefirst
gastricsurgeryin1879,manystepsforwardhavebeenmadeand,today,gastriccancerisregarded
asamorecurabledisease;oneimportantdiscoveryinthisfieldhasbeentherevelationoftherole
ofHelicobacterpyloriinthepepticulcerdisease(PUD)andinsomeformsofgastriclymphoma.
Conclusions:Gastriccancerhasthefourthhighestincidenceofvariouscancersworldwideandis
rankedsecondasacauseofcancerrelateddeath.Itexistsfromtheantiquityandalotofhypotheses
havebeendevelopedaboutitsetiologyduringthecenturies,influencingitstherapy.Duringthe
20thcentury,thankstothescientificandtechnologicalprogressesthecausesofthecancerhavebeen
discoveredandtheroleofthebacteriumHelicobacterpylorihasbeendemonstrated,andnew
perspectiveresearcharecurrentlytryingtoinvestigatetheroleofothermicroorganismsingastric
physiopathology,aswellasitspossiblemodulationbyprobiotics.
Cancers2020,12,2642of14
Keywords:gastriccancer;Helicobacterpylori;gastritis;atrophicgastritis;pepticulcerdisease(PUD);
gastricsurgery;epidemiology;historyofmedicine;famouspatients;personalizedmedicine
1.Introduction
Gastriccancerisawellknown,lifethreateningconditionaffectingmanypeopleworldwide.Today,
gastriccancerrepresentsoneoftheleadingcausesofdeathworldwide,butverylittleisknownaboutthe
antiquity,epidemiologyandevolutionofcancerinpasthumanpopulations[1].Currently,theincidence
isdecreasingthankstoearlydiagnosis,reducedincidenceofHelicobacterpyloriinfection,diffusionof
healthylifestyles(includingsmokecessationandgoodnutrition),butsomegeographicaldifferences
stillremaininitsincidenceandmortalityrate.
However,duringthetimesgastriccanceraccountedforalargenumberofdeaths,mainlybecause
ofthelackofknowledgeaboutitscausesandoftheabsenceofeffectivetherapies.Infact,thefirstofficial
surgicalinterventionforgastriccancerwasperformedinthelate19thcenturythankstoProf,Theodor
Billroth.
Ifthetherapyofgastriccancerisrecent,itshistoryisverylong,asreportedinsomedocumentsfrom
ancientcivilizations.Startingfromourownexperienceassurgeonsandanesthesiologists,oralhealth
professionals,pathologists,microbiologistandlaboratoryclinicians,wehavefocusedthemainstepsof
theevolutionoftheknowledgeaboutgastriccancer,itsetiology,andtreatmentsthroughtime.
Forthispurpose,selectedarticleswereidentifiedthroughmultipleformalsearchmethods
includinghandsearchingofkeyjournals;electronicsearchingofmaindatabasesincludingtheuseof
freetext,indextermsandnamedauthor.Electronicsearchesofthefollowingdatabaseswere
conducted:WebofKnowledge,WebofScience,GoogleScholar,Elsevier’s(EMBASE.com),PubMed,
Medline,NationalLibraryofGreece(StavrosNiarchosFoundation,Athens,Greece),andtheLibraryof
theschoolofHealthSciencesoftheNationalandKapodistrianUniversityofAthens.Searchtermssuch
as“Historyofgastriccancer”,“Gastricsurgeryhistory”,and“Helicobacterpyloridiscovery”wereused
incombinationtofurtherfocusandlimittheselectiontohistoricalarticles,includingpaperspublished
inpeerreviewedEnglishlanguagejournalsandbooksfromasearlyas1937throughto2019.
2.ThePaleoOncologyEvidenceandtheEarlierStudies
Ancientmedicaltextswhichdescribepathologicalconditions,identifiedascancer,werewritten
bothbytheAncientEgyptiansandGreeks.Oneoftheearliestknowndescriptionofcancerfirst
appearedindifferentpapyrifromEgypt,suchastheKahun(orFayoum)papyrus(1950BC),which
consistsofthreesections,withonerelatingtohumanmedicine,theEdwinSmithpapyruswhich
waswrittenapproximatelyin1600BC(butsupposedtobeacopyofadocumentdatingbackto3000
BC)and,finally,the“EbersPapyrus”(1600BC),whichisconsideredamongthemostimportant
medicalpapyriofancientEgypt;containsthefirstreferencetopossiblecancersoftheskin,uterus,
stomach,andrectum.Thoseancienttextstreatedcancerswithhotblades,knives,salts,andarsenic
paste[2–5].Inhistractateon“AncientEgyptianMedicine”,JohnF.Nunndrawsonhisownclinical
experienceasaphysicianandanEgyptologisttoreassesstheevidence:hetranslatedandreviewedthe
originalEgyptianmedicalpapyri,reconsideringothersourcesofinformation,includingmummies,
skeletons,tombpaintings,statues,andcoffins.Hedescribedinhisworkthecriteriabywhichthe
Egyptiandoctorsmadetheirdiagnosesofseveraldiseases,includinggastrointestinalones[5].During
theperiodofthetenthdynastyofthepharaohs(2125BC),Irynakhtywasthecourtphysician,who
conductedextensivestudiesinthefieldofgastroenterologyandproctology[5].
Itisverydifficultforarcheologistsandphysicianstodiagnosecancerinhumanskeletonsand
mummifiedindividualsbecausedifferentiationfromotherlyticpathologiesisnotalwayspossible
whenbasedonlyonmorphologicalappearancebutalsobecausetheskeletalcollectionsareoften
confinedtoskullsorselectedpathologicalbones.Thedistributionanddensityofmetastaticlesions
dependontheprimarycancer:malignanttumorswhichcauseosteolyticlesionsare,forexample,
thyroid,kidneys,adrenalglands,uterus,andgastrointestinaltracttumors.Todate,onlyaround200
Cancers2020,12,2643of14
caseshavebeenreported.Acaseofmultiplemetastaticlesionsduetocancerwasfoundinthe
archaeologicalsiteofAmaraWestinNorthernSudan(1200BC):amale,youngadultindividual
displayingmultipleosteolyticlesionsonhisbones.Afteraradiographic,microscopic,andscanning
electronmicroscopicimagingofthelesions,andaconsiderationofdifferentialdiagnoses,adiagnosis
ofmetastaticcarcinomasecondarytoanunknownsofttissuecancerwassuggested.Thisistheearliest
completeexampleintheworldofahumanwhosufferedmetastaticcancertodate[6,7].
OneofthefirstGreekphysiciansandphysiologistsofthepreHippocraticmedicinewas
AlcmaeonofCroton(ΑλκμαίωνὁΚροτωνιάτης),inthe6thcenturyBC.Somestudiesabouthiswork
asaphysicianclearlydemonstratehisknowledgeaboutsomegastrointestinalmechanismsand
digestivefunctionsthathetriedtostudythroughouttheanimal’svivisection[8].
Afterwards,onereferenceaboutapossiblegastriccancerwasreportedalsobyHippocratesof
Kos(ἹπποκράτηςὁΚῷος,460377BC)inthe4thBC.Hebelievedthatthispathologyattackedthe
humanbodyfromtheoutside,penetratingthroughtheskinandinfiltratingtissuesandinternal
organs.Accordingtolegend,hewasthefirsttousethewordsκαρκίνος(karkìnos=cancer),and
καρκίνωμα(karkìnoma=carcinoma)becauseofthefingershapedprojectionsthatspreadoutof
thetumorresembletheshapeofthecrab’sfingers.Untilthen,withoutasectionalanatomy,allthe
diseaseswereconsideredtobecausedbytheabsorptionofblackbilefromthebowelintotheblood,
butalsobythepoorqualityofenvironmentalairandwerecuredbypurging,enemas,andblood
lettings[9].Indeed,inhismedicalworkΠερί αέρων, τόπων, υδάτων(AboutAir,Earthand
Water),hedescribedthehydrotherapyefficacy[10].
VeryinterestedingastrointestinaldiseasesandtheirpossibleremediesweretheHellenistic
AlexandriaofEgyptmedicalschool’sscholars(288–300BC)andwasfoundedbyHerophilusof
Chalcedon(ἩρόφιλοςὁΧαλκηδών,330–260BC),anAlexandrianphysician,receivedhismedical
trainingunderPraxagorasofKos(Πραξαγόραςὁ Κῷος,4th–3thC.BC)afamousphysicianand
anatomistwhotaughtattheHippocraticmedicalschoolontheislandofKos.Withhiscontemporary
colleague,ErasistratusofCeos(Ἐρασίστρατος,304–250BC),hepracticedalargenumberof
dissectionsonanimal’sbodiestostudyanatomy;however,theyconductedanexceptionalactivity:
thefirsteverscientifichumandissectionsoncadavers.Humandissectionsthenwerenotallowed
againfor1800years.Itseemsthatonlythesetwophysicianseverperformedhumandissectionsuntil
theRenaissance,around1530AC,Herophilus’discoveriesonhumanbodywerebasilarforhuman
medicine,soiscalledtheFatherofAnatomy[11].HerophilusandErasistratusweretwoofan
importantgroupofgreatGreekphysiciansoftheAlexandriamedicalschoolwhodedicatedgreat
dealoftimestudyinghumanmedicineandtriedtoachievealargeknowledgeaboutseveralhuman
diseasesandtheirpossibletreatments.Subsequently,attheRomanagestheGreekphysician
AsclepiadesofBithynia(ἈσκληπιάδηςτηςΒιθυνίας,124–40BC)studiedmedicineinAthensandin
AlexandriaofEgypt,practicedinRome.Hewasthefounderofthe“Methodicschool”(Μεθοδική
Σχολή),averyimportantcenterformedicalstudies.Heusedtotreatgastrointestinaldiseaseswith
mixeddrinksbasedonwineandplant’sextracts[12].Indeed,inthe“DeMateriaMedica”by
DioscoridesPedanius(ΔιοσκουρίδηςΠεδάνιος,40–90AC),theGreekdoctorwhoisconsideredthe
fatherofpharmacology,influencedbythetheoriesofAsclepiades,hetalkedaboutseveralpossible
treatmentsofgastrointestinalsymptoms,usingadrinkbasedonwineandsometimeshoney,mixed
withdifferentplant’sextracts.Somewinebasedpreparationswiththeirspecificnamesand
indicationswere:avronitis(αβροτονίτης)withAbsinthiumponticumorArtemisiaafraorArtemisia
abrotanum,thrimbitis(θυμβρίτης)withSaturejathymbra,thimitis(θυμίτης)withThymusvulgarisor
Coridothymuscapitatus),origanitis(οριγανίτης)withΟriganumvulgare,calaminthitis(καλαμινθίτης)
withThymuscalamintha,gliconitis(γληχωνίτης)withMenthapulegium,fordyspepsiaand
abdominalpains,apitis(απίτης)withPyruscommunis,apsinthitis(αψινθίτης)withArtemisia
absinthium,mirtitis(μυρτίτης)withMyrtuscommunisorValerianadioscoridisοrV.italicalam.orV.
officinalis,nectaritis(νεκταρίτης)withInulahelenium,roitis(ροΐτης)withPunicagranatumorScilla
maritimewereconsiderateagoodremedyforstomachdiseases[12,13].
ThetheoriesofHippocratesreachedtheRomanage,whereweresharedbytheGreekphysician
GalenofPergamon(ΓαληνόςὁΠεργαμηνός,130–200AC),whofirstusedthetermόγκος(tumor)
Cancers2020,12,2644of14
todescribecancer.HealsousedtheGreekprefix“onco(όγκο,whichistheGreektermfor“swelling”)
andthesuffixoma”(‐ομα)todescribetumorsingeneral,reservingtheHippocraticterm“carcinoma”
formalignantones.Theseancienttermsarecurrentlyusedintheactualoncology[14].
IntheEarlyMiddleAges,alargeandcompleteclassificationofhumandiseasesinaheadtotoe
orderwasmadebytheByzantine(EasternRomanEmpire)GreekphysiciansOribasiusofPergamum
(Ορειβάσιος ὁ Περγαμηνός,325–403AC),inhisgreatencyclopediaΙατρικαί Συναγωγαί
(Collectionesmedicae),composedbyseventyvolumes[15],andlaterbyPaulofAegina(Παύλοςὁ
Αιγινήτης,625–690AC),inhismedicalcompendiumcomposedbysevenbooks,called
Πραγματείας ιατρικής βιβλία επτά”,inLatin“Epitomaemedicaelibriseptem”(Onmedicine,
sevenbooks),inspiredontheHippocraticandOribasiusthought.Inthesesevenbooks,heclassified
alltheknowndiseases,suchasgastrointestinalillness,diseasesrelatedtohumannutrition,fever,
urogenitalinfectiousdiseases,parasiticinfestations,butwithoutanyseparationbetweenexternal
andinternaldiseases.Hedescribedalsothetherapiesusedatthattimeandthefirstsurgical
techniques[16].Accordingtohim,cancerwasakindofsensitiveandpainfulswellingthathasablack
color,anuglyandirregularappearanceandcouldbeulcerative.Inaddition,thecanceroustissuehasvessels
stretchedindifferentdirections.Whenforminginanorganthatcouldbecut,cancershouldbeeradicated,and
itsscarcauterized…”Later,duringthe10thcenturyaC,theByzantineGreekphysician
ChrysobalantesTheophanesorNonnos(ΧρυσοβαλάντηςΘεοφάνηςΝoννός)wrotetheΣύνοψις
ενΕπιτομήτηςιατρικήςαπάσηςτέχνης(SynopsisinanEpitomeofallMedicalArt),composedby
297chapterswithalargenumberofreferencestothepreviousphysicians,suchasOribasiusof
Pergamumandothers.Hewroteaboutmanydiseasesofhistimeandtheirpossibletherapies.Finally,
the13thcenturyischaracterizedbytheworkofNikolausMirepsus(ΝικόλαοςΜυρεψός)Actuarius
(Ακτουάριος)andhewasatthecourtoftheEmperorJohnIIIDoukasVatatzes(ΙωάννηςΓ´Δοκας
Βατάτζης,12221254AC,EastRomanEmpire)whichwasgreatimportanceofthefollowingyears.He
wroteacollectionofprescriptions,theΜέγαΔυναμερόν(GreatDynameronorMedicamentorum
Opus)whichwastheofficialtextondrugtherapyofhistimeandforthesubsequentmedicalschools
andoneofthemainsourcesofmodernpharmacology.Thecollectionclassifiesintwentyfourunits,
becausethepharmaceuticalrecipesbasedalwaysonthelettersoftheHellenicIonicalphabet(Α‐Ω),
fromwhichthetitleoftherecipebeginsanditwastranslatedintoLatinandprintedinthe16th
century,anduntilthe17thcentury.Inthiscollectiontextaredescribedovertwothousandvarious
recipessuchasthosewithpsychoactiveherbs,suchasmandrake,orthosewithopiumasapain
reliever,antitussive,andagainsthysteria(eveninourdayitisaddedtoantitussiveandanalgesic
formulations)andothersforalltypesofdiseasessuchasgastrointestinalones.
Thus,althoughtheheadtotoeclassificationwasafeatureoflaterGreekmedicine,itwasthe
Arabicmedicinewhodevelopeditalotandclearlyseparateexternaldiseasefrominternalones.In
the11thcentury,apossibledescriptionofagastriccancerisfoundinAvicenna’s(9801037AC)
MedicalEncyclopedia.
IbnSina(Persian:ﺎﻨﻴﺴﻨﺑﺍ),alsoknownasAbuAliSina(ﺎﻨﻴﺴﻴﻠﻋﻮﺑﺍ),PurSina(ﺎﻨﻴﺳﺭﻮﭘ)and,inthewest,
knownasAvicenna,wasoneofthemostsignificantPersianphysiciansandthefatherofthemodern
Arabicmedicine.HisencyclopediaincludedallthemedicalknowledgeofthetimefrombothGreek
andIslamiccivilizations[17–19].
Atthesametime,wemustmentiontheimportantmedicaltext“LiberPantechne”(παντεχνη,
allmedicalarts),writtenbytheBenedictinemonkConstantineAfricanusinthe11thcenturyAC,
scholarofthefamousScholaMedicaSalernitana(themostimportantmedicalschooloftheantiquity,
basedinSalerno,southernItaly,fromthe9thtothe19thcentury),whichisbasedontheworksof
manyothersphysicians,suchasIbnAlJazzar(ﻲﻧﺍﻭﺮﻴﻘﻟﺍﺭﺍﺰﺠﻟﺎﻨﺑﺪﻟﺎﺨﻴﺑﺄﻨﺑﺪﻤﺣﺃﺮﻔﻌﺟﻮﺑﺃ,898–980AC),authorof
Destomacho”.
ThemedievalmedicalknowledgeradicallychangedwiththeRenaissance,probablybecause
newscientificmethodstostudypathologieswereallowed,suchasautopsy.ItwasMorgagni,in1761,
whofirstusedthedissectiontolinkanatomopathologicalfindingswiththepatient’sillness.Hewas
anItaliananatomistwhointroducedtheanatomoclinicalconceptinmedicineandestablished
anatomyastheinstrumenttoidentifytheseatandetiologyofanydisease.Thankstothisnew
Cancers2020,12,2645of14
scientificwaytostudycancer,theoncologyfieldstartedtodevelopquickly[20].Inthe18thcentury,
Dr.PeyrilepublishedattheAcademyofLyonhisthesisaboutthecancerorigin,entitled“Dissertatio
AcademicadeCancro,”(1774);ithasbeenconsideredthestartingpointofthemodernoncological
era[8].ItwastheItalianLazzaroSpallanzani(1729–1799),inthe18thcentury,whofirsttriedto
explaintheactionofthegastricjuiceonfoodstuffs[21].
Thelackofknowledgewasconsideredapossibleexplanationofthesuddenandmysterious
deathofNapoleonBonapartein1821.Hebegantosufferfromrecurrentepisodesoffever,abdominal
pain,vomiting,andpersistenthiccuppingtwoyearsbeforehisdeath,whenhevomitedcoffee
groundmaterial,withprogressiveweakness,profusesweating,severhiccuppingandtachycardia.
Inalucidmomentofhisdelirium,heaskedhispersonalphysician,Dr.FrancescoAntonmarchi,
anatomistandpathologistofPisaUniversity,tomakeanautopsyonhiscadaverafterhisdeathand
toexaminehisstomach,becausegastricpathologieshadcausedthedeathofatleastfourofhis
relatives:grandfather,father,onesister,andonebrother.Hediedfewhourslaterforamassivebowel
movementfollowedbyacirculatorycollapse.Intheautopsyreport,writtenbyDr.Antonmarchi,
wasreportedadetaileddescriptionofwhathesaw...thevolumeofthestomachwassmall,itsanterior
surfaceseemstobenormalbutontherightsideexistsacloseadhesionwiththeinferiorfaceoftheleftliver.
Nearthesmallcurvaturetherewasahardarea,perforatedinthecenter.Theperforationwasclosedbytheliver
adhesion.Onopeningtheorganalongitslargecurvatureitscapacityappearedfilledwithaconsiderable
quantityofmattersmixedwithaliquidresemblingthesedimentofcoffee.Theinternalsurfaceofthestomach
wasoccupiedbyacancerousulcerwhosecenterwasonthelessercurveandthedigitationswereextendedfrom
thecardias‘till1or2centimetersbeforethepylorus,withascirrhousthickeningofthewall…”Previously,
Napoleonhadsufferedvagueabdominalsymptoms,perhapsduetochronicgastritiswhichpreceded
hisfamilialgastriccancer[8,22–24].Itisverycuriousthatinmanypaintingsrepresentingthe
Emperor,heisportrayedwithhishandonhisabdomen,maybeforabdominalpain.
Otherfamouspeoplelosttheirlivestogastriccancer,suchasMarshalJosephPilsudski,the
PolishherooftheWorldWarI,whodiedforthiscancerin1935;theIrishwriterJamesJoyce,who
diedofagastriccancerin1941;inJapan,China,Korea,andtheothercountriesofthePacificarea,
gastriccancerhasbeenwellknownasoneofthemostimportantkillers:itisconsideredendemic.To
citesomeexamples,manymembersoftheshogunTokugawafamily,whodominatedthecountry
betweenthe17thandthe19thcenturies,wereaffectedbythiscancer;thefounderofthedynasty,the
firstshogunIeyasuTokugawa,whounifiedJapanin1615,probablydiedfromgastriccancerin1616.
DiedofthiscanceralsoimportantpersonalitiesofthehistorysuchasKingCharlesthe11thofSweden
andPopeJohnXXIII[8].
DuringtheNapoleon’speriod,however,gastriccancerswereformallyunknown.Afteradecade
fromtheEmperor’sdeath,benignandmalignantgastriculcersweredescribedin1835inthetextsof
J.Cruveilhier,aFrenchanatomist;in1839,RobertBaylemadeadetaileddescriptionofthepathology
ofgastriccancerinatreatise[25].Between1649and1652,twodutchphysicians,NicholasTulp(1593–
1674)andZacutusLusitani(1575–1642)affirmedthatcancerwascontagiousbecausetheyobserved
manycasesofcancerinmembersofthesamehousehold.Theyproposedtoisolatecancerpatients,
preferablyoutsideofcities,inordertopreventthespreadofcancer.Forthisreason,JeanGodinot
(1661–1739),canonofthecathedralintheFrenchcityofRheims,accepted,in1740,totransformhis
cathedralinthefirstcancerhospitalforthepoorforaconsiderableamountofmoney.Itwascalled
Hôpitaldescancers”;however,afterfewyears,in1779,thehospitalwasdislocatedoutsidecityto
avoidmultiplesinfections[26].
Fromthelate19thtotheearly20thcentury,thephysiciansconsideredgastriccancera
consequenceofanabdominaltraumaticinjury,sotheystartedtocausemechanicaltraumaon
experimentalanimals,inordertoinducecancerintheirstomachs.Thistheorywassoonabandoned
aftermanyunsuccessfulattempts.
The19thcenturywascharacterizedbymanydiscoveriesinthemedicalfieldsabout
gastrointestinalpathologies:in1805,PhilippBozziniwasthefirsttoobserveinsidetheurinarytract,
therectumandthepharynxusingalightguidinginstrument.Heisconsideredthefatherof
endoscopy,butitwasonlyin1868thataGermanphysician,AdolfKussmaul,couldwatchinsidethe
Cancers2020,12,2646of14
stomachwithagastroscope,andin1883,HugoKroneckerandSamuelMeltzerdevelopedan
esophagealmanometer.CharlesEmileTroisier(1844–1919)firstdescribedtheenlargedleft
supraclavicularlymphnodeanditsconnectionnotonlywithgastriccarcinomabutalsowithseveral
otherabdominalmalignancies[27–29].In1823,WilliamProutdiscoveredthatstomachjuicescontain
hydrochloricacid,whichcanbeseparatedfromgastricjuicebydistillation[30,31].
3.GastricSurgeryandtheDevelopmentofEndoscopy
Theofficialhistoryofgastriccancersurgerybegan40yearslater,whentheFrenchsurgeonJules
Peanattemptedthefirstgastricresectionin1879;thepatient,unfortunately,diedfewdaysafter.In
1880,LudwigvonRydygier,professorofsurgeryatKrakowUniversity,triedanothergastric
resection,butitwasunsuccessful.ThefirstsuccessfulgastricresectionwasattemptedbyTheodor
Billroth,oneyearlater,intheAllgemeineKrankenhausClinicinWien.Thepatientwasa43old
womanwhosurvivedfourpostoperativemonths.TheoperatorytechniqueusedbyBillroth
maintainedhisnamestilltodayasBillrothI,whichconsistsinagastroduodenalanastomosisdirectly
connectingthegastricstumptotheduodenalone.Thisintervention,technicallymoredifficult,
consistsinreconstructingthealimentarytractsimilarlytothephysiologicalone.Billroth,soonafter,
modifiedthisoperationforamoreradicalresection,knownasBillrothII.Thesetypesofresections
arecurrentlyusedinthemoderngastricsurgery,butnotforoncologicpurposes[32].
In1897,theSwisssurgeonKarlSchlatterperformedthefirsttotalgastrectomyforadiffusegastric
cancerinZurich,atthesurgicaldepartmentdirectedbyKronlein.Heremovedthewholestomachand
madeanesophagojejunostomyforreconstruction.Theoperationwassuccessful,andshediedfor
recurrenttumorafter14months.Totalgastrectomywasthenpracticedallovertheworldwithdifferent
techniques,firstbyCharlesB.BrighaminSanFranciscoandbyRichardsoninBoston[8].
Thecontinuousdevelopmentofresearchandnewdiscoveriesinthefieldofgastroenterology
andgastricsurgerycontinuedinthe20thcentury.
Duringthelastcenturymanyhypotheseshavebeenproposedtoexplaintheetiologyand
pathophysiologyofgastriccancer.Basedonthecurrentknowledgesofthetime,environmental,and
dietarycauseswereproposed,aswellastheincreasedriskinpersonshavinggroupAbloodor
menopausalwomen,etc.Suchetiopathogeneticlinkswerevariouslyexplainedbut,inmostcases,
neverconfirmeddifferingfromtheHelicobacterpyloriinfectionthatiscurrentlyconfirmedasthemain
causeofgastricdiseases,includingcancer.Table1summarizesthemaincausesofgastriccancer
proposedduringthetime.
Table1.Summaryofproposedcausesofgastriccancer.Duringthe20thcenturygastriccancerwas
consideredaconsequenceofpreexistingorcoexistingconditions(i.e.,chronicatrophicgastritis),poor
lifestyles,orparaphysiologicalconditions(i.e.,dietpoorinfibers,menopause,etc.),andtoagenetic
predisposition(genemutations,groupAblood,etc.).Mostoftheselinkswereneverconfirmed,
exceptthecausativeroleofH.pylori.
Precursor Conditions Enviromental Factors Genetic Factors
H.Pyloriinfection(CagA
positivestrains)
Perniciousanemia
Gastroesophagealreflux
Barrett’sesophagus
Chronicatrophicgastritis
andintestinalmetaplasia
Ménétrierdisease
Gastricadenomatous
polyps
Previousgastricsurgery
(especiallyinpartialgastrectomy:
highriskofcancerofthegastric
stump)
Lifestyle(alcohol,tobaccosmokers,
obesity,lowphysicalactivity)
Lowsocioeconomicstatus
Dietaryfactors(dietsrichinsalt/sodium,
richinstarchandpoorinprotein,smokedor
poorpreservedfoods,lowintakeoffruitand
vegetables)
Occupationalexposures(workers
processingrubber,asbestosandtimber,or
farming,mining,refining,aswellasexposureto
dustyandhightemperatureenvironmentsasin
woodprocessingplantoperators,cooks,food
andrelatedproductsmachine)
Estrogensdecreasewithmenopause
Viralinfections(EBV,HBV?)
Familyhistoryof
stomachcancer
Elderly(fordegenerative
changesandaccumulated
DNAdamages)
Hereditarynon
polyposiscoloncancer
LiFraumenisyndrome
DownregulationofE
cadherinexpression
Interleukin1Bgene
mutationHypogamma
globulinemia(primary
immunodeficiency)
GroupAblood
Cancers2020,12,2647of14
Radiations
In1915asmallamountofgastricjuicewastakenfromahumanstomachtostudyits
characteristicsbyJesseMcClendon.Gastrointestinalendoscopyhaspassedthroughthreeprincipal
changesintheformsofendoscopesusedtoexaminethegastrointestinaltract:the“rigidendoscope”
era(1805–1932);the“semiflexibleendoscope”or“Schindler”era(1932–1957);andthe“fiberoptic”
era(1957–present)[33].
Manyimportantstepsforwardandprogressesweremadebyscientistsinthefieldofhuman
nutritionanddigestivesystem,researchingaboutthechemicalprocessesandthebiochemical
mechanismofphysiologicaldigestion,butalsoabouttheunknownetiopathogeneticagentsthat
couldcausethestomachcancer.Inparticular,basedonpreviousdemonstrationsofclose
relationshipsofbacteriawithcancersandtumorlikeconditions,manypathologistsand
microbiologistswereaimingtofindoneormoremicroorganismsrelatedtogastriccancer[34–36].
Beforethe1950s,thereweremanymicrobiologicaldescriptionsofbacteriainthestomachand
ingastricacidsecretions,lendingcredencetoboththeinfectivetheoryandthehyperaciditytheory
asbeingcausesofpepticulcerdisease:fromthetheoryofprofessorFrancoisdelaBoeSylvius,a
FlemishscientistborninHanau(currentlyaGermancity),whobelievedthatacidiclymphfluid
wasthecauseofcancers,tothetheoryofhiscontemporary,NicolaesTulp,whobelievedthat
cancerwasacontagiouspoisonthatslowlyspreadsinthewholebody.Itwasjustin1926that
JohanesAndreasFibiger(1867–1928),professorofpathologyinUniversityofCopenhagen,received
theNobelPrizefordiscoveringtheetiopathogeneticagentcausingthestomachcancer.He
demonstratedthattheroundwormwhichhecalledSpiropteracarcinomacouldcausestomachcancer
inratsandmice.Hesupposedthiswasthecauseofgastriccancerbecauseheobservedinflammatory
anddegenerativemucosalchangesintherats’stomachafterfeedingthemwithinfectedcockroaches.
Germanscientists,suchasWalterKrienitz,foundspiralshapedbacteriaintheliningofthehuman
stomachin1875,buttheywereunabletoculturethem,andtheresultswereeventuallyforgotten[35].
In1915,Rosenowpublishedhistheoryafterheinfectedalargenumberofexperimentsanimals
withstreptococci.Inhispaper[36],hedemonstratedstreptococcusasanetiologicfactorinninediseases,
includinggastricandduodenalulcer,duetoitsaffinityforthegastricmucosa.
4.TheDiscoveryoftheHelicobacterpyloriandItsRelationshipwithGastricCancer
ItwasasignificantturningpointforthehistoryofthegastriccancerwhenBarryJ.Marshalland
RobinWarren,twoAustralianresearchers,discoveredthebacteriumHelicobacterpyloriand
deciphereditsroleingastritis,pepticulcerdisease(PUD)andgastrictumors.Fortheirgreatwork
theywereawardedin2005theNobelPrizeinPhysiologyorMedicine[37].Theirstudiesrevealed
thatgastritis,gastricandduodenalulcerationsandsometypeofgastriccancersweretheresultof
infectionwithsomecurved,Gramnegativebacilli.TheGramnegativecurvedbacillusH.pylorihas
becometheprizebugofalltimes.BarryMarshallandRobinWarrenthetwodiscoverersofthis
organismhavebeenawardedwiththisyear’sNobelPrize.TheNobelcommitteeattheKarolinska
InstituteofSwedenhasselectedthisparadigmshiftdiscoveryof1982asthemostimpactingin
medicalsciences.ThisawardhassurprisedmanyastheNobelassemblyhasselectedthis‘Robert
Kochstyledmedicaldetectivework’fortheprizeascomparedtomanyoutstandingbasicresearch
storiesonthewaitlist.ThiseditorialbrieflytouchesthesignificantimpactofH.pylorion
gastroduodenalmanagementandthepathforwardasthebughasbecomequitecontroversialin
recenttimes.Bacteriacolonizesthehumanstomachandperiodontalpockets,causingachronicactive
gastritis,whichcancomplicatewithpepticulcerdisease[38].Beforetheyannouncedtheirfindings,
alargenumberofphysiciansthoughtthatstressandlifestylefactorswerethemajorcausesofthese
diseases.WarrenandMarshall,atthefirsttime,wereregardedwithskepticismandalotofcriticism
buttheirmajorbreakthroughsweresoonwidelyaccepted.Toenforcetheirtheoryaboutthelinkage
betweentheHelicobacterandgastroduodenalpathologies,Warreninfectedhimselfwiththe
bacteriumanddevelopedtheclassicalsymptoms.This‘selfhelp’experimentwaspublishedinthe
Cancers2020,12,2648of14
MedicalJournalofAustralia[39].Inthe1994theWorldHealthOrganization(WHO)andthe
InternationalAgencyforResearchonCancer(IARC)declaredH.pyloriaGroup1carcinogen.
AGreekphysician,JonhLykoudis(ΙωάννηςΛυκούδης,1910–1980),whowashimselfaffected
bygastritisandpepticulcer,in1968developedatreatmentwhichconsistedofthreetypesof
antibiotics(2quinolines,5,7diiodo8oxyquinoleine0.125g;5iodo7chloro8oxyquinoleine
0.125g,andstreptomycinsulfate0.075g),withvitaminA10,000UI.HenamedthesepillsElgaco
(fromtheGreektermἕλκος =ulcer,andthetwowords γαστρίτιδα =gastritisandκωλίτης=
colitis).Heusedthesepillsasatherapyforgastritisandgastriculcer,6–8timesdailyfor10days,
becausehewasconvincedthattherealcauseofthesediseaseswasinfectious,butwithoutknowing
specificallywhatkindofinfectiousagentwasinvolved.VitaminAwasincludedtoincreasethe
mucosalregeneration.Hestartedtreatingthousandsofpatients(around30,000)withgreatresults
andnotoxicity.Despitethistreatmentbeingasuccessfulone,hedidnotmakearealclinicaltrial,
soeachtreatmentandoutcomewasnotscientificallyresumed.In1966,Lykoudisattemptedto
publishhisobservations“UlcerofStomachandDuodenum”intheJournaloftheAmerican
MedicalAssociation,butitwasrejected.Unfortunately,nocopyofthistextsurvived[40].
TheactualHelicobacterpyloriwasoriginallynamedCampylobacterpyloridisandthen
Campylobacterpyloriin1987(pyloriisthecircularopeningleadingfromthestomachintothe
duodenum,fromtheGreekwordπυλωρός=gatekeeper)[41,42].HisRNAanalysisshowed,in
1989,thatthebacteriumdidnotbelonginthegenusCampylobacter,soitwasplacedinthegenus
Helicobacter(fromtheGreekwordέλιξ=spiralandβακτήριον=bacterium)[43,44].
In1987,ThomasBorody,anAustralianphysician,proposedthefirsttripletherapyforthe
treatmentofduodenalulcers[45].In1994,theNationalInstituteofHealthrecommendedantibiotics
inthetreatmentofrecurrentduodenalandgastriculcerscausedbyH.pylori.Pepticulcerdisease
associatedwithHelicobacteriscurrentlytreatedwithantibioticstoeradicatetheinfectionandtoallow
theulcertoheal.Previously,theonlyoptionwassymptomcontrolusingantacids,H2antagonistsor
protonpumpinhibitorsalone.Nowadays,hefirstlinetherapyisthe“tripletherapy”,basedonthe
useofacombinationofaprotonpumpinhibitorandtwoantibiotics,clarithromycinandamoxicillin.
Inpeoplewhoareallergictopenicillin,amoxicillincanbereplacedwithmetronidazole.Other
optionsareavailableincaseoftreatmentfailureforantibioticresistantbacteria:a“quadruple
therapy”,whichaddsaprotonpumpinhibitor,twoantibioticsandabismuthcolloid,suchasbismuth
subsalicylate.Incaseoftreatmentfailureforantibioticsresistance,whichisanincreasingproblemin
H.pyloriinfections,theycanbereplacedbytheuseofanotherantibiotictowhichthebacteriais
sensitive;forthetreatmentofclarithromycinresistance,theuseoflevofloxacinhasbeensuggested
[46,47].Ithasbeendemonstratedthatgastricmucosaassociatedtissuelymphoma(MALT
lymphoma,orMALToma),ararematureBcellneoplasmisassociatedwithH.pyloriinfection.Itis
oneoftherareandincrediblecasesoftumorscurablebyantibioticstherapyalone[48–51].
Table2summarizestheevolutionofmedicalknowledgeaboutgastricconditionsfromancient
EgypttothediscoveryofHelicobacterpylorianditspossiblecure.
Table2.Overviewofthemainstepsoftheknowledgeaboutgastriccanceranditstherapy.
2125 BC First researches in gastoenterological field during the 10th dynasty of the Pharaos by Irynathty,
the court physician
1600 BC First descri
p
tions of cancer in the “Kahun
(
or Fa
y
oum
)
”, “Edwin Smith” and “Ebers”
p
a
py
ri
1200 BC Earliest complete skeleton with multiple osteolytic metastatic bone lesions found in northern
Sudan
6th century BC Alcmaeon of Croton’s studies on gastrointestinal mechanisms and digestive functions through
animal’s vivisection
4th century BC First use of terms “καρκίνος” (karkìnos=cancer) and “καρκίνωμα” (karkìnoma= carcinoma) by
Hi
pp
ocrates
3rd century BC Development of human anatomy’s knowledge through dissections on cadavers made by
Herophilus of Chalcedon and Erisistratus of Ceos
1st century BC–1st
century AC
Use of drinks based on plant’s extracts for gastrointestinal symptoms by Asclepiades and
Dioscorides
2nd century AC Introduction by Galen of the prefix “onco-” (όγκο-) and the suffix “-oma” (-ομα) to describe
tumors in
g
eneral, reservin
g
the term “carcinoma” for the mali
g
nant ones
Cancers2020,12,2649of14
3rd–6th century AC Classification of gastrointestinal diseases in the Oribasius Encyclopedia and in the Paul of
Aegina’s Compendiu
m
11th centur
y
AC Avicenna’s Enc
clo
edia included all the Arabic medical knowled
e of the time
15–17th century
AC
Hôpital des cancers” were created in France to isolate cancerous patients, considering cancer a
contagious disease
17th centur
y
AC Auto
p
s
y
was allowed as a le
g
al method for medical studies
18th century AC Dr. Peyrile published his thesis about the cancer’s origins, starting-point of the modern
oncological era
1805 Rigid endoscope was first used to explore the gastrointestinal tract
1881 First successful
g
astric resection was attem
p
ted b
y
Theodor Billroth
1897 First successful total gastrectomy was attempted by Karl Schlatter for a diffuse gastric cancer in
Zurich
1926 J.A. Fibiger received the Nobel Prize for demonstrating the “Spiroptera carcinoma”
1932–1957 Semi-flexible endoscope first and then fiber-optic one were first used to explore the
gastrointestinal tract
1968 J. Lykoudis developed a treatment (Elgaco) based on antibiotics and vitamin A to treat peptic
ulcers
1982 B.J.Marshall and R.Warren recognized Helicobacter pylori as the cause of gastritis and peptic
ulcers
1987 T.Bodor
y
p
ro
p
osed a tri
p
le thera
py
for the treatment of duodenal ulcers
1994 WHO and IARC declared H.pylori a Group 1 carcinogen. NIH recommended antibiotics for the
treat
m
ent of recurrent duodenal and gastric ulcers caused by this bacterium.
2005 B.J.Marshall and R.Warren received the Nobel Prize in Ph
y
siolo
gy
or Medicine
5.TowardstheFuture
Omicshaschangedourunderstandingofthebiologyofmanydiseases.Theprogressof
knowledgeinthisfieldisveryrapid,eitherintermsofnewbasicscientificknowledgesortheir
clinicalapplication.Oneofthemostimportantknowledgeofmolecularbiologyofthelastdecadeis
thedifferentandubiquitousroleofsmallRNAmoleculesingeneregulation.Manystudiessuggest
thatthisclassofmoleculescontributestothepathogenesisofdiseases,especiallyincancerand
immunologicaldisorders,andteststargetedtotheidentificationofpatternsofmiRNAexpressionin
gastriccancersmightbeaddedtotraditionaltechniquesinthenextfuturetodeterminetheirorigin
andtoameliorateprognosisandtherapy.
6.Conclusions
Gastriccancerisprobablyaveryancientdisease,thathasnotbeenrecognizedbythepast’s
civilizationsforthelackofhistologicalandpathophysiologicknowledge.Itwasconsideredadivine
punishmentfromEgyptianculture,assomethingwhoattackedthebodyfromtheoutsidebyGreek
physicians.FromtheRenaissance,alargenumberofscientificdiscoveriesallovertheworldbrought
actualknowledgeaboutallthepathophysiologicmechanismswhichcancausegastricmucosal
alterationsandthedevelopmentoftheduodenalandgastriculcers.Manyeffortshavebeenmadeto
investigateabouttheriskfactorsofgastriccancerandtothesurgicaltechniquestoobtainaneven
moreradicalresult,especiallyinthosecountrieswherethiscancerisoneofthefirstleadingcauseof
cancerdeath,suchasJapan.However,theroleoftheresidentmicrobiotaintheregulationofthe
immunesystemandoncogenesis,especiallygutmicrobiota,iscontinuouslygrowing[52–54].
Specialattentionhasbeendedicatedtothetherapiesforthisconditionandtheirconsequences.In
fact,duetotheeliminationofanextensivepartorofthewholestomach,manynutrientsbecameno
moreavailable,worseningtheclinicalconditionimmediatelyafter,aswellasforlifespan.Possible
consequencesincludepostsurgicalsepsis,malabsorption,dumpingsyndrome,etc.[55–59].
Basedonthewellknownpositiveeffectsassupportivetherapyinalargenumberofinfective
andinflammatoryconditions,newhorizonsinresearcharefocusedtoinvestigatethepotentialrole
ofthelacticacidbacteriaingestionfortheirsuppressiveeffectonH.pyloriinfectioninbothanimals
andhumans[60–65].
Infact,ithasbeendemonstratedthateatingyogurtsupplementedwithLactobacillusand
BifidobacteriumimprovestheratesoferadicationofH.pyloriinhumans,confirmingandexpanding
ourknowledgeabouttheroleofourmicrobiotainthemaintenanceofhealth[66–68].Thisisdueto
Cancers2020,12,26410of14
theprobioticsproductionofbeneficialsubstancesforthegastrointestinalsystem,suchasbutyrate,
whichhelpsuppress H.pylori infectionsasanadjuncttoantibiotictherapy.Theavailabilityof
moleculardiagnostictoolsandcontinuousscientificprogressesallowustotestanddetectrapidly
thepossiblepresenceofmanymicroorganismsinanytissue.
Infact,thecytokine‐ andcelladhesiondependentbonemarrownicheandstromal
microenvironmentsupportnewvesselformationandcancerproliferation,irrespectiveofimmune
surveillance[69].
Recently,somemedicalresearchersareinvestigatingaboutthepossibleroleofothersinfective
agents,suchastheHumanPapillomaVirus(HPV)andtheEpstein–BarrVirus(EBV),whenthey
infectedhumancellstogetherwithH.pylori[70–72].
Forinstance,EBVappearstoimpacttheimmuneenvironmentandthepatient’ssurvival[73],is
implicatedintheimmunestatusequilibrium,amajordriverofgastriccancer(GC)initiation[74].
ThisintimateinteractionbetweenGCcell,microenvironmentviabystanders(i.e.,endothelialcells),
andCD8+Tcellscreatesapermissiveimmunemicroenvironmentthatallowsundisturbedcancer
proliferationinbothsolidandhematologicalmalignancies[75,76].
TheprevailingpointofviewhasbeenthatNterminallytruncatedp53familyisoforms(ΔNp53,
ΔNp63,andDNp73)predominantlycounteractcellcyclearrestandapoptosis.Recentprogressinthe
fieldextendthesewellknownfunctionsandplacetheseisoformsinthecenterofacomprehensive
regulatorynetworkcontrollingmajorepithelialtomesenchymaltransition(EMT)relevantsignaling
pathways[suchastransforminggrowthfactor‐β(TGF‐β),winglessint(WNT),insulinlikegrowth
factor(IGF),andsignaltransducerandactivatoroftranscription(STAT)),microRNAs,andEMT
associatedtranscriptionfactorsthatpromoteinvasion,lossoftumorcellpolarity,andmetastatic
behaviorinconjunctionwithachemoresistantphenotype[77].
Inframeofthisthinking,oneopenscientificdebateisongoingaboutthetranslationalvalueof
immunemicroenvironmentinGC.Indeed,immunemicroenvironment,antigenstimuliandantigen
presentingcells,suchasdendriticcellsappeartobeconnectedinacomplexnetworkinvolving
WNT/CTNNB1pathway,awellknowndriverofcanceraggressivenessandtumordissemination
withfundamentalimplicationforimmunelandscape,therapeuticapproachesandpatientmolecular
stratificationinaplethoraofsolidtumors[78,79].
Theseobservationsaddnewweighttotheconceptthatcurrentlyunderappreciatedtruncated
formsofthistumorsuppressorfamilyplayanequallyimportantroleinpromotingcancer
aggressivenessasdomutantp53proteins,alsoexemplifyinghowtheconsequencesofΔN/DN
expressiondependoncellularcontexts[76].
Manyeffortsmustbemadeinthefuturetocontrastthisterriblehumandisease,whichstillkills
thousandsofvictimseveryyear.Newmoleculartechniquesandnewknowledgeaboutthecausesof
gastriccarcinoma,aswellasaboutitsmicroenvironmentwillhelpresearcherstounderstandhowto
fightand,moreover,preventthiskilleratbest[80].Asapracticalconsequence,acontinuousand
synergiccooperationbetweenhealthprofessionalsfrommanymedicalspecialtyfields
(gastroenterologists,surgeons,immuneoncologists,periodontists,pharmacologists,etc.)willbe
neededforthemanagementofapersonalizedapproachtopatientswithgastriccancer.
AuthorContributions:Conceptualization:L.S.andI.A.C.;methodology:L.B.andI.A.C.;validation:S.T.and
A.B.;formalanalysis:F.I.;investigation:S.T.,L.S.,L.B.,andI.A.C.;resources:F.I.;datacuration:L.S.,L.B.,and
I.A.C.;visualization:G.D.andA.D.I.;supervision:L.B.;projectadministration:L.S.andA.B.;writing—original
draftpreparation:S.T.andI.A.C.;writing—reviewandediting:L.S.,L.B.,andA.B.Allauthorshavereadand
agreedtothepublishedversionofthemanuscript.
Funding:Thisresearchreceivednoexternalfunding.
ConflictsofInterest:Theauthorsdeclarenoconflictofinterest.
Cancers2020,12,26411of14
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