Helicobacter pylori (H. pylori) infection occurs when a type of bacteria called Helicobacter pylori (H. pylori) infects your stomach. This usually happens during childhood. A common cause of peptic ulcers, H. pylori infection may be present in more than half the people in the world.Infection with H. pylori causes chronic inflammation and significantly increases the risk of developing duodenal and gastric ulcer disease and gastric cancer. Infection with H. pylori is the strongest known risk factor for gastric cancer, which is the second leading cause of cancer-related deaths worldwide.H. pylori is truly an “opportunistic” bacterium that uses various well defined virulence factors as tool for attachment and persistent colonization of human gastric mucosa.

1. Role of Helicobacter pylori in gastric cancer
By: Omid Yeganeh , Nassir Rashnaei

2. H.pylori
• gram-negative
• microaerophilicbacterium
• helix-shaped
• foundusuallyinthestomach
• linkedtothedevelopmentofduodenalulcersandstomachcancer
• Morethan50%oftheworld'spopulationharborH.pyloriintheir
uppergastrointestinaltract

3. Signsandsymptoms
• Upto85%ofpeopleinfectedwithH.pylorineverexperiencesymptomsorcomplications
• Acuteinfectionmayappearasanacutegastritiswithabdominalpain(stomachache)or
nausea
• IndividualsinfectedwithH.pylorihavea10to20%lifetimeriskofdevelopingpepticulcers
• Analysisconductedin2009concludedtheeradicationofH.pylorireducesgastriccancer
riskinpreviouslyinfectedindividuals,suggestingthecontinuedpresenceofH.pylori
constitutesarelativeriskfactorof65%forgastriccancers
• H.pylorihasbeenassociatedwithcolorectalpolypsandcolorectalcancer

4. Transmission

12. Urease
• Tocolonizethestomach,H.pyloritosurviveinthe
presenceofacidproducedinthestomach,H.pylori
producesanimportantenzyme,urease,which
hydrolysesureaintoNH3 andCO2
• Ureasecausesdamagetotheepitheliumthroughthe
productionofammonia,thatinconjunctionwith
neutrophilmetabolites
• Ammoniaiscapableofcausedifferentcellalterations,
includingswellingofintracellularacidic
compartments,alterationsofvesicularmembrane
transport,repressionofproteinsynthesisandATP
production,andcell-cyclearres

14. Lipopolysaccharides and peptidoglycan
•H.pyloriLPSareessentialcomponentsofthebacterialoutermembrane
thatinducesalowimmunologicalresponseincontrarytootherbacteria
•AnotherimportantcomponentofthecellwallofH.pylori,
peptidoglycan,interactswiththeintracellularpatternrecognition
receptorNod1
•thisinteractionleadstoactivationofNF-κBsignaling,whitthe
subsequentsecretionoftheinflammatorymoleculesIL-8andβ-
defensin-2

15. Adhesins
• Approximately4%oftheH.pylorigenomeispredictedtoencodeoutermembrane proteins
(OMPs)manyofwhichserveasadhesins
• EpithelialadhesionprovidestoH.pyloribetteraccesstoepithelialsurfaceandinthisway
contributestodeliverbacterialtoxinssuchasCagA
• Theoutermembraneinflammatoryprotein(OipA),isinvolvedintheattachmentofH.pylori
togastricepithelialcellsinvitro
• Bloodgroupantigenbindingadhesin(BabA),hasbeenthoughttobetheprimaryprotein
involvedinadherencetothegastricmucosa

17. Vacuolating cytotoxin (VacA)
• AllstrainsofH.pyloricontainthevacAgene,although,thereis
considerablegeneticdiversityamongthem,andconsequentlythe
cytotoxicityactivityofthetoxinvariesbetweenstrains
• VacAisapore-formingcytotoxinidentifiedinsupernatantsofH.
pyloribrothculturesthatcauseaberrantvacuolationofcultured
cells
• VacAinducesmultiplecellularactivities,thebeststudiedisthe
alterationonendosomalmaturationwhichconsequentlyleadsto
vacuolationofepithelialcells
• VacAisalsocapableofinducemembrane-channelformation,
cytochromecreleasefrommitochondria,andbindingtocell-
membranereceptorsactivatingaproinflammatoryresponse

18. Cytotoxin associated gen-Pathogenicity Island (cag-PAI)
• ThesehighlyvirulentH.pyloristrainsharbora(cytotoxin-associatedgenes)
pathogenicityisland(cag-PAI)thatencodeproteinsthatarecomponentsofatypeIV
secretionsystem(T4SS)apparatusandtheCagAeffectorproteinintohosttargetcells
• T4SStranslocatesthebacterialoncoproteinCagAandpeptidoglycanthatinducesproin
flammatorychemokineandcytokinesecretion,includinginterleukin-8(IL-8)ingastric
epithelialcells
• T4SSsarealargegroupofhighlyversatilesecretionmachineriesinmanyGram-
negativepathogenicbacteriathatareevolutionarilyrelatedtobacterialconjugative
systems

19. Cytotoxin-associated protein (CagA)
• Itwasfirstlydescribedasaveryimmunogenicproteininhumansinfectedwith
cytotoxin-producingstrains
• Afterthat,itsassociationwithgastriccancerandpepticulcerwaswell
established
• RecentreportssuggestthatCagAisabletodownregulatethevacuolationeffects
ofVacAonhostcells,andconversely,VacAisabletodownregulatesCagA
activity
• CagAisencodedbythecagAgene,locatedatoneendofthecag-PAI
• OthermainfeatureofCagAproteinisitshighvariablesize,whichrangefrom
120-145 kDa.Thisvariationisduetothepresenceofpolymorphismatthe
carboxy-terminalregiongivenbythepresenceofrepeatsequencescalledEPIYA
motifs,whicharepresentinacopynumbervaryingfromonetoseven

21. As shown on the figure in the next page:
TheinteractionofHpylori,environmentalfactors,andinflammationin
thepathogenesisofgastriccancer.Eachplaysimportantrolesleadingto
progressivechromosomeinstability.Hpylori-inducedinflammationleads
tohighgastricendothelialcellturnoverandamicroenvironmentthatis
highinreactiveoxygenandnitrogenspecies,increasingopportunitiesfor
DNAdamageandsomaticmutations.ROS=Reactiveoxygenspecies.

23. β-catenin
• Ahostproteinthathasreceivedstrongattentionforitsroleinthedevelopment of
carcinogenesis inassociationwithH.pyloriisβ-catenin
• IntheabsenceofWntligand,cytoplasmicβ-cateninisboundwithinaninhibitorycomplex
consistingofaxin,adenomatouspolyposiscoli(APC),andglycogensynthasekinase-3
• H.pyloriinducesβ-cateninactivitythroughinjectionofCagAintogastricepithelialcells
• Inadditiontoitscytoplasmicform,β-cateninalsoexistsinamembrane-bound formthat
linkstheE-cadherinreceptortotheactincytoskeleton

24. Conclusion
• OurunderstandingofthebiologyofH.pyloriandthehostresponsetothebacteriumhas
advancedremarkablyduringthepastthreedecadesthroughalargebodyofelegantscientificand
clinicalinvestigation
• Itisevidentthatgastriccarcinomaresultsfromacomplexinteractionbetweenbacterial,
environmental,host-geneticandmolecularmechanisms
• InadditionvacA,urease,adhesionfactor,Lipopolysaccharidesandpeptidoglycanplayimportant
roleinpathogenesisofH.pylori