Chapter 2 Tobacco Addiction: Effect on Human Health Premalignant and Malignant Lesions of the Oral Cavity: Tobacco as an Etiological Factor Aritra Laskar 1 ; Sayantan Jana 2 ; Anjana Mazumdar 3 ; Snehasikta Swarnakar 2* 1 Department of Oral Pathology/Diagnosis/Medicine/Radiology, Burdwan Dental College and Hospital, West Bengal, India; 2 Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata-700032, India. 3 Department of Oral Pathology, Dr. R. Ahmed Dental College and Hospital, Kolkata, India *Correspondence to: Snehasikta Swarnakar, Cancer Biology and Inflammatory Disorder Division, CSIR- Indian Institute of Chemical Biology, 4 Raja S C Mullick Road, Jadavpur, Kolkata-700032, India. Email: [email protected]1. Introduction The precancerous lesion was defined by World Health Organization (WHO), in 1978 as a morphologically altered tissue associated with a significantly increased risk of cancer. Precancerous lesions of oral cavity include oral submucous fibrosis (OSMF), Plummer Vin- son syndrome, erosive lichen planus, dyskeratosis congenita, chronic hyperplastic candidi- asis, Cowden’s syndrome, discoid lupus erythromatosus, dystrophic epidermolysis bullosa, and xeroderma pigmentosa [1]. In 2005, WHO decided to use the term ‘Potentially Malignant Disorders (PMD)’ as it describes that the pathological condition may transform into cancer. Abbreviations WHO: World Health Organization; OSMF: Oral Submucous Fibrosis; HPV: Human Papilloma Virus; OSCC: Oral Squamous Cell Carcinoma; NFHS: National Family Health Survey; GATS: Global Adult Tobacco Sur- vey; GYTS: GlobalYouth Tobacco Survey; PVL: Proliferative Verrucous Leukoplakia; TSG: Tumour Sup- pressor Gene; UV: Ultra Violet; DNA: Deoxyribonucleic Acid; HTLV: Human T-Cell Lymphoma Virus; HIV: Human Immunodeficiency Virus; CD: Cluster Of Differentiation; EBV: Epstein-Barr Virus; HHV8: Human Herpes Virus 8; HBV: Hepatitis B Virus; P53: Tumor Protein 53; Rb: Retinoblastoma Protein; ICAM: Inter- cellular Adhesion Molecule; TGFR: Transforming Growth Factor Beta Receptor; MMP: Matrix Metallopro- teinase; TIMP: Tissue Inhibitor Of Metalloproteinase
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Tobacco Addiction: Effect on Human Health · 2018-03-09 · 4 Tobacco Addiction: Effect on Human Health found in Melanesia, South-Central Asia, and Central and Eastern Europe (Figure
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Chapter 2
Tobacco Addiction: Effect on Human Health
Premalignant and Malignant Lesions of the Oral Cavity: Tobacco as an Etiological
Africa,4.5and2.8forEasternAfrica;and1.7and1.4forWesternAfricarespectively.AmongEuropeancontinents,theoralcancerincidencesformaleandfemalesare9.1and2forCentral&EastEurope,7.9and3.2forWesternEurope,5.9and3.2forNorthernEuropeand5.8and2.1forSouthernEuroperespectively.AmongAmericans,NorthernAmericahashighestinci-dencesoforalcavitycancers,7.2and3.2formaleandfemalerespectively.SouthAmericahas5.3and2.4,andCentralAmericahas2.6and1.7incidencesoforalcavitycancersformalesandfemalesrespectivelyper100,000people[7].Australiahasincidencesof8.3and3.7formalesandfemalesrespectivelyoutof100,000people.Aetiologicalfactorsfororalcarcinomainthesecountriesincludehighrateofsmokingtobacco,increasedalcoholconsumption,dietlowinfruitsandvegetables.OverallincidenceoforalcancerinAustraliaisdecreasing.Thereis a highprevalenceof oropharyngeal carcinomadue toHPV infection in these countries,whichhasabetterprognosisthanthatinducedbysmoking[17,18].
InsomepartsofIndia,suchasthestatesofBiharandMaharashtra,smokelesstobaccouseismorecommonthansmoking.Apartfromregionalpreferencesduetodifferentsocio-culturalnorms,thepreferenceforsmokelesstobaccoisinverselyrelatedtoeducationandin-come.IncountriesofSouthAsia,particularlyIndia,traditionalvaluesdonotfavoursmokingbytheyoungorbywomen,butthereisnosuchtabooagainstusingsmokelesstobacco.Mostwomen,whousetobaccoinIndia,useitinsmokelessforms.InIndiaithasbeenestimatedthatroughlyone-thirdofwomenandtwo-thirdsofmenusetobaccoinoneformoranother.InanepidemiologicalstudyconductedineightruralareasofIndia,smokelesstobaccousewas3–53%amongmenand3–49%amongwomen.Moreover,2-26%ofmenand0–4%ofwomenoftheseareaswereindulgedinconsumingbothsmokingandsmokelessformsoftobacco[21].AstudyconductedbyNationalFamilyHealthSurvey(NFHS)during2005–06, found thattobaccouseismoreprevalentamongmen,illiterates,poor,andvulnerablesectionofthesoci-ety[22].Anotherstudyconductedamongindividualsof15yearsofageorolderin2009–10
Whosurveyedastudyontobaccoaddictionformorethan10yearsofspanwith35,288respondentsofKarnatakaand29,931respondentsofUtterPradesh.Accordingtothestudy,tobaccouseinsmokelessformwaspredominantamongwomenandamongmenlessthan30yearsinbothurbanandruralareas;however,smokingwasthepredominantformoftobaccouseamongmenmorethan30yearsage.Theoverallprevalenceforuseofsmokelesstobaccowasobservedtobe13.9%inKarnataka(13.4%amongmenand14.4%amongwomen)and17.5%inUttarPradesh(24.3%amongmenand6.6%amongwomen).Useofsmokelessto-baccowashigheramongfemalesascomparedtomalesintheage-groupsabove40yearsinKarnataka[25].InUttarPradesh,theproportionofmenusingsmokelesstobaccowashigherthanwomen,inallage-groupsandprevalenceofsmokelesstobaccouseincreasedwithageinbothsexes.Betel-tobaccoquidwasfoundtobeextensivelyconsumedinKarnataka,buthadlimitedpracticeinUttarPradesh.Theprevalencerateofuseofthistobaccomodalitywas14.2%(26.9%amongmalesand0.6%amongfemales)inKarnatakaand2.0%(2.3%amongmalesand1.4%amongfemales)inUttarPradesh.Overall,ahigherprevalenceamongruralareaswasobservedinallage-groupsofKarnatakaascomparedtourbanareas,butthetrendswere variable in different age-groups inUttar Pradesh.An inverse correlation of decreaseinprevalenceratesofbetel-tobaccoquid/smokelesstobaccousewithincreasingeducational
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levelswas observed in different age-groups inKarnataka, and similar patternwas noticedonlyamongfemalesinUttarPradesh.Aninverseassociationofbetel-tobaccoquidusewithincreasingfamilyincomelevelswasobservedinKarnatakabutnotinUttarPradesh[12,25].
Lymphaticspreadoforalcarcinomausuallyinvolvesthesubmandibularanddigastricnodes, theuppercervicalnodes,andfinallytheremainingnodesof thecervicalchain.Thenodesmost commonly involved are those that are on the same side as the primary node,althoughthecloserthetumouristothemidlineandthemoreposteriorintheoralcavityororopharynx,themorecommonaretheinvolvementofthebilateralorcontralateralnodes.Thenodesarenottenderuntilandunlesstheyareassociatedwithsecondaryinfectionoraninflam-matoryresponseispresent,whichmayoccurafterbiopsy[28].Oralmalignantmelanomasarerelativelyrarecancersandoccurcommonlyinthemaxillarygingival,morefrequentlyonthepalatewithfewerincidencesinthemandibulargingival[30].Though,theselesionsarebio-logicallyaggressive,theyareclinicallyasymptomaticintheearlystagesandusuallypresentmerelyasahyperpigmentedpatchonthegingivalsurface(Figure5).
Chemical carcinogens have highly reactive electrophile groups that directly damagetheDNA.Therearetwotypesofchemicalcarcinogens:directandindirectacting.Directact-ingagents(fore.g.alkylatingagentsusedforchemotherapy)arecarcinogenicfromtheini-tialstates,whereasindirectactingagents(foreg.benzopyrene,azodyes,aflatoxins)arenotcarcinogenduringinitialstatesandareconvertedintocarcinogensbyendogenousmetabolicpathways.Hence,polymorphismsofendogenousenzymesthatarecriticalformetaboliccon-versionofchemicalscompounds(suchas,cytochromeP-450),maypromotecarcinogenesis.
Thestudyofoncogenicretrovirusesinanimalshasprovidedspectacularinsightsintothegeneticbasisofcancer.ThehumanT-celllymphomavirus-1(HTLV-1)hasbeendemon-stratedtocausecancerinhumans.HTLV-1hasbeenreportedtobeassociatedwithavariantofTcellleukemia/lymphomainhumans.SimilartotheHIV,HTLV-1hasaffinityforCD4+Tcells,andtheseTcellsarethemajorvictimsofneoplastictransformations.Theroleofviruses,suchasHTLV-1andHPVareanewparameterforthepathogenesisofhumancancers.TheHTLV-1genome,inadditiontotheusualretroviralgenome,containsauniqueregioncalledthepXwhichencodesamajorTAXprotein,whichturnsongenesforcytokinesandtheirre-ceptorsininfectedTcells.Althoughthisproliferationisinitiallypolyclonal,theproliferatingTcellsareatincreasedriskforsecondarymutationsthatleadtotheoutgrowthofamonoclonalleukemia.Byinterferingwithseveraltranscriptionfactors,suchasNF-ĸB,theTAXproteincantransactivatetheexpressionofgenesthatencodecytokines,cytokinereceptorsandco-stimulatorymolecules.Thisinappropriategeneexpressionleadstoautocrinesignalingloopsand increased activation of promitogenic signaling cascades. Furthermore,TAX can driveprogressionthroughthecellcyclebydirectlybindingtoandactivatingcyclins.Inaddition,TAXcanrepressthefunctionofseveraltumoursuppressorgenesthatcontrolthecellcycle,includingP16andP53[33,34].
Recently, severalDNAandRNAviruses, have been identified and correlated to thedevelopementofOSCC.FourDNAvirusesHPV,Epstein-Barrvirus(EBV),humanherpesvirus8(HHV8),andHepatitisBvirus(HBV)aregainingimmenseattentionincancerbiologybecausetheyarestronglyassociatedwithhumancancer.Veryrecently,theassociationofHPV,specificallyHPV-16and-18,withoralsquamouscellcarcinomaisalsogainingimportance.
Figure 1: Countries with high incidence and mortality from oral cancer (in red). Theareascharacterizedbyhighincidenceratesfororalcancer(excludinglip)arefoundin theSouthandSoutheastAsia(e.g.SriLanka,India,PakistanandTaiwan),partsofWestern(e.g.France)andEasternEurope(e.g.Hungary,SlovakiaandSlovenia),partsofLatinAmericaandtheCaribbean(e.g.Brazil,UruguayandPuertoRico)andinPacificregions(e.g.PapuaNewGuineaandMelanesia)[15].
Figure 4: (fromleft toright)Hyperkeratoticareasignificantofepithelialdysplasiaseenin the leftbuccalmucosa;Carcinomainsituoftheleftbuccalmucosa;SquamousCellCarcinomaoftherightbuccalmucosaandassociatedalveolus.Thelesionwasassociatedwithextensiveboneloss,(picturestakenintheDept.ofOP&ODofBDC&H)
Figure 5: Malignantmelanoma of the hard palate(left); Histological section stained with H&E showingmalignantmelanomafromsamplecollectedfromthesamepatient(right)(slidepicturetakenintheDept.ofOPofBCD&H).
Figure 6: Endogenousandexogenousagentsaffectingsomaticmutations,epigeneticalterations,telomeraseshortening and DNA damage that leads to cancer progression through chromatin modifications andtranscriptionalregulationofoncogenes.
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Figure 7: Different signaling molecules associated to cancers that are targeted for therapeutic purpose.CDK,Cyclin-DependentKinase; PARP, PolyADP-Ribose Polymerase; EGFR,EpidermalGrowth FactorReceptor;MAPK,Mitogen-ActivatedProteinKinase;TGF,TransformingGrowthFactor;HGF,HepatocyteGrowthFactor;VEGF,VascularEndothelialGrowthFactor; APC,Anaphase-PromotingComplex,PI3K,Phosphatidylinositide3Kinase.10. References