BSE631TermPaper VidurKumar(Y8560) Obesityandcancerlinkedtowhatlevel?

Abstract
Obesitytodayisamajorhealthissueinpopulationsacrosstheglobe.Thelifestylechangesoccurringinthe21st centuryhaveresultedinabundanceofallthingsincludingthatofvisceralfatinallagegroupsacrosstheglobe. Therearemanyhealthconditionsalreadylinkedwithobesitysuchasdiabetes,highbloodpressure,congestive heartfailure,reproductivecomplications,etcbut,couldbeingobesemakeonesusceptibletocancer?Orpossibly makeforaworsecancerprognosis? Theseissuesareaddressedinthisreport,withreferencestomanystudiesperformedatthepopulationlevel,andat themolecularlevelattemptingtolinkcancerprogression(prostratecancer),severityandoccurrence,with symptomsofobesitysuchasvisceralfat,adipokinelevels,etc. Focusingprimarilyontheadipokinelevelsinobese(cancer/noncancer)patients,invitrotumourculturestudies anddatafromprostrate/breastcancerpatientsthisreportaimstohintatapossiblemechanismwhichunderlies cancerprogressiononthebasisofthedatafromabovestudiesandexplainhowobesityasacondition,fitsinthe mechanismoftumorprogression.

Introductiontoobesity
Thefirstaspectregardingobesityisthequantificationofthephysicalconditioncalledobese.Forthepurposeof thisreport(andformostofthestudiesreferredto)computertomographygeneratedmeasurementsintheorder of~300cm2areainthecentralabdominalregions(i.e.ofvisceralfat),isdefinedastheconditionforobesity. Alternatively,otherquantifications,suchasWasittoHipratios,BodyMassIndex,etcarealsousedtodefineor correlatespecificaspectsofbodystructuretotheconditionofbeingobeseoritsrelatedmetabolicsyndromes.[9] Central(visceral)obesityischaracterizedbymetabolicsyndromessuchasinsulinresistance,hyperglycaemia, hyperinsulinaemia,dyslipidaemia,hypertension,andprothromboticandproinflammatorystates[8].Allofwhich arefairlyconditionsthatcausemanycomplicationsincontemporarilyoccurringdiseaseshoweverthefocusof thisreportdetailsthedirectimplicationsofobesity,andthemoleculesinvolvedfollowedbyageneralizationfrom thiscasestudyonhormonalcancers. ThemolecularsymptomsandeffectsofobesityonapatientsphysiologicalsystemarebestdescribedinFig.1.

Fig.1Diagrammaticrepresentationofsomeofthepossiblemechanismsforobesityrelatedprostatecancerprogression.IGF1= insulinlikegrowthfactor1;IL6=interleukin6;VEGF=vascularendothelialgrowthfactor;SHBG=sexhormonebindingglobulin. [8]

Molecularcharacteristicsofobesity Thefollowingarecharacteristics/byproductsofobesityandtheirrespectiverolesidentifiedinvarioushormonal (prostrate/breast)cancerstudies

HyperinsulinaemiahigherserumlevelsofinsulinresultsindecreasedproductionofSexHormone BindingGlobulin(SHBG).SHBGmediatedinhibitionofbreasttumorshasrecentlybeenidentifiedin literature[1].Hence,thischaracteristicisanalogoustolossofinhibitionforbreastcancercells. Also,itresultsinhigherlevelsoffreeandrogensandoestrogenwhichhavebeenimplicatedin proliferationofbreastcancers,andprogressionofhormonalcancersingeneral. DecreasedTestosteronelevelshavesignificanceinprostratecancer,aslowertestosteronelevelshave beenassociatedwithhighgradeprostratecancers.Thecharacteristicbeingofhigherproliferationandless differentiationinthetumor.[2] UpregulationofTNFalphabyvirtueofhigherlevelsofTNFalphainserum,thereishighersusceptibility toinflammationandinflammationbyitselfhasapotentialroleasacancerpromotingeventatanygiven site.[AsmitasTermPaper] Adipokinesecretionsbyadiposetissuearecoveredwithafewexamples o LeptinisanadipokinesecretedprimarilybyWhiteAdiposeTissue(WAT),andhasbeenshownto beactiveintheformationofreproductivetissue(includingtheprostrate).Andhasbeenpositively correlatedwithvisceralobesityandlargeprostratetumors[4]. Studieshaveshownthatleptinpromotestheproliferationofandrogenindependentprostate cancercelllines.Ithasalsobeenshowntopromotevascularendothelialcellproliferationinvitro andangiogenesisinvivo,processesthatarecrucialtoallowcancerprogression.Also,ithasbeen positivelycorrelatedwithincreasedprostratecancercellmigration(implyinginvasionand metastasis)[5]. MechanismofactionTheproliferativeresponseofprostatecancercellstoleptinhasbeenshown toinvolveintracellularsignallingmoleculessuchasphosphatidylinositol3kinase(PI3K)andcJun NH2terminalkinase(JNK).[10] o Interleukin6onethirdofthecirculatinglevelsecretionofIL6isfromadiposetissue.Itisdirectly proportionaltovisceralobesityandinsulinresistance.Itsnormalrolebeinginmodulationof immuneresponseandcellfunctionsitisbasicallyagrowthinhibitor.However,recentlyithas beenshowntoundergoatransitioninitsrolefromgrowthinhibitorassociatedwith neuroendocrinedifferentiationtostimulatoraccompaniedbyandrogenreceptoractivationin prostratecancerprogression[6]. ProstratecancercultureshavebeenshowntosecretehighlevelsofIL6,anditisbelievedthat chronicexposuretothisadipokineleadstolossofgrowthinhibitionintumorcells.SerumIL6 levels>7pg/mlareassociatedwithapoorprognosisinmenwithprostatecancer. o VascularEndothelialGrowthFactor(VEGF)VEGFlevelsarepositivelycorrelatedwithvisceral obesity,anditisapotentmitogenthatallowsforcellmigration,angiogenesisandmicrovascular permeability.Ithence,hasadirectgrowthfactoreffectontumorprogressionofallkindsof cancer.AggressivehighgradecancersallshowhighlevelsofVEGFsecretions.Itishypothesized thatobesitydrivenelevationinVEGFlevelsisapotentprimingeventforallformsofcancer, speciallyhormonalcancers. o Adiponectinthisisanadipokinethatisnegativelycorrelatedwithobesityandvisceralfat.Ithas beenidentifiedasapossibletherapeuticagentinmanyobesityrelatedmetabolicconditions,such asdiabetes,hypertension,etc.Hence,byvirtueofitsoppositenaturetootheradipokines,itis hypothesizedtobetheanticanceradipokine.Itisalsonegativelycorrelatedwithhighgrade prostrateandbreastcancers. Thefunctionofadiponectinisviaitstwoprimaryreceptors,whichhaveaspatialdistributionthat isgovernedbyothergrowthfactorsandadipokines. MechanismofactionStudieshavealsoidentifiedJNKandsignaltransducerandactivatorof transcription3(STAT3)ascommondownstreameffectorsofadiponectin.BothJNKandSTAT3play crucialrolesinobesityandinsulinresistanceandarealsoinvolvedintheregulationofcell proliferation,differentiation,andapoptosisduringvariousphysiologicandpathologiceventssuch astumourdevelopment.[7]

Discussion/Analysis
Gettingfat Startinginchronologicalorderofoccurrence,inapatientslifefirst,onemustbecomeobeseforanyriskstobe present.Isthisnecessarily,true?Yes.Notthatnonobesepeoplearenecessarilyriskfreeorunlikelytogetcancer butobesityispositivelycorrelatedwithmultipleformsofcancer,sothatriskisassured. Foodscontaininghighlevelsofsaturatedfattyacidsandcholesterolarespecificallytheonesthatareimplicatedin developmentofcentralabdominalobesity.Linoleicacid(orOmega6polyunsaturatedfattyacid)isaconstituentof animalfatthathasbeenpositivelyimplicatedinprostaticcancermigration/metastasis[12].Also,lowfatculture mediumforinvitrotumorculturesresultedindecreasedproliferationratesandlowfatdietsfortumorbearing nudemicealsoshowedslowerprogressionoftumors. WhiteAdiposeTissue(WATasubclassificationofadiposetissue,whichislargelypresentinvisceralfat),is significantlycorelatabletoconsumptionofanimalfatandsaturatedfattyacids.Itisrecognizedasametabolically activeendocrineorgansomeofthesecretionsofwhichhavebeenlistedabove. Hence,thereisdefinitelyarelationbetweenonesdietandcancerprognosis. Theroleofobesity Obesityhasbeengenericallyclassifiedasaconditionthatsuppressesnonaggressivediseasesandacceleratesthe aggressiveones.Howtruethisstereotypemaybe,isnotthesubjectofthisreportbutnonethelessthestatement doesholdtrueforcancerprogression. Tosaythatcancer(ofanyform)maybeinducedbyobesity,isnotajustifiablestatementonthebasisofcurrently availabledata.However,cancerprogressionisdefinitelyataskthatobesityisabletopromotetosufficiency(of thetumor). Withreferencetotheabovegivendata,thetwomostabundantadipokinesleptinandadiponectinarepolar oppositesintheiraffectsoncancerprogression.However,theyareupregulatedanddownregulated,respectively, resultinginahigh[leptin:adiponectin]ratiowhichhasbeenpositivelyidentifiedinadvancedstagebreastcancer patients.Likewise,theelevatedlevelsofmitogenicandangiogenicfactorsinbloodserumlevelscausedby adiposetissuesecretions,areconditionsthatuniversallypromotegrowthoftumorsofallkinds. Thisandotherexamplespreviouslygivenpositivelyidentifytheroleofadiposetissueasareservoirofparacrine factorsthatpromotetumorprogression. DiagnosisandPrognosis Sowhatisthemeaningofitall? Theansweristhereissufficientevidencetosupporttheclaimthatobesityisadefinitive,sufficientandsignificant conditionthatpromotestumorprogression(atleastofcertaintypesofcancer).Theimplicationsofthisstatement, intermsofdiagnosis,wouldbe Frequentandrigorouscheckupsofobesepersonsforidentificationofgrowingtumorsinearlystages Formulationofstandardsfromexistingpatients,toestimateserumlevelsoflistedmolecularcandidatesfor differentstagesofcancer(orsimplyevenabsenceorpresenceoftumors) Bettercharacterizationofbiopsysamplesinordertoidentifypotentialriskfactorspresent(withregards adipokinelevelsandpotentialfortumorformation) Weightlossbecomesaneasyandsignificanttreatmentmethodologytoslowcancerprogression(ofcertain typesofcancer). Predictabilityofdiseaseprogressionimproves,byvirtueofcharacterizationofadipokinelevelsattumor site Lowfatdietsbecomeagiven,fortreatmentofhormonalcancers

Intermsofprognosisandtreatment

Hence,allinalltherelationbetweenobesityandcertainformsofcancerhasdefinitelybeenestablishedbeyond doubt.Andthepotentialavenuesoftherapyandpreventionthathaveopenedasaresultoughttobethoroughly investigatedtobattlethisdisease.

References
VM Bowers-Morrow and S.O. Ali - Sex-hormone binding globulin receptor-mediated growth inhibition in breast cancer cells: a proteomics approach : Breast Cancer Research 2005, 7(Suppl 2) : P2.10 doi:10.1186/bcr1121 2. Schatzl G, Madersbacher S, Thurridl T, et al. - High-grade prostate cancer is associated with low serum testosterone levels. : Prostate 2001;47:528. 3. Platz EA, LeitzmannMF, Visvanathan K, et al. -Statin drugs and risk of advanced prostate cancer. J Natl Cancer Inst 2006;98:181925 4. Chang S, Hursting SD, Contois JH, et al. - Leptin and prostate cancer; Prostate 2001;46:627. 5. Somasundar P, Frankenberry KA, Skinner H, et al. - Prostate cancer cell proliferation is influenced by leptin ; J Surg Res 2004;118:7182 6. Lee SO, Chun JY, Nadiminty N, Lou W, Gao AC - Interleukin-6 undergoes transition from growth inhibitor associated with neuroendocrine differentiation to stimulator accompanied by androgen receptor activation during LNCaP prostate cancer cell progression. : Prostate. 2007 May 15;67(7):764-73. 7. Davis RJ. - Signal transduction by the JNK group of MAP kinases. Cell 2000;103:23952 8. Tina Mistry et. al Obesity and Prostate Cancer: A Role for Adipokines; European Urology 52 ( 2 0 0 7 ) 4653 9. Von Hafe P, Pina F, PerezA, Tavares M, Barros H. Visceral fat accumulation as a risk factor for prostate cancer. ObesRes 2004;12:19305 10. OnumaM, Bub JD, Rummel TL, Iwamoto Y. - Prostate cancer cell-adipocyte interaction: leptinmediates androgenindependent prostate cancer cell proliferation through c-Jun NH2-terminal kinase. J Biol Chem 2003;278:426607 11. Chen DC, Chung YF, Yeh YT, et al. - Serum adiponectin and leptin levels in Taiwanese breast cancer patients. Cancer Lett 2006;237:10914 12. Brown MD, Hart CA, Gazi E, Bagley S, Clarke NW. - Promotion of prostatic metastatic migration towards human bone marrow stoma by omega 6 and its inhibition by omega 3 PUFAs. Br J Cancer 2006;94:84253 1.