Thompson opac2013


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Thompson opac2013

  1. 1. CancerPreventionLaboratoryHenry J. ThompsonCancer Prevention LaboratoryColorado State UniversityFort Collins, COhenry.thompson@colostate.eduhttp//:www.cpl.colostate.eduEnergy metabolism within organisms and cellsand cancer processes
  2. 2. • Review evidence regarding energy restriction inanimal models• Review evidence for relevance of energy pathwaysin in vitro systems• Discuss the cellular and molecular mechanismslinking energy balance and flux and cancer• Be sure to consider how animal model findings are ornot relevant to human cancer• Highlight challenges and opportunities for futureresearchWhat this presentation has beenrequested to address
  3. 3. Above is the image at: ascompressed complexity,complexity as unwovensimplicity.“Genius of the AND”rather than the“Tyranny of the OR”Jim Collins (Built toLast)
  4. 4. This presentation is less aboutgiving you answers and moreabout stimulating thinking anddiscussion in order to create theopportunity for epiphanies“Education is not about the filling of a pail; it is aboutthe lighting of a fire” Yates• How does energy restriction relate to the “human condition?• How does energy restriction affect carcinogenesis in animalmodels?• What is energy restriction and how does the organism andcell “sense” its energy status (balance vs flux)?• What links energy status to cancer: host systemic and cellautonomous affecters?PAUSE
  5. 5. • How does energy restriction relate to the“human condition”?• How does energy restriction affect carcinogenesis in animalmodels?• What is energy restriction and how does the organism and cell“sense” its energy status (balance vs flux)?• What links energy status to cancer: host systemic and cellautonomous affecters?CALORIC RESTRICTION
  6. 6. 1000.01100.01200.01300.01400.01500.01600.01700.01800.01900.02000.017.5 18.3 19.1 19.9 20.7 21.6 22.4 23.2 24.1 24.9 25.7 26.6 27.4 28.2 29.1 29.9 30.7 31.6 32.4 33.2 34.1 34.9 35.7 36.6 37.4 38.2 39.1 39.9 40.7 41.5105 110 115 120 125 130 135 140 145 150 155 160 165 170 175 180 185 190 195 200 205 210 215 220 225 230 235 240 245 250kcalBMI & Body Weight (lbs.)Maintenance Energy Requirements: 55" FemaleAge 25 Age 45 Age 65HealthyWeightUnderWeight Overweight ObeseMorbidlyObeseWhat does energy (calorie) restriction mean to you?Energy stress—energy balance stress—energy availability stress(quantitative and qualitative dimensions)
  7. 7. Calle et al.Energy restriction relative to starvationEnergy hormesis
  8. 8. Limitation in Pre-Clinical Science• Few (any?) reports of obesity reduction inan autocthonous model for cancer• Lewis Chodosh- inducible residual disease model• Our lab “new” autochthonous model• Transplant models• Not many• Hursting lab• Cell based models: What’s the question being modeled?• Sabatini- Nutrostat experiments: consequences of[glucose]: AACR 2013 (high/low glucose-energy chargeand 3 cell fates)• AVANTAGGIATI: Glucose availability regulatesaccumulation of mutant p53 protein: Cell Cycle 2012
  9. 9. • What is energy restriction and how does it relateto the “human condition?• How does energy restriction affectcarcinogenesis in animal models?• How does the organism and cell “sense” itsenergy status (balance vs flux)?• What links energy status to cancer: host systemicand cell autonomous affecters?
  10. 10. Pre-Clinical ModelsCarcinogenTransgene/KOInterventionIDP DCIS Invasion Metastasis Recurrence
  11. 11. (Energy=Obesity?) Sensitive CancersSensitivePre-clinical ClinicalInitiation Promotion Progression RecurrenceInsensitivePre-clinical ClinicalInitiation Promotion Progression Recurrence
  12. 12. IncreasingAgeBodyWeightIncreasingAd Libitum10%ER20%ER40%ERPre-Clinical Model for Positive Energy Balance:What is the effect of different planes of energy nutrition?0102030405060708090100ACIncidence(%)27 28 29 30 31 32 33 34 35 FIDays Post CarcinogenControl 10%ER 20%ER 40%ERZhu et al, Carcinogenesis 1997. 19990123456Number/RatControl 90RF 80RF 60RFGroupIDP DCIS AC050100150200250300350400450mm3Control 90%RF 80%RF 60%RFGroup
  13. 13. 11 18 25 32 39 46DR DS0. 27 32 35 39 42 46 49 53 59 63AVE.#OFCANCERSPERANIMALDPCDR DS0.0%10.0%20.0%30.0%40.0%50.0%60.0%70.0%80.0%90.0%100.0%24 27 32 35 39 42 46 49 53 59 63%CANCERINCIDENCEDPCDR DS(Cecchini et al Cancer Prev Res; 5(4);583–92, 2012). In that publication fromthe National Surgical Adjuvant Breastand Bowel Project (NSABP), BMI >30was significantly associated withincreased risk of invasive breast cancerin high-risk premenopausal women(HR= 1.70).
  14. 14. 35 44 48 52 56 60 63 66 69 71 74 76 78 82 85 89AVE#OFTUMORSPERANIMALDays post ovariectomyMultiplicityDR DS0%10%20%30%40%50%60%70%80%90%26 35 44 48 52 56 60 63 66 69 71 74 76 78 84 89INCIIDENCEOFTUMORSDays post ovariectomyDR DS
  15. 15. • What is energy restriction and how does it relate to the “humancondition?• How does energy restriction affect carcinogenesis in animalmodels?• What is energy restriction and how doesthe organism and cell “sense” its energystatus (balance vs flux)?• What links energy status to cancer: host systemic and cellautonomous affecters?
  16. 16. NormalQuiescentNormalProliferatingCancerProliferatingCancerQuiescentHost systemic factorsAND, NOT OR
  17. 17. Temperature varies widely within the cellOkabe, 2012 Nature CommunicationWhat does this imply about the distribution of energy within cells?
  19. 19. Energetics Paradigm(How cells respond to continuous energy stress)AMPKSirtuinsAMPKAMPGlycogenNAD+/NADHFreeFatty acidsATPcGuanylyl-CyclaseEnergyStatusPPARsE messengersE sensorsInsulin/IGF-1GlucocorticoidsLeptin/Adiponectin
  20. 20. Energy Availability (Net)StressWhat time scale is important relative to cancer?• Second, minute, hour, day week, month?• As a systems biologist, how should you view energy availability?Energy expenditure• Physical activity• SDA• Futile cycling• ThermogeneisEnergy intake• Food• FluidEnergy Reserves• Glycogen• Fat
  21. 21. NormalQuiescent(growth)Cancer-metastatic[Growth factors/hormones]•IGF-1•Insulin•Cortisol•CytokinesBUILDING BLOCKSDe novo BIOSYNTHESISATPAND REDUCINGEQUIVALENTS[Substrates]•Glucose•Glutamine•EAA•Fatty AcidsMETABOLISMINTERMEDIARYOncogenes: PI3K, Ras, Raf Akt, Src, Myc, HifSupressor genes: Lkb1, NF1, P53, PTEN, TSC1/2
  22. 22. Glucose and glutamine fuel proliferation.Cantor J R , and Sabatini D M Cancer Discovery2012;2:881-898©2012 by American Association for Cancer Research
  23. 23. Time to reformulate?What insights will advance the field?• How do cells solve the problem of getting what theyneed to proliferate in the energy restricted state?• What is that cell’s fate when the problem cannot besolved in a particular snapshot in time?– Energy balance– Availability of energy substrates/reducing equivalents– The metabolic flexibility of the “target cell” defineswhether it is energy restriction Sensitive or Insensitive• Sensitive: lacks ability to make adaptive changes in coremetabolism to accommodate its current replicative potential• Insensitive: flexibility is not compromised: cell uses alterativepathways to satisfy its requirements for proliferation– Intervention development: ability to impose constraintson metabolic flexibility in order to prevent or control thefate of transformed cells)
  24. 24. • What is energy restriction and how does it relate to the“human condition?• How does energy restriction affect carcinogenesis inanimal models?• How does the organism and cell “sense” its energystatus (balance vs flux)?• What links energy status tocancer: host systemic and cellautonomous affecters?
  25. 25. Cellular Mechanisms (Failed size homeostasis)• Cell Proliferation– Jiang et al Cancer Res.2003• Apoptosis– Thompson et al.Cancer Res. 2004• Vascularization– Thompson et al.Cancer Res. 200405101520253035ProliferationIndex(%)UI IDP DCIS ACLesionControl10%ER20%ER40%ER0. IDP DCIS ACLesionLesion
  26. 26. 4EBP1Thr37/46 p70S6KRaptorGrowth factors, nutrient and energy sensing networkPRAS40IGF-1PI3K-I IRS-1AKTS473AMPKT172Adiponectin,LeptinmTORC1Ser2448LKB1S428Ser792 Thr246Thr389G1SG2MCyclin D1 ApoptosisBax Bcl-2p27GADD153FoxO3AThr32ATP↑/AMP ↓FoxO1Thr24IGF1RTSC2TSC1Integrates IC, ECNutrient/EnergyCuesMediates StressResponseWhat’s missing: The HIPPO Pathway• Controls cell/organ size and polarity• Deregulated during carcinogenesis• No studies of energy restriction
  27. 27. 2-Deoxyglucose (2-DG)•Glucose analogue•Accumulates in tumor cells•Blocks glycolysis
  28. 28. Summary: What can help us advance the field?• Relevance of in vitro experiments or animal studies or human subjectprotocols (inclusion/exclusion criteria) : depends on the question beingasked. No model is ideal, but is it inform our understanding of thequestion?• There are in reality a lot of gaps in the preclinical literature on energeticsand cancer: addressing which gaps will advance the field?• Broaden the focus: energy balance suggests constancy but we learnmore if we realize that constancy is a measurement “artifact”. Energeticsystems are dynamic, constantly in flux, differentiated by adaptability(flexibility) and heterogeneity of response .• Perhaps what is most important for human health is hormetic energyregulation: the level of energy stress that places the organism at anadaptive advantage.
  29. 29. Our TeamZongjian ZhuWeiqin JiangAudrey BarnettNick Fernandez*Joy HesterWeiqin JiangJohn McGinleyElizabeth NeilAndre Powell*Jennifer PriceDenise RushJennifer SellsMatthew ThompsonJay Waterman*Pamela WolfeZongjian ZhuJarrod Zacher*Jack SneddinJohn McGinleyLiz Neil