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  • Human physical activity (they run all the time, no strength training)
  • Add gut microbiome
  • stronger intervention effects on CRP in women with higher baseline physical fitness (P(heterogeneity) = 0.040) was found.
  • -8% to -24% change in SAA
  • N=320 randomized, 308/310 at 6 and 12 month time pointTER = treatment effect ratio of exercisers to controls

Ulrich opac2013 Ulrich opac2013 Presentation Transcript

  • Physical activity change: what biomarkerstell us about cancer mechanisms and effectsProf. Dr. Cornelia UlrichDirectorNational Center for Tumor Diseases (NCT)German Cancer Research Center (DKFZ)andFred Hutchinson Cancer Research Center,SeattleWorld Cancer Research FundObesity, Physical Activity &CancerApril 2013, London
  • The next 25 minutes• Evidence base for mechanisms linkingphysical activity to cancer• Mechanisms – results and questions Inflammation Immunity Oxidative stress and DNA repair Sex hormones, metabolic hormones,adipokines…• Mechanisms in cancer patients• Summary
  • Evidence base for mechanisms linkingphysical activity to cancer risk (1)• Animal studies Direct mechanistic effects in tissue and key biospecimens Limited generalizability compared to:• Human physical activity• Human biomarkers (e.g., inflammatory processes, PNAS 2013)• Dose-response achievable in humans• Observational epidemiological studies measuringbiomarkers concurrently with physical activity levels Detect long-term associations E.g., training status and DNA repair capacity Limitation: confounding factors, such as supplement use,body weight, etc…
  • Evidence base for mechanisms linkingphysical activity to cancer risk (2)• Human intervention studies Experimental design (randomized controlled trial)allows direct measurement of effects and inference ofcausality Biomarkers can be “intermediate endpoints” in cancerresearchCRP  increases colorectal cancer risk (Toriola, Int J Ca 2013) is associated with cancer survival (Pierce,J Clin Onc 2009) Limited to:• Shorter time periods (generally up to 1 year)• Certain biospecimens Dependent on:• Adherence
  • Physical Activity Caloric RestrictionCancer RiskDNA RepairCapacityVitamin DImmunityObesityInflammationSex hormonesInsulin/GlucoseAdipokinesGutmicrobiome?
  • Physical activity is highly correlatedwith vitamin D levels (NHANES)25 (OH)Vit DFrequency of outdoor activity (times in past month)Scragg & Camargo, Am J Epi 2008Non-Hispanic White Mexican American Non-Hispanic Black
  • Exercise Trial – PhysicalActivity for Total Health Study• Randomized controlled trial examining in overweight,sedentary, postmenopausal women (n=173 PATH Study) the effects of a one-yearexercise intervention (5d/wk 45min) compared to a one-yearstretching program on cancer biomarkers(0, 3,12 months)• Very good adherence and minimaldrop out• Significant improvement in VO2 maxMcTiernan, Ulrich (IMEX) and colleagues
  • 01234CRP(mg/L)Ctrl-BLCtrl-12mEx-BLEx-12mWaist circ. <88cm Waist circ. >88cm12m exercise reduces C-reactive proteinamong obese womenP. Campbell, Medicine Sports Science Exerc 2009n.s.CtrlCtrl ExerExerp<0.001
  • Alberta Physical Activity andBreast Cancer Prevention Trial –similar effects on CRP• RCT, parallel design, larger sample size(n=160/160), biomarkers at 6 & 12 months Also excellent adherence and minimal dropout• Differences over 12 months: Exercisers versus controlsReduced CRP (TER = 0.87, 0.79-0.96, P = 0.005)• But no changes in IL-6 or TNF-alpha. Decreasing CRP with increasing exercise Effect mediated by fat loss No intervention effect if adjusted for dietaryfiber  confounding?Friedenreich et al, Cancer Prev Res 2012
  • Energy balance – is it aboutexercise or aboutweight loss? Better chubby and fitor thin at every price?
  • PI: Anne McTiernan, Seattle TREC(Ulrich Project Leader)• Randomized, controlled, 12 month,4-arm clinical trial of diet and/or exercise• 439 postmenopausal overweight-to-obese women• Average Age: 58 years• Average BMI: 30.8 kg/m2 Body fat: 48%AIMS:Assess effects of a moderate-intensityexercise program, weight reduction diet,or both exercise + diet in postmenopausalwomen on body weight and composition,and cancer biomarkers
  • CRP concentrations % change as a result of12-month diet or exercise intervention* p<0.0001*Imaya, Ulrich, McTiernan et al. Cancer Res 2012*-46.9%P= <.001- 37.7%P= <.001-46.9%P= <.001-11.4%P= .091.1%
  • Changes in CRP by weight loss*-51.2%P< .001†-52.0%P< .001†-27.8%P= .001†0.9% 0.9% 0.9%-3.7%-13.0%-7.3%Diet Diet + Exercise ExerciseImaya, Ulrich, McTiernan et al. Cancer Res 2012
  • Percent leukocytes % change as a result of12-month diet or exercise intervention*-2.0%-9.2%P< .001-7.1%P< .001-2.5%p=.78Imaya, Ulrich, McTiernan et al. Cancer Res 2012
  • 00.10.20.30.40.50.6Incidence ofcolds1st Qtr 2nd Qtr 3rd Qtr 4th Qtr12-month study periodExerciseControlP=0.02Chubak et al Am J Med 2006
  • No effects of exercise intervention on broadspectrum of biomarkers of immune function• No effects on Lymphocyte proliferationfrom cryopreserved cells Natural killer cellcytotoxicity Cell counts andphenotypes Immunoglobulins• Despite excellentretention, adherence andintervention efficacy• Value of snapshotimmune markers?Campbell P et al, J Appl Physiol 2008
  • Oxidative stress and DNA repair-- why do we expect effects?Exercise or general metabolism inducesoxidative DNA damage• Training of the DNA repair system throughexercise?• Reduced levels of oxidative damage?Supporting preliminary data from animalexperiments, cross-sectional studies(frequently athletes) and smallinterventions
  • -15-10-505%ChangeOverall By % gain in V02maxPhysical Activity for Total Health Study:Exercise reduces urinaryF2-isoprostane levels among those with greatesttraining efficacy (n=173)Campbell P et al. Med Sci Sports Exerc 2010CtrlExn.s.P-trend=0.005Ctrl***<55-15 >15No effects on DNA repair capacity overall, as measured by Comet AssayOther assays needed?(Habermann, Ulrich et al, in prep.)
  • NEW: Diet & Exercise interventions decrease serumleptin levels among postmenopausal women (n=439)051015202530Diet+Exercise Diet Exercise ControlLeptinµg/mLBaseline12 monthsAbbenhardt J Int Med 2013P<0.0001 P<0.0001 P<0.005
  • NEW: Diet, but not exercise interventionsincrease serum adiponectin levels amongpostmenopausal women(n=439)Abbenhardt C et al. J Int Med 20131010.51111.51212.51313.51414.515Diet+Exercise Diet Exercise ControlAdiponectinµg/mLBaseline12 monthsP=0.001 P=0.001N.S.
  • Alberta Physical Activity andBreast Cancer Prevention Trial(Friedenreich et al)• Across the study period comparingexercise group to controls (treatmenteffect ratio:statistically significant reduction inleptin (TER=0.82, 0.78-0.87)increase in the adiponectin/leptin ratio(TER=1.21, 1.13-1.28)Friedenreich et al. Endocr.-related Ca 2011
  • Half-time summary• Intervention trials of exercise have shownsignificant and reproducible effects onbiomarkers of cancer risk Inflammation, adipokines, sex hormones,insulin/IGF, oxidative stress• Unclear effects on immunity, DNA repair &Vit D• Effects strongest in diet and exercise group• Fat-loss important mediator for many, butnot all mechanisms
  • Inflammation -What’s fat got to do with it?
  • Targeting tissue – effects ofenergy balance on adiposetissue biology• Adipose tissue is active in metabolism and synthesisof IL-6, TNFalpha, sex steroid metabolism… Goal: To learn about molecular mechanisms in target tissue• N=49 women randomized to exercise and or weight-loss intervention• Subcutaneous adipose tissue sampling at baselineand 6 months
  • Adipose tissue biopsies andbiomarkersCollagenasedigestion AdipocytesStromavascular cells (SVC)for flow cytometry (Kratz)Snap-frozenwhole tissue forRNA extractionand geneexpressionBiopsy:subcutaneous abdominal fatlocal anaesthetic (incision, 14-gauge needle)yield ~ 500 mgCampbell, Ulrich et al. Cancer Prev Res 2013Analysis:• candidate genes• candidate pathways• unsupervised clustering• By intervention• By weight-loss
  • Weight loss affects adiposetissue gene expression• Analysis by weight loss:% change P trendadj. PvalueSex Steroid-Related:HSD17B1 -0.35 0.0002 0.01ESR1 0.24 0.0037 0.08STS -0.26 0.0198 0.20HSD17B10 -0.05 0.045 0.37Inflammation-Related:CRP 0.23 0.0081 0.13ICAM4 -0.09 0.0110 0.13SAA1 -0.38 0.0110 0.13VCAM1 0.34 0.044 0.37Other Genes of Interest:LEP -0.44 0.0000 0.00IGFBP3 0.37 0.0032 0.08Campbell, Ulrich et al. Cancer Prev Res 2013
  • –omics results• Unsupervised clustering of >37,000 transcriptsby weight loss• Reveals 78 transcripts with statisticallysignificant adjusted p-values Multiple hits in histone clusters Leptin is #33  suggests strong effects ofweight loss on other pathways in adiposetissue• However: unsupervised approach results alsomisses significant hits in candidate pathways(=false negatives)• Combination of hypothesis-driven andempirical approach is complementary!!Campbell, Ulrich et al. Cancer Prev Res 2013
  • 6m 12m 24m 36mTreatmentinformation• Blood draws• Urine• Feces• Questionnaires onsymptoms, QoL &current health habits,Food frequency (FFQs)• Accelerometer3m• Questionnaireson symptoms,QoL & currenthealth habitsSurgery• Pre-surgery blood• Urine• Feces• Tumor & normal tissue• Visceral & subcutaneousadipose tissue• Fascia• QuestionnairesOutcomes•Surgical outcomes•Treatment toxicity• Recurrence• Survival• Symptoms, QoLBaselineDiagnosisColoCare – Study DesignMulticenter colorectal cancer patient cohort
  • Exercise in the adjuvant therapy ofcancer patientsThere is substantial potential for exercise in aiding in the recovery ofcancer patients unknowns regarding type, timing, intensity and duration of interventionClinical trial: n=170 hematopoietic stem-cell transplantation patients exercise prior to and during the transplant process cancer-related fatigue, distress and  physical functioning/fitnessPFS (months)Wiskemann, Blood 2011Greatest benefiton physical fitnessin the initiallyunfit!
  • Biomarkers in cancer patients undergoingenergy balance interventions• Little research during time periods during andright after therapy Impact of therapy? Impact on therapy success? E.g., Biomarkers of inflammation related tofatigue  differential effects of energy balanceon inflammation than in healthy individuals?Multiple exercise trials underway inHeidelbergBreast, HSCT, lung, soon pancreasWith Karen Steindorf and Joachim Wiskemann
  • Summary and outlook• There are many possible mechanisms by whichexercise/energy balance can affect cancer These are likely to act in combination• Exercise/diet trials among overweight/obese show: ↓ Inflammation in plasma and tissue• Substantial effect, but weight loss required ↓ Oxidative stress Effects on estrogens, adipokines, adipose gene expression Immunity? DNA repair?• Studies in cancer patients are needed to understandmechanisms and substantiate recommendations forpatients Different setting for biomarkers, e.g., biomarkers ofinflammation under therapy• Interdisciplinary studies are needed that address multipledimensions of energy balance Physical activity, biomarkers, adipose tissue, etc…
  • FHCRC:Anne McTiernanKristin CampbellMario KratzKaren Foster-SchubertClare AbbenhardtMarc HortonKristin CampbellPeter CampbellBrandon PierceAlanna BoyntonLiz PooleJessica ChubakLaura HooperJulie MeyersNCT/DKFZ:Karen SteindorfJoachim WiskemannDirk JägerMartina SchmidtUrsula BollowDominik van den Bergh+ many others…Support : NIH Grants (TREC)Manfred Lautenschläger StiftungStiftung Leben mit KrebsMilonColleagues and staff from theHeidelberg ISZBNIH TREC InitiativeHEAL Study