Efficacy and Mechanisms of Aerobic Exercise on Cancer Initiation, Progression, and Metastasis

20 Pages·2016·0.86 MB·English

Published OnlineFirst July 5, 2016; DOI: 10.1158/0008-5472.CAN-16-0887
Cancer
Review Research
Efficacy and Mechanisms of Aerobic Exercise on
Cancer Initiation, Progression, and Metastasis:
A Critical Systematic Review of In Vivo
Preclinical Data
KathleenA. Ashcraft1, Ralph M. Peace1, Allison S.Betof2, Mark W. Dewhirst1, and
Lee W. Jones3
Abstract
Amajorobjectiveoftheemergingfieldofexercise–oncology effectsofexerciseincancerpreventionandprogression.Stud-
researchistodeterminetheefficacyof,andbiologicalmechan- ies were evaluated on the basis of tumor outcomes (e.g.,
isms by which, aerobic exercise affects cancer incidence, incidence, growth, latency, metastasis), dose–response, and
progression,and/ormetastasis.Thereisastronginverseasso- mechanisms of action, when available. A total of 53 studies
ciation between self-reported exercise and the primary inci- were identified and evaluated on tumor incidence (n ¼ 24),
dence of several forms of cancer; similarly, emerging data tumorgrowth(n¼33),ormetastasis(n¼10).Wereportthat
suggest that exercise exposure after a cancer diagnosis may the current evidence base is plagued by considerable metho-
improveoutcomesforearly-stagebreast,colorectal,orprostate dologicheterogeneityinallaspectsofstudydesign,endpoints,
cancer. Arguably, critical next steps in the development of and efficacy. Such heterogeneity precludes meaningful com-
exercise as a candidate treatment in cancer control require parisonsandconclusionsatpresent.Tothisend,weprovidea
preclinicalstudiestovalidatethebiologicalefficacyofexercise, framework of methodologic and data reporting standards to
identify the optimal "dose", and pinpoint mechanisms of strengthen the field to guide the conduct of high-quality
action. To evaluate the current evidence base, we conducted studies required to inform translational, mechanism-driven
a critical systematic review of in vivo studies investigating the clinical trials. CancerRes;76(14);4032–50.(cid:1)2016AACR.
Introduction Astrongbodyofobservationalevidenceindicatesthathigher
levelsofself-reportedexercise,physicalactivity,aswellascardio-
Structured exercise training (hereto referred to as exercise) is respiratoryfitness(i.e.,objectiveassessmentofexerciseexposure)
consideredanintegralcomponentof"standardofcare"therapyin
are inversely associated with the primary incidence of several
primaryandsecondarypreventionofnumerouscommonchronic
forms of cancer. This evidence base is summarized by several
conditions(1–4).Incomparison,theroleofexercisehasreceived excellentsystematicreviewsandmeta-analyses(6–9).Forexam-
surprisinglylittleattentioninindividualsathigh-riskoraftera
ple,exerciseparticipationconsistentwiththenationalguidelines
diagnosis of cancer. Over the past two decades, however, an
(i.e.,150minutesofmoderate-intensityor75minutesofvigor-
increasing number of groups are investigating the effects of
ous-intensity exercise per week) is associated, on average, with
generalphysicalactivityaswellasexerciseintheoncologysetting,
25%,and30%to40%riskreductionsinbreastandcoloncancers,
afieldnowcommonlyreferredtoas"Exercise–Oncology"(5).
respectively,comparedwithinactivity.Thereisalsoevidenceofa
linear dose–response relationship in prevention of breast and
coloncancer.Onthisbasis,theevidencefortheexercise–preven-
1DukeUniversityMedicalCenter,Durham,NorthCarolina.2Massachu- tion relationship is categorized as "convincing" for breast and
settsGeneralHospital,Boston,Massachusetts.3MemorialSloanKet- colon cancer by several national agencies, and regarding as
teringCancerCenter,NewYork,NewYork. "encouraging" or "promising" for the prevention of prostate,
Note: Supplementary data for this article are available at Cancer Research lung,andendometrialcancers(10,11).Onthebasisofthisdata,
Online(http://cancerres.aacrjournals.org/). severalphaseIIrandomizedcontrolledtrials(RCT)wereinitiated,
M.W.DewhirstandL.W.Jonescontributedequallytothisarticle. predominantly in breast cancer prevention, to investigate the
effectsofhighlystructuredexerciseonmodulationofhost-related
CorrespondingAuthors:LeeW.Jones,DepartmentofMedicine,MemorialSloan
KetteringCancerCenter,485LexingtonAvenue,NewYork,NY10017.Phone: factors (e.g., adiposity, circulating factors including sex-steroid
646-888-8103;Fax:[phone];E-mail:[email protected];andMarkW. and metabolic sex hormones, and the immune–inflammatory
Dewhirst,DepartmentofRadiationOncology,DukeUniversityMedicalCenter, axis)thatmayunderpintheexercise–cancerpreventionrelation-
Box3455,MedicalSciencesResearchBuilding1,Room201,Durham,NC27710. ship(6,12–14).Ingeneral,exercisewasassociatedwithmodest
Phone:[phone];E-mail:[email protected]
changes in markers of adiposity and select circulating factors
doi:10.1158/0008-5472.CAN-16-0887 (6,12,13).Whethertheobservedalterationsareofbiologicor
(cid:1)2016AmericanAssociationforCancerResearch. clinicalimportanceremainstobedetermined,asonlyonetrialto
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Published OnlineFirst July 5, 2016; DOI: 10.1158/0008-5472.CAN-16-0887
ExerciseinCancerInitiation,Progression,andMetastasis
datehasinvestigatedtheexercise-inducedchangesincirculating crypt foci, ApcMin), or hematopoietic and ascites tumors were
factorsoccuringinconjunctionwithchangesinfactors/pathways excluded. Only mouse and rat studies were included. Articles
intheorgan/tissueofprimaryinterest(i.e.,coloncrypts;ref.15). unavailableinEnglishwereexcluded.
Whether exercise reduces cancer incidence or modulates estab-
lished surrogate markers of cancer incidence has not been Studyselectionandclassification
investigated. Fourauthors(K.A.Ashcraft,R.M.Peace,A.S.Betof,andL.W.
Inpatientswithcancer,asteadilygrowingandeverdiversifying Jones) assessed study eligibility by reviewing the titles and
series of studies indicate that, in general, exercise is a tolerable abstracts of all potential citations according to the inclusion
adjuncttherapyassociatedwithsignificantbenefitacrossawide criteria.K.A.Ashcraft,R.M.Peace,M.W.Dewhirst,andA.S.Betof
rangeofsymptomcontrolvariablesbothduringandafterprimary extracted and interpreted data from published articles. When
adjuvant therapy (5, 16, 17). These data combined with the necessary,effortwasmadetocontactauthorsandacquirepub-
powerfulinverserelationshipswithprimarycancerincidencehas lications for evaluation. Studies are summarized by type of
ledresearcherstoinvestigatewhetherexerciseinfluencesdisease exercise model and method of tumor initiation. Exercise char-
outcomesafterdiagnosis(18,19).Althoughnotnearlyasmature acteristics are described using common prescription elements:
astheevidenceinthepreventionsetting,emergingobservational modality, frequency, duration, intensity, and total length of
data suggest that regular exercise exposure is associated with intervention.
between a 10%–50% reduction in the risk of recurrence and
cancer-specific death in patients with colorectal, breast, and Tumorinitiationversusgrowth
prostatecancer(reviewedinref.20),comparedwithinactivity. Articleswereclassifiedbytheendpointsreportedintheindi-
In the development of potential drug candidates, data from vidualstudies:(i)"Incidence"(tumorpresenceormultiplicity),
observational studiesis insufficientto supporttheinitiation of (ii)"Growth"(dataontumorgrowth,latencyorsurvival),and
human trials; appropriate preclinical evidence is first required (iii)"Metastasis"(evaluationoftumorsdistinctfromtheprimary
prior to human testing (21). While exercise is not a drug and tumorordevelopingfollowingthecommonmetastasismodelof
exhibitsamarkedlydifferentsafetyprofilethanmostanticancer intravenoustumorcellinjection).Studycategorizationwasnot
agents,theuseofpreclinicalmodelsareofcriticalimportanceto always mutually exclusive; thus, studies that included multiple
confirmthebiologicalplausibility,establishthetherapeuticwin- endpoints applicable to more than one categorization were
dow of efficacy, a biologically effective dose, and identify pre- includedinboth.
dictorsofresponse(22).Thisevidence,combinedwithdatafrom
epidemiologic and molecular epidemiologic studies facilitates Analysisofmechanisticfindings
thedesignofearly"signal-seeking"clinicalstudiesandultimately Forevaluationofmechanisticfindings,analternativeclassifi-
definitiveRCTs.Accordingly,weconductedacriticalsystematic cationwasappliedonthebasisoftheinitiationoftheexercise
reviewofinvivopreclinicalstudiesacrossthecancercontinuum intervention relative to the time of tumor cell transplant or
(i.e.,preventionthroughmetastasis).Asecondarypurposewasto applicationofcarcinogens."Prevention"wasdefinedasexercise
providerecommendationstofacilitatethestandardizationofthe initiatedpriortotumortransplant/induction."Progression"was
conductofinvivoexercise–oncologystudiesaswellasdirections definedasexerciseinitiated(cid:2)3dayspost-transplant/induction.
forfutureresearch. StudiesinvolvingGEMMswerecategorizedaspreventionstudies.
Distinguishingbetweenexerciseinitiationandtumorcellinoc-
Materials and Methods ulationisimportantbecauseexercise-inducedadaptationsprior
totumorinjectioncould"prime"thehostand/ortissuemicro-
Searchstrategyandinclusioncriteria environment,makingitphysiologicorbiologicallydistinctfrom
AsystematicliteraturesearchwasconductedusingOVIDMED- tumor inoculation into a sedentary host. Mechanistic findings
LINE(1950toMay2015),PUBMED(1962toMay2015),and wereclassifiedaseitherintratumoralorsystemic.
WEB OF SCIENCE (1950 to May 2015) with MeSH terms and
keywordsrelatedtoexercise,cancer,andanimals.Textwordswere Interpretationandanalysis
searchedandappropriateMeSHtermswerefound(Supplemen- Studieswereassessedforchangesintumorgrowth(aswellas
taryTableS1).Whenpossible,BooleanlogicwasusedwithMeSH the related parameters of time to tumor-related endpoint, and
terms to build searches. All results and reference lists were tumor size/mass at the end of the study), incidence (tumor
searchedmanually.Peer-reviewedresearcharticlesinvolvingani- presence),andmultiplicity(numberoftumors/metastases).All
malswithcancerandexposedtochronicexercise(repeatedbouts study results that were reported to be "statistically significant"
of more than3 sessions) adopting either forced (i.e.,treadmill achievedP<0.05accordingtotheauthorsoftheoriginalmanu-
runningorswimming)endurance(aerobic)trainingorphysical scripts. Preliminary analysis of included studies indicated con-
activity (i.e.,voluntary wheel running)paradigms wereconsid- siderable methodologic heterogeneity in all aspects of study
ered eligible. All types of animal models of solid tumors were design,endpoints,andefficacy.Assuch,itwasnotpossibleto
considered eligible including genetically predisposed models compare the efficacy of exercise across cancer setting (i.e., inci-
[transgenic, genetically engineered mouse models (GEMM)], dence, progression, metastasis),cancer histology, exercise para-
orthotopic, subcutaneous, and intravenous injections, tumor digm(i.e.,forcedvs.voluntary),orexercisedose.
transplant,andspontaneousorcarcinogen-inducedsolidtumor
models.Studiesthatincludedmultipletreatments,suchasstudy
Results
arms with dietary restrictions, were eligible, as long as it was
possible to compare sedentary (control) and exercise alone Atotalof426potentialcitationswereinitiallyidentifiedusing
groups.Studiesthatevaluatedpreneoplasticlesions(e.g.,aberrant searchterms.Aftersecondaryscreening,53articlesweredeemed
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Ashcraftetal.
eligible and underwent full review (Supplementary Fig. S1). Effectsonsystemic(host)pathways
Classification of articles was as follows: (i) incidence (n ¼ 24; Correlative systemic pathways examined are summarized
45.3%; refs. 23–46), growth (n ¼ 33; 62.3%; refs. 24, 26, 34, inTable4.Tenprevention(24,28,29,40,46–49,59,62),seven
37,39,40,42,44–69),andmetastasis(n¼10;18.9%;refs.53,55, progression(23,31,37,42,51,55,64,76),andfivemetastasis
63,64,70–75). studies(70–72,74,75)reportedsignificanteffectsofexerciseon
changesinsystemiceffectors,predominantlychangesinfactors
Tumormodelsandexerciseprescriptioncharacteristics involvedinimmunesurveillanceormetabolism.
Includedstudiestestedtheeffectsofexerciseon15different
tumor types/cell lines, using six different tumor initiation Discussion
methods (Supplementary Table S2). Details of the exercise
The findings of this critical review indicate that the current
prescriptionsare summarizedin Tables 1, 2,and3.The most
common modalities included voluntary running (n ¼ 22; evidencebaseisplaguedbyheterogeneityinallaspectsofstudy
41.5%; refs. 24–28, 31, 33, 35, 42, 43, 51, 52, 55, 57, 64– methodologyanddatareporting.Unfortunately,suchheteroge-
66,70,71,73–75)forcedrunning(n¼25;47.2%;refs.26,29, neityprecludesrigorousevaluationofessentialquestionssuchas
36–41,44–46,48,49,54,56,58–60,63,67–70,72,74),and thebiologicallyeffectiveexercisedosetomodulatespecifictumor
swimming (n ¼ 10; 18.9%; refs. 23, 30, 32, 34, 47, 50, 53, pathways or inhibit tumor growth, the effects of manipulating
exerciseintensityordurationorthedifferentialimpactofexercise
54, 61, 62).
acrosstumorsubtypes(22).Nevertheless,ourreviewdidpermit
identificationofthemostsalientmethodologicissuesthatpru-
Effectofexerciseontumoroutcomes dentinvestigatorsmayconsiderwhendesigninginvivopreclinical
In incidence studies, 58% reported that exercise inhibited exercise–oncology studies. These aspects are described in the
tumorinitiationormultiplicity(23–25,27,28,31,33,35,36, proceedingsectionsandsummarizedinTable5.
41, 43–46), 8% reported that exercise accelerated tumor inci-
dence(26,42),and3%foundnulleffects(29,30,32,34,37–
Heterogeneityinexerciseprescription
40).Inthegrowthcategory,exercisewasassociatedwithtumor
Thecomponentsoftheexerciseprescriptionbeinginvestigated
inhibition in 64% of studies (24, 39, 47–54, 58–63, 65–69),
inpreclinicalstudiesshouldmirror,ascloselyaspossible,exercise
while 21% (37, 40, 44, 55–57, 64) and 9% (26, 34, 42) of
prescriptionparameterstestedinhumanstudies(22).Keypara-
studiesreportednullandacceleratedtumorgrowth,respective-
metersinclude:(i)modality/paradigm(i.e.,forcedvs.voluntary),
ly. Finally, in the tumor metastasis category, three studies
(ii)dose(i.e.,intensity,session duration,frequency oftraining
utilized models in which metastases arose from a primary
sessions/week,andlengthoftreatment),and(iii)schedule(i.e.,
tumor; of these, two reported non-significant inhibition of
timeofinitiation).
tumor growth (55, 64), while the other found accelerated
tumor growth with exercise (53). Eight studies utilized intra-
Exercise modality (forced vs. voluntary paradigms). A foremost
venouslyinjectedtumorcellmodelofmetastases.MacNeiland
decisionistheuseofforcedversusvoluntaryexerciseparadigms.
Hoffman-Goetz found that exercise did not alter retention of
Anoftenoverlookedkeypointisthatvoluntarywheelrunningisa
lung tumor cells, but increased the median number of lung
modelofphysicalactivity,whereasforcedparadigmsareamodel
metastases (74). Conversely, Jadeski and Hoffman-Goetz
ofexercisetraining(i.e.,structuredandpurposefulphysicalactiv-
reportedthatexercisedecreasedretentionoflungtumorcells,
ity). Observational (epidemiologic) studies typically measure
buthadnoeffectonthenumberoflungmetastases(72).One bothphysicalactivityandexercise,whereasefficacy-basedclinical
additionalpaperreportednodifferenceintumorcellretention
trials largely examine highly structured exercise training. The
in the lungs (71), whereas three papers reported no effect of
decision of which exercise modality is selected should depend
exerciseonlungmetastasis(64,70,73).Twopapersreported onwhethertheinvestigatorsenvisagethestudyfindingsdirectly
thatexerciseinhibitedlungmetastasismultiplicity(63)ortotal
informing clinical translation or plausibility/mechanisms of a
volume (75).
clinicalobservation.
Animportantcaveattoconsiderinallexerciseparadigmsisthe
Effectsontheintratumoralmicroenvironment degree of associated negative stress, as evidenced by exercise-
MechanisticfindingsaresummarizedinTable4andFig.1. inducedincreasesinserumcorticosteroneandfecalcorticosterone
Studieswereclassifiedasprevention(n¼20;37.7%),progres- metabolites(77,78),asobservedinbothvoluntaryandforced
sion (n ¼ 26; 49.1%), or metastasis (n ¼ 7; 13.2%). Eight exerciseparadigms.Furthermore,voluntaryrunningmayresultin
preventionstudies(40%)reportedsignificanteffectsofexercise "addictivebehavior"withnegativeeffectsonthehypothalamic–
inmodulationoflocalimmuneresponse,tumormetabolism, pituitary–adrenal (HPA) axis and animal health (79). Human
and tumor physiology/angiogenesis. Ten progression studies studieshavetaughtusthatexerciseinducesspikesincortisolatthe
(38.5%)examinedmechanismsunderlyingtheeffectsofexer- beginning of exercise and immediately after bout of exercise
ciseontumorprogression(32,41,42,44,52,55,57,61,68, ceases(80).Stress-inducedactivationoftheHPAaxismayaccel-
69). The mechanisms examined included multiple different eratetumorgrowth(81),andhavediverseeffectsontheimmune
factors/pathways such as apoptosis, perfusion, and immune response(reviewedinref.82),therebyconfoundingtheefficacyof
cellinfiltration.Onlyonemetastasisstudyexaminedchangesin exerciseontumorgrowthcharacteristics.HPA-mediatedchanges
tumor biology: Higgins and colleagues found that exercise on the immune response could contribute to discordance
favored a proapoptotic environment (75), reflecting changes betweenstudieswithrespecttoimmunefunction.Forexample,
in immune cell populations/function, tumor physiology, and Zhu and colleagues reported a decrease in TNFa (43) whereas
signaling cascades. Abdallaandcolleaguesreportedanincrease(23).
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ExerciseinCancerInitiation,Progression,andMetastasis
Tumorincidenceresults -Tumorspresentin18/20SEDratsand6/11EXrats #-EXincidenceandmultiplicityofcolonandsmallintestinaladenocarcinomas,andliverfoci. -Livertumorsnotedin7%ofAOMtreatedSEDonly. -65%reductionintumorincidence. -84.5%incidencevs.98.1%,(SEDvs.EX) ><-18%(5K)and55%(5K)ofanimalswithhighgradeneoplasiaat20weeks-57%reductioninincidenceofhighgrade><neoplasiain5Kvs.5Kmice –-Duringweeks60120,38%ofEXratsweretumor-bearinganimals(vs.42%PAratsand54%SEDrata).-Atweek88,tumormultiplicitywas0.69forEXanimals,0.75forPA,and0.96forSED. "-Tumorincidenceinwheelrunningmiceby32% -96%,74%and70%incidenceincontrols,non-motorizedandmotorizedmice,respectively -97%tumorincidenceincontrols,80%tumorincidenceinWR-High-CannotcompareWR-HighandWR-Low,becausedietaryenergyrestrictionwasappliedtoWR-Lowonly #-EXcolonneoplasiaincidence,53%vs.78%inSEDcontrols. -IncreaseintumorincidenceatDay7inbothEXgroups,butnodifferencesinanysubsequenttimepoints. -Incidence/multiplicityat24wpost-NMU:58tumorsinSEDrats,33tumorsinEXratsfi-Nosignicantdifferenceinlatencyorincidence
Exerciseinitiationfi1wpriortorstinjection 4dpost-AOM 4dpost-injection. 0-17wpriortodietary3Me-DAB 1wpost-injection 10wofage Spontaneoustumors,animalsfollowedforlife. 11wofage 1wpost-injection 1wpost-injection 3dafterlastinjection 3dpriortoinjection. 21dofage(29dpriortoinjection)
ExerciseprotocolExerciseprescriptionFreq/week|Dur|Intens|Length Wheelrunning Wheelrunningfor38weeks 38w Wheelrunningfor62weeks,usingfoodasarewardforachievingfispecieddistances Voluntarywheelrunningfor8w Wheelrunningfor10weeks Dataanalyzedbasedonmicethatran><5Kor5Kaday Wheel:everyotherday,24haccessthroughoutanimals'life. Activitybox(PA):1hinlargeactivityboxtwiceaweekforlife. Treadmillrunning:TREX1:5x|45min|20m/minat5%grade|untilcompletionTREX2:5x|45min|24m/minat5%grade|untilcompletionVoluntarywheelrunningwith24houraccess. Voluntarynon-motorizedandmotorized(40m/min)wheelrunning Threelevels:WR-High:maximum3500m/dWR-Low:maximum1750m/d.SEDcontrol. 5x|2km/day|7m/min|38w. Firstweekwasacclimatization. Treadmillrunning:Moderate:7x|30min|18m/minat5%grade|1w.Exhaustive:7x|varied|18m/minfor30"min,then3m/minevery30minuntilexhausted|1w Progressivetrainingto5x|60min|18m/minat15%grade|4w ngpage)
wi
Methods Exercisemodality Voluntarywheelrunning Voluntarywheelrunning Voluntarywheelrunning Voluntarywheelrunning Voluntarywheelrunning Voluntarywheelrunning Voluntarywheelrunningoractivitybox Voluntarywheelrunningandforcedtreadmillrunning Voluntarynon-motorizedandmotorizedwheelrunning Voluntarywheelrunningatafixeddailydistance Forcedtreadmillrunning Forcedtreadmillrunning Forcedtreadmillrunning (Continuedonthefollo
Tumortype/inductionmodel Intestinal/DMH,i.p.q1wfor6w Intestinal/SubcutaneousAOM15(cid:3)mg/kgBW,q1w2wat7wkofage. Hepatocellular/15mg/kgAOMs.c.q1wfor2w Hepatoma/0.0177g/day/kgBW0-Me-DABfor35dietary3weeks. Mammary/25or50mg/kgMNU,i.p. Prostate/transgenicmousemodel Spontaneoustumors Mammary/Transgenic Mammary/50mg/kgMNUi.p. Mammary/50mg/kgMNUi.p. Intestinal/15mg/kgAOMs.c.onDays1,4and8. 5(cid:3)mammaryMammary/2.510SCA-1cellss.c.intheback. Mammary/50mg/kgNMUi.p.at50dofage
e
es Rodentmodel–5woldmaleSpragueDawleyrats MaleF344rats 5woldF-344rats Jc1:Wistarrats –21doldfemaleSpragueDawleyrats C3(1)Tagmice –3woldfemaleSpragueDawleyrats Femaleheterozygousþ(cid:4)/):MMTV-Wnt-1(p53transgenicmice –21doldfemaleSpragueDawleyrats –21doldfemaleSpragueDawleyrats 5woldmaleFischerrats 6woldmaleC3H/HeNmic –21doldfemaleSpragueDawleyRats
di
stu nce
nce ere
cide Ref 25 33 35 28 42 27 24 26 31 43 36 40 38
n
TumoriTable1. Study Andrianopoulosetal.,1987 Reddyetal.,1988 Sugieetal.,1992 Ikuyamaetal.,1993 Zhuetal.,2008 Esseretal.,2009 Alessioetal.,2009 Colbertetal.,2009 Mannetal.,2010 Zhuetal.,2012 Thorlingetal.,1993 Woodsetal.,1994 WhittalandParkhouse,1996
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Ashcraftetal.
Tumorincidenceresults -Incidencesofcarcinomas,highgradeandlowgradetumorswere29.2%,10.4%,and25%inSED,and38%,14.3%and21.4%inEX "-LatencyinEX(35.8dvs.33.1d).-Nodifferenceinmediantumor-freesurvivaltimewasobservedintheEXversussham-EX(SHAM),norwerethereanydifferencesinmultiplicityateitherahighormoderatedoseofMNU #-EXtumorappearance -66.7%and92.6%incidenceinEXandSED -Nodifferencesinnumberofratswithnodules,nodules/ratormeanareaofnodules."-Short-termEXratswithmicrocarcinomas,karyomegaliccellsanddegenerativetubulescomparedtoSED.#-Long-termEXratswithmicrocarcinomas,karyomegaliccellsanddegenerativetubulescomparedtoshort-term. -Incidence64%,67%,40%and43%inSED,LIT,MITandHITgroups,respectively(Notfisignicant)-Multiplicity:Ratswithtumorshadanaverageof2.4,1.6,1and1tumorsinSED,LIT,MITandHITgroups,respectively(Statisticsnotperformed.) -Tumorincidence100%inSEDvs.71%inEX -Nodifferenceintumorincidence-Aerobicswimmingtrainingwith2%bodyweightofloadprotectedagainsttheDMH-inducedpreneoplasticcolonlesions,butnotagainsttumordevelopmentintherat fi-Nosignicanteffectsofaerobictrainingonlungcancerincidence.-Aerobictrainingresultedin8lungnodulesperfianimalvs.52inthecontrol.Notsignicant.-Mediancontrolnoduleswas2.0,medianaerobiccontrolnoduleswas0.0.Notfisignicant. #-EXtumorincidence -Nodifferenceinsurvivaltimeortumormultiplicity activitygroups;Fe-NTA,ferricnitrilotriacetate;
Exerciseinitiation 21dofage(29dpriortoinjection) 1wpost-injection Firstsessionimmediatelybeforeinjection. 1wpost-injection Trainingdone15mbeforeeachinjection ImmediatelyafterMNUinjection –79wofage fi24hpostrstinjection Withinaweekafterinjection Sameastumorinitiation 1dafterappearanceoffirsttumor benzene;EX,exerciseor
o
ExerciseprotocolExerciseprescriptionFreq/week|Dur|Intens|Length Progressivetrainingto5x|60min|18m/minat15%grade|4w –Week1:5x|1015min|30m/min|1w.––Week29:5x|30min|2325m/min|8w 7x|3horuntilvolitionalfatigue|graduallyincreasingspeed,––2040m/min,5%grade|514d Motorizedrunningwheel;detailsnotprovided Short-term:15m|8m/min,0%|12w.Long-term:15m|8m/min,0%|12w;then5x|30m|8m/min,0%|12wforatotalof24wtrainingExercisecontinueduntil40weeks,butatlowerintensitytoaccountforthedeclineinrathealth. –Lowintensity(LIT):5x|1035–min|0.481.34km/h|12w –Moderateintensity(MIT):5x|1035–min|0.61.68km/h|12w –Highintensity(HIT):5x|1035–min|0.722.0km/h|12w 5wacclimationperiodfollowedby:5x|60m|12.5m/min|27w ––2:5x|520min|-load|2wWeek1––þWeek35:5x|520min|load|3wþWeek6-35:5x|20min|load|30w –Aerobic:4x|20m||19wWeek1:10m/dto50min5daysAnaerobic:3x|20m(2mswimming/2mresting)|progressiveloadingof–520%BW|20w –5x|45m||8weeks(cid:6)(cid:5)Watertemperature304C –30m/d,5d/wfor3865d. 0Me-DAB,3-methyl-4-dimethylaminoaz
03-
e;
Methods Exercisemodality Forcedtreadmillrunning Forcedtreadmillrunning Forcedtreadmillrunning Forcedwheelrunning Forcedtreadmillrunning Forcedtreadmillrunning Forcedtreadmillrunning Forcedswimmingwith0%,2%or4%BWload Forcedswimming Forcedswimming Forcedswimming DMH,1,2-dimethylhydrazinweeks.
Tumorincidencestudies(Cont'd)Table1. Tumortype/inductionStudyReferenceRodentmodelmodel –Whittal-Strange3921doldfemaleSpragueMammary/37.5mg/kgNMUi.p.etal.,1998Dawleyratsat50dofage,(1dayafterlastboutofEX) –Westerlindetal.,3721doldfemaleSpragueMammary/25or50mg/kgMNU,2003Dawleyratsi.p. 7–(cid:3)Zielinskietal.,4468woldfemaleBALB/cNeoplasticlymphoidcells/210EL-4cellss.c.intheback2004micebehindtheneck –Zhuetal.,20094121doldfemaleSpragueMammary/50mg/kgMNU,i.p.Dawleyrats Katoetal.,2011295woldmaleFischer344ratsRenal/5mg/kgBWFe-NTAi.p.onceadayfor7days,then10mg/kgFe-NTA3x/wkfor11w. –Malickaetal.,2015454woldfemaleSpragueMammary/180mg/kgMNUi.p.Dawleyrats –Piguetetal.,20154679woldmaleAlbCrePtenHepatocellularcarcinoma/flflox/oxmiceTransgenic Lunzetal.,20083011woldmaleWistarRatsIntestinal/4s.c.injectionsDMH3daysapart. Pacelietal.,201232AdultmaleBalb/cmiceLung/1.5mg/kgBWurethanei.p.twice,2daysapart Abdallaetal.,2013238woldfemaleBalb/cmiceMammary/1mg/mLDMBAp.o.onceweeklyfor6weeks (cid:1)–3450doldfemaleSpragueMammary/5mg/wDMBAgastricSaezMdeletal.,Dawleyratsintubationfor4w2007 Abbreviations:AOM,azoxymethane;BW,bodyweight;d,dayDMBA,7,12-dimethylbenz(a)anthracene;MNU,1-methyl-1-nitrosourea;NMU,nitrosomethylurea;q1w,onceperweek;SED,sedentarycontrols;w,
4036 CancerRes;76(14)July15,2016 CancerResearch
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ExerciseinCancerInitiation,Progression,andMetastasis
Tumorprogressionresults #-EXtumorvolumeby34%. fi-13.4gvs.16.4gEXvs.SEDnalLTWweights -Tumorweight0.62gvs.1.16g(SEDvs.EX) "Nochangeinprimarytumorgrowth(EX21%) -Nodifferenceintumorcross-sectionalareaandtumorvolume. -Primarytumorgrowthwascomparablebetweengroups -Inverserelationshipbetweendistancerunandfinaltumormass -GrowthratesofSSandRSweresimilar,andgrowthratesofSRandRRweresimilar-EXslowedtumorgrowthcomparedtoSED(bothtumormodels) #-EXtumorgrowthrate -Timetotumorsizeof1.5cm:24.8d,13.8d,and19.5dincontrol,TREX1andTREX2animals.-Treadmillrunningledtofastertumorgrowth,nodifferenceduetovoluntarywheelrunning#-Treadmillrunningsurvival #fi-EXnaltumorweightvs.SEDcontrol.þ#fi-EarlylifemanipulationEXnaltumorweightvs.EXaloneandSED. #-200mgrouptumorweight
Exerciseinitiation Immediatelyafterinjection Immediatelyafterinjection 1wpost-injection 2dpost-implant 9wbeforetumorimplantation 14daftertumortransplant 60dayspriortotumortransplant,followedby30dayspost-transplant SS:SEDbeforeandaftertransplantRS:EXfor9weekspriortotransplant;SEDaftertransplantSR:SEDbeforetransplant;EXaftertransplantRR:EX9weekspriortotransplant,continuingaftertransplant Spontaneoustumors,animalsfollowedforlife. 11wofage 5dbeforetumor(cid:5)implantation4daftertumorimplantation 4wbeforeand2wafterinjection
ExerciseprotocolExerciseprescriptionFreq/week|Dur|Intens|Length 13d 32d Voluntarywheelrunningfor8w –Voluntarywheelrunningfor4148d Primarytumorsexcisedat1cmdiameter,accesstowheelscontinuedforadditional2w. Wheelrunningfor8weeks Voluntarywheelrunningfor90days Voluntarywheelrunningbeginningeither9weekspriortotumortransplant,oratthetimeoftumortransplant Wheel:everyotherday,24haccessthroughoutanimals'life.Activitybox(PA):1hinlargeactivityboxtwiceaweekforlife. Treadmillrunning:TREX1:5x|45min|20m/minat5%grade|untilcompletionTREX2:5x|45min|24m/minat5%grade|untilcompletionVoluntarywheelrunningwith24houraccess. Pre-Tumor:50hover5dat950ft/hr.Post-Tumor:138hover10dat950ft/hr. 7x|distancesof200m/400m/800m|0.3m/s|2w ollowingpage)
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Methods Exercisemodality Voluntarywheelrunning Voluntarywheelrunning Voluntarywheelrunning Voluntarywheelrunning Voluntarywheelrunning Voluntarywheelrunning Voluntarywheelrunning Voluntarywheelrunning Voluntarywheelrunningoractivitybox Voluntarywheelrunningandforcedtreadmillrunning Forcedtreadmillrunning Forcedtreadmillrunning (Continuedonth
Tumortype/inductionmodel 3Leydigcell/1.5mminjectionofLeydigcellsarcoma(LTW) 3injectionofLeydigcell/1.5mmLeydigcellsarcoma(LTW)orNitrosoguanine-inducedadenocarcinomas.c.intoeachflank Mammary/25or50mg/kgMNU,i.p. 6(cid:3)MDA-MB-231Mammary/110cells,injectedorthotopically 5(cid:3)/50l/mouseLung/2.510mLewislungcarcinomacellss.c.lowerdorsalregion 5(cid:3)Prostate/510mouseprostateC-1cells,orthotopically 4th(cid:3)cellsin4Mammary/110mammaryfatpad 5(cid:3)4T1-lucor2.5Mammary/5105(cid:3)E0771cellsindorsal10mammaryfatpad Spontaneoustumors Mammary/Transgenic Carcinoma/EqualvolumesofWalker-256cellss.c.intotheflrightank. 4(cid:3)L-1cellss.c.Sarcoma/2.410
Rodentmodel FemaleWistarFurthrats FemaleWistarFurthrats 21doldfemale–SpragueDawleyrats –34woldfemaleathymicmice 3woldmaleC57BL/6mice –68woldmaleC57BL/6mice 18moldBalb/cBymice FemaleBalb/corfemaleC57Bl/6mice –3woldfemaleSpragueDawleyrats Femaleheterozygousþ(cid:4)/):MMTV-(p53Wnt-1transgenicmice –45doldSpragueDawleyrats BALB/cmice
hstudies Reference 51 52 42 57 64 55 66 65 24 26 60 63
wt
TumorgroTable2. Study Danerydetal.,1995 Danerydetal.,1995 Zhuetal.,2008 Jonesetal.,2010 YanandDemars,2011 Jonesetal.,2012 Gohetal.,2014 Betofetal.,2015 Alessioetal.,2009 Colbertetal.,2009 Newtonetal.,1965 UhlenbruckandOrder,1991
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Tumorprogressionresults Nodifferenceingrowthrateoftumorsizeattimeofeuthanasia(twoweels) -Tumorgrowthrateat22wpost-NMU:0.043g/dayinSEDvs.0.107g/dayinEX-Finaltumorweight:(3.2ginSEDvs.1.2ginEX -Day15tumorweight1.82%vs.19%ofBW(EXvs.SED)-EXprolongedsurvivalby1.9fold "-LatencyinEX(35.8dvs.33.1d).-Nodifferenceinmediantumor-freesurvivaltimewasobservedintheEXversussham-EX(SHAM),norwerethereanydifferencesinmultiplicityateitherahighormoderatedoseofMNU -Nodifferenceintumordensity -Nochangeintumorgrowth. -Survival:16dforSED,45dforEXfi-EXtumorswere6.9%ofnalbodymassvs.17.33%forSEDcontrol. -Tumorweight:17.2ginSED;1.9ginEX #-Tumorvolume:inEXat21and22w. -EXratshadsmallertumorsat14and21dayscomparedtoSEDcontrolsfi-TumordoublingtimewassignicantlyslowerinEXvs.SED(6.19dvs.8.81d) fi-ETEhadsignicantlyslowergrowthcomparedtoRTRfi-NodifferenceinnaltumorvolumeofRTEandETRgroups
Exerciseinitiation 3dpriortoinjection. 21dofage(29dpriortoinjection) 8wpriortoinjection 1wpost-injection Firstsessionimmediatelybeforeinjection. 14dpost-injection 8wpriortoinjection 8wpriortoinjection 4wofage 15daftertumorimplantation RTR:SedentarybeforeandaftertransplantRTE:EXaftertumortransplantonlyETR:EXbeforetumortransplantonlyETE:EXbeforeandaftertransplant9wbeforetumortransplant,and/or6waftertransplant
ExerciseprotocolExerciseprescriptionFreq/week|Dur|Intens|Length Treadmillrunning:Moderate:7x|30min|18m/minat5%grade|1w.Exhaustive:7x|varied|18m/minfor30"min,then3m/minevery30minuntilexhausted|1w Progressivetrainingto5x|60min|18m/minat15%grade|4w 5x|60min|60%ofVO2peak|10w –Week1:5x|1015min|30m/min|1w.––Week29:5x|30min|2325m/min|8w 7x|3horuntilvolitionalfatigue|graduallyincreasingspeed,––2040m/min,5%grade|514d 5d/w|10m/minfor10minupto18m/minfor45min|0%grade|8w max|10w5x|30min|85%ofVO2 –5x|60min|6065%ofVO2peak|10w2wpre-trainingperiod:ratsranprogressivelyfrom15to60minat10m/min.Runningwasincreasedto20m/minfortwoweeksafterinjection. 6x|60m|20m/minat5%|20w ––5x|1560m|2025m/min|5w ––-|2040min|620m/min|15w ollowingpage)
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Methods xercisemodality orcedtreadmillrunning orcedtreadmillrunning orcedtreadmillrunning orcedtreadmillrunning orcedtreadmillrunning orcedtreadmillrunning orcedtreadmillrunning orcedtreadmillrunning orcedtreadmillrunning orcedtreadmillrunning orcedtreadmillrunning (Continuedonth
E F F F F F F F F F F F
Tumortype/inductionmodel 5(cid:3)Mammary/2.510mammarySCA-1cellss.c.intheback. Mammary/37.5mg/kgNMUi.p.at50dofage,(1dayafterlastboutofEX) 7(cid:3)Walker-256Carcinoma/210flcellss.c.intheank Mammary/25or50mg/kgMNU,i.p. 7(cid:3)Neoplasticlymphoidcells/210EL-4cellss.c.inthebackbehindtheneck (cid:3)Mammary/Flankinjectionof56MDA-MB-231cells10 7(cid:3)Carcinoma/210Walker-256flcellss.c.intheank 7(cid:3)Carcinoma/210Walker-256flcellss.c.intheank Mammary/Transgenic(tumorsbegandevelopingat12wofage). Prostate/surgicals.c.implantationofR3327DunningAT1tumorfragment 6(cid:3)MC4-L2s.c.inMammary/110fltheank
Cont'd) Rodentmodel 6woldmaleC3H/HeNmice 21doldfemale–SpragueDawleyrats 12woldmaleWistarrats 21doldfemale–SpragueDawleyrats –68woldfemaleBALB/cmice –34woldfemaleathymicmice 8woldmaleWistarrats MaleWistarrats 4woldC3(1)SV40Tagmice –1012woldCopenhagenrats –46woldBalb/cmice
(
hstudies Reference 40 39 49 37 44 56 48 58 59 69 67
wt
TumorgroTable2. Study Woodsetal.,1994 Whittal-Strangeetal.,1998 Bacurauetal.,2000 Westerlindetal.,2003 Zielinskietal.,2004 Jonesetal.,2005 Bacurauetal.,2007 Liraetal.,2008 Murphyetal.,2011 Gueritatetal.,2014 Shalamzarietal.,2014
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ExerciseinCancerInitiation,Progression,andMetastasis
Tumorprogressionresults -EXdecreasedtumorvolume fi-Nodifferenceinnalvolumeoftotaltumorvolume -EXdecreasedtotalvolumeoflivertumors -97%inhibitionoftumorgrowth.#-TumorweightinEXgroup #-EXtumorsize.-Nochangeinsurvivalrates. #fi-EXnaltumorweight,bothgroups. -ECanimalshadslowertumorgrowththanET3(cid:7)vs.2andcontrol,(endpointswere1.24cm33and2.4cm)cm "-EXtumorgrowthby200%. #-50%workloadtumorweightandtumor3)vs.controlvolume(0.18mg/gand0.11mm3)(0.55mg/gand0.48mm-Tumorvolumeandweightwere270%and"280%inSEDmice. #fi-ETCnaltumorweightvs.SEDcontrol. ygroups;Fe-NTA,ferricnitrilotriacetate;MNU,1-
Exerciseinitiation 10daftertumortransplant ImmediatelyafterMNUinjection –79wofage Immediatelyafterinjection Immediatelyafterinjection. 2Groups-3wofswimming,tumortransplant,then3wadditionalswimming.-3wofswimmingbeginning3dpost-transplant 10wbeforeinjection. fi1dafterappearanceofrsttumor 4wbeforeinjection 10wbeforetumorimplantation. oazobenzene;EX,exerciseoractivit
n
ExerciseprotocolExerciseprescriptionFreq/week|Dur|Intens|Length ––7x|2055min|1020m/min|7w –Lowintensity(LIT):5x|1035–min|0.481.34km/h|12w–Moderateintensity(MIT):5x|1035–min|0.61.68km/h|12w–Highintensity(HIT):5x|1035–min|0.722.0km/h|12w 5wacclimationperiodfollowedby:5x|60m|12.5m/min|27w 21dofEX,allEXdidall3modalitieseachday:Runway:continuousrunningon20ftrunway,durationandintensitynotclearSwimming:increasing20min/dayto4h/dayRevolvingdrum:5.4miin12h –10x|15min||10d Low:5x|5min/d,increasedby5min/dfor3w. Medium:5x|10min/d,increasedby10min/dfor3w.High:5x|15min/d,increasedby15min/dfor3w. –5x|60min||10wET:trainingterminatedattumorimplantation.EC:trainingcontinuedfor18daftertumorimplantation. –30m/d,5d/wfor3865d. 5x|60min|50/80%maxtest|6w.Progressiveloadtestbeganafter1w:loadincreasedby2%BWevery3minuntilexhaustion. –5x|60m||10wETT:cellsinjectedafterEX.ETC:EX(10w),cellsinjected,EX(18additionaldays)00-Me-DAB,3-methyl-4-dimethylamie;3
n
Methods Exercisemodality Forcedtreadmillrunning Forcedtreadmillrunning Forcedtreadmillrunning Continuousrunningonþa20ftrunwayþswimmingrevolvingdrum Forcedswimming Forcedswimming Forcedswimming Forcedswimming Forcedswimming Forcedswimming DMH,1,2-dimethylhydrazi
Cont'd) RodentmodelTumortype/inductionmodel 6(cid:3)5woldfemaleBalb/cMammary/1.210MC4-L2cellsmiceinrightdorsalmammaryfatpad 4woldfemaleMammary/180mg/kgMNUi.p.–SpragueDawleyrats –79woldmaleHepatocellularcarcinoma/flflAlbCrePtenox/oxTransgenicmice WistarratsCarcinoma/2mLWalker256cellsuspensions.c.intotherightthigh. HoltzmanratsCarcinosarcoma/Walker-256tumori.m.intobothhindlimbs. –SpragueDawleyratsHepatoma/20uLMorrishepatoma777s.c. 6(cid:3)P-388AdultfemalehybridSolidleukemia/510lymphoidleukemiacellss.c.BDF1mice 50doldfemaleMammary/5mg/wDMBAgastric–SpragueDawleyintubationfor4wrats 6(cid:3)7woldmaleSwissmiceCarcinoma/210Ehrlichtumorcellss.c.inthedorsum. 6(cid:3)AdultfemaleBDF1miceSarcoma/510S-180cellss.c.injected. W,bodyweight;d,day;DMBA,7,12-dimethylbenz(a)anthracene;hylurea;SED,sedentarycontrols;w,weeks.
Tumorgrowthstudies(Table2. StudyReference Avesehetal.,201568 Malickaetal.,201545 Piguetetal.,201546 Hoffmanetal.,196254 Gershbeinetal.,197453 Baracos,198950 Radaketal.,200261 (cid:1)34SaezMdeletal.,2007 Almeidaetal.,200947 Sasvarietal.,201162 Abbreviations:AOM,azoxymethane;Bmethyl-1-nitrosourea;NMU,nitrosomet
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Ashcraftetal.
Tumormetastasisresults"-OlderEXratslowerabdominalandinguinalsecondarytumornodules. -Trendtoinverserelationshipbetweenrunningdistanceandmetastatictumoryield #-EXtumornodalinvolvementby36%,metastasesweightby88%andnumberoffimetastasesby34%(Noneweresignicant) -EXdecreasedlungtumormultiplicity-Differencesinrunningprescriptionsmakeitfidifculttodetermineifexercisecessationaftertumorcelltransplantwasdifferentfromcontinuousexercise fi-Nosignicanteffectofactivityonlungtumorretention.fi-Signicantbutweakcorrelationofdistancerunandmultiplicityoflungmetastases.-MediannumberoflungmetastasesperanimalwasgreaterinEXmice(21vs.10SEDcontrol). -EXhadnoeffectonlungtumordensity"-EXpriortotumorinjectionincidenceinthelowesttertileoftumordistributionvs.SEDcontrols. #-EXretentionofradioactivityinlungs5minand30minpost-injection. -NoEXeffectonnumberoflungtumors."-TTtendedtohavetumormultiplicity.#-STandSWtendedtohavetumormultiplicity. #-EXtumorcelllungretention(44.2vs.52.8%control).#-EXlungretentionofthelessaggressiveCIRAS1,nodifferenceinCIRAS3cells.fi-EXdidnotalternaltumorlungmetastasesnumbers,(subgroupevaluated3wafterEXandinjection). -Nodifferenceinnumberoflungmetastasis -EXdecreasedtumorvolume,asmeasuredbybioluminescentimaging
Exerciseinitiation Immediatelyafterinjection. 9wbeforetumorimplantation 14daftertumortransplant 4wbeforeinjection,followedbyeitherrestoranadditional2wrunning 9wbeforeinjection 9wpriortoand/or3wafterinjection 9wbeforeinjection 8wprioror36hafterinjectionfor3w 9wbeforeinjection 9wbeforetumorimplantation Afterlungtumorsweredetectable
ExerciseprotocolExerciseprescriptionFreq/week|Dur|Intens|Length–10x|15min||10d Tumorsexcisedat1cmdiameter,accesstowheelscontinuedforadditional2w. Wheelrunningfor8weeks 7x|predetermineddistancesof––200850m|0.30.5–m/s|46w Treadmill:5x|30min|15m/min,0%|9w.VoluntaryWheel:24haccesstowheelfor9w.AllanimalsremainedSEDafterinjectionfor3w. –312w. 24haccesstorunningwheelfor9w. Treadmillrunning:5x|30min|18m/minat0%|8wor3w. Groups:WS:wheelmice,24haccessfor8w,thenSEDfor3w.TS:treadmillmice,thenSEDfor3w.TT/WT:ContinuousEXfor11wtotal.STorSW:SEDfor8wthentreadmill(ST)orwheel(SW)for3w.SS:SEDfor11wtotal. 5x|30min|20m/min,0%|9wAcclimatizationperiodof1week. Melanoma:24haccesstowheels,continued2wpost-implantation. 28d –Miceaveraged6001200m/day
y
Methods Exercisemodality Forcedswimming Voluntarywheelrunning Voluntarywheelrunning Forcedtreadmillrunning Forcedtreadmillandvoluntarywheelrunning Voluntarywheelrunning Voluntarywheelrunning Forcedtreadmillrunningorvoluntarwheelrunning Forcedtreadmillrunning Voluntarywheelrunning Voluntarywheelrunning
Tumortype/inductionmodel Carcinosarcoma/Walker-256tumori.m.intobothhindlimbs. 5(cid:3)/50l/mouseLung/2.510mLewislungcarcinomacellss.c.lowerdorsalregion 5(cid:3)mouseprostateProstate/510C-1cells,orthotopically 4(cid:3)L-1cellsi.v.Sarcoma/2.410 6fi(cid:3)Transformedbroblasts/1.510CIRAS1tumorcellsi.v.viatailvein. 5fi(cid:3)Transformedbroblasts/310CIRAS1cellsi.v. 5fi(cid:3)Transformedbroblasts/510CIRAS1orCIRAS3radiolabeledtransformedfibroblastcellsi.v.viatailvein. Mammary/Lateraltailvein4(cid:3)injectionof110MMT66cells 5fi(cid:3)Transformedbroblasts/510CIRAS1orCIRAS3fitransformedbroblastcellsi.v.viatailvein. 5m(cid:3)/200l/Melanoma/0.7510mouseB16BL/6cellsinlateraltailvein 5(cid:3)A549-luc-C8cellsLung/510i.v.viatailvein
Rodentmodel Holtzmanrats 3woldmaleC57BL/6mice –68woldmaleC57BL/6mice BALB/cmice –45woldmaleC3H/Hemice C3H/Hemice þC3H/He-bg2J/andC3H/HeJmice 3woldfemaleBALB/cmice –49woldC3H/þHe-bg2J/andC3H/HeJmice 3woldmaleC57BL/6mice 6woldmalescid-beigemice ntarycontrols.
e
d
Reference 53 64 55 63 74 73 71 70 72 64 75 ps;SED,se
u
TumormetastasisstudiesTable3. Study NaturallyoccurringGershbeinetal.,1974 YanandDemars,2011 Jonesetal.,2012 fiArticial(intravenousUhlenbruckandinjectionoftumorOrder,1991cells) MacNeilandHoffmann-Goetz,1993a MacNeilandHoffmann-Goetz,1993b Hoffmann-Goetzetal.,1994a Hoffman-Goetzetal.,1994b JadeskiandDemars,1996 YanandDemars,2011 Higginsetal.,2014 Abbreviations:EX,exerciseoractivitygro
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ExerciseinCancerInitiation,Progression,andMetastasis
PotentialimplicationsReducedliverdamage Prolactinhasbeenassociatedwithtumorgrowth Decreasedtumorcellproliferation Increasedmicrovesseldensityandmaturity,whichleadstoimprovedtumorperfusion;increasedtumorcellapoptosis Increasedtumoricidalimmuneresponse Increasedtumoricidalimmuneresponse Modulationofphysiology Associatedwithreducedcachexia Increasedtumoricidalimmuneresponse flBrowndropletscouldreectrenaldamagecausedbycarcinogenapplied.Increasesinadrenalweighthavebeenlinkedtopsychologicalstress. flReducedinammationandsubsequentangiogenesis Alteredlipogenesis.SomelipogenesispathwaysareprognosticindicatorsfollowingHCCsurgicalremoval Alteredimmuneresponse;futureanalysisoffimacrophagesubsetswouldbebenecialtofitheeld Reducedoxidativestressorimprovedanti-oxidantactivity
fiMechanisticndingsSystemic#"-EXgamma-glutamyltranspeptidaseandALP. #-Meanserumprolactinlevelswerein"exercisingratsandinSEDratsat24and52wofage. andrespiratoryexchange-EXincreasedVO2rate -Nonereported -Nonereported #-EXglucoseconsumptionandproduction,"andlactateproductionandglutamineconsumptionofmacrophages"#Oproductionbymacrophages,and-EXH22phagocytosis."-EXlymphocyteproliferation "-EX,non-tumorplasmacorticosteronevs.control.-EXpreventstumor-inducedreductioninbodyweightandfoodintake,activationofglutaminemetabolisminmacrophagesandlymphocytes. #-EXlivertriacylglycerol(TAG)contentcomparedtoSED."-SEDtumoranimalshadserumandliverTAG,#andrateofVLDLsecretion,apoBexpressionandmicrosomalTAGtransferproteincomparedtocontrol. #-spleenweightcomparedtowild-typemice.-NodifferenceinspleenweightduetoEX.#-EXplasmaIL-6andMP-1. #-Long-termEXandFe-NTArenalbrown"dropletscomparedtoSED,adrenalweightcomparedtobothothergroups. -Nonereported -EXalteredgeneexpressionoffattyacidmetabolismpathways -Nonereported -80%workloadinducedcardiachypertrophyvs.50%. #fi-EXoxidativemodicationofproteinintheliverasmeasuredbyproteincarbonyls.
Intratumoral-Nonereported. -Nonereported. -Inversecorrelationbetweendistancerunandmitoticindexwithintumors -EXincreasedcolocalizationofdesminandCD31anddecreasedtumorhypoxiaandnecrosis-EXincreasedexpressionofFas,caspase8andcleavedcaspase3 "-ModerateEX:phagocyticcells#-ExhaustiveEX:totalandhighlyphagocyticcells -Nonereported -EXimpairstumorcellglucoseandglutaminemetabolism. -Nonereported. -Nonereported. -Nonereported. -EXaftertumortransplantdecreasedtumorIL-6andVEGF-IL-6andVEGFlevelsinETRmicewerenotdifferentfromRTR(sedentary)mice. -EXdecreasedproliferation(Ki67staining)3>.intumornodules15mm -EXincreasedTUNELpositivecells #fi-50%workloadmacrophageinltrationandneutrophilaccumulation. -Nonereported. ntinuedonthefollowingpage)
o
C
(
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ExercisemodalitVoluntarywheelrunning Voluntarywheelrunning Voluntarywheelrunning Voluntarywheelrunning Forcedtreadmillrunning Forcedtreadmillrunning Forcedtreadmillrunning Forcedtreadmillrunning Forcedtreadmillrunning Forcedtreadmillrunning Forcedtreadmillrunning Forcedtreadmillrunning Forcedtreadmillrunning Swimming Swimming
or or
TumortypeCarcinogeninducedhepatoma Spontaneoustumors Orthotopicmammarytum Orthotopicmammarytum s.c.mammarytumortransplant s.c.carcinomatransplant s.c.carcinomatransplant s.c.carcinomatransplant Transgenicmammarytumors Carcinogen-inducedrenaltumors s.c.mammarytumortransplant Transgenichepatocellularcarcinoma Carcinogen-inducedmammarytumor s.c.carcinomatransplant s.c.sarcomatransplant
e
nc
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er
Ref28 24 66 65 40 48 49 58 59 29 67 46 45 47 62
4
echanisticresults StudyIkuyamaetal.,1993 Alessioetal.,2009 Gohetal.,2014 Betofetal.,2015 Woodsetal.,1994 Bacurauetal.,2000 Bacurauetal.,2007 Liraetal.,2008 Murphyetal.,2011 Katoetal.,2011 Shalamzarietal.,201 Piguetetal.,2015 Malickaetal.,2015 Almeidaetal.,2009 Sasvarietal.,2011
M
n
Table4. Preventio
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