ﬁcacy and Mechanisms of Aerobic Exercise on Cancer Initiation, … · effects of exercise in cancer prevention and progression. Stud-ies were evaluated on the basis of tumor outcomes

Review

Efficacy and Mechanisms of Aerobic Exercise onCancer Initiation, Progression, and Metastasis:A Critical Systematic Review of In VivoPreclinical DataKathleen A. Ashcraft1, Ralph M. Peace1, Allison S. Betof2, Mark W. Dewhirst1, andLee W. Jones3

Abstract

A major objective of the emerging field of exercise–oncologyresearch is to determine the efficacy of, and biological mechan-isms by which, aerobic exercise affects cancer incidence,progression, and/or metastasis. There is a strong inverse asso-ciation between self-reported exercise and the primary inci-dence of several forms of cancer; similarly, emerging datasuggest that exercise exposure after a cancer diagnosis mayimprove outcomes for early-stage breast, colorectal, or prostatecancer. Arguably, critical next steps in the development ofexercise as a candidate treatment in cancer control requirepreclinical studies to validate the biological efficacy of exercise,identify the optimal "dose", and pinpoint mechanisms ofaction. To evaluate the current evidence base, we conducteda critical systematic review of in vivo studies investigating the

effects of exercise in cancer prevention and progression. Stud-ies were evaluated on the basis of tumor outcomes (e.g.,incidence, growth, latency, metastasis), dose–response, andmechanisms of action, when available. A total of 53 studieswere identified and evaluated on tumor incidence (n ¼ 24),tumor growth (n ¼ 33), or metastasis (n ¼ 10). We report thatthe current evidence base is plagued by considerable metho-dologic heterogeneity in all aspects of study design, endpoints,and efficacy. Such heterogeneity precludes meaningful com-parisons and conclusions at present. To this end, we provide aframework of methodologic and data reporting standards tostrengthen the field to guide the conduct of high-qualitystudies required to inform translational, mechanism-drivenclinical trials. Cancer Res; 76(14); 4032–50. �2016 AACR.

IntroductionStructured exercise training (hereto referred to as exercise) is

considered an integral component of "standard of care" therapy inprimary and secondary prevention of numerous common chronicconditions (1–4). In comparison, the role of exercise has receivedsurprisingly little attention in individuals at high-risk or after adiagnosis of cancer. Over the past two decades, however, anincreasing number of groups are investigating the effects ofgeneral physical activity as well as exercise in the oncology setting,a field now commonly referred to as "Exercise–Oncology" (5).

A strong body of observational evidence indicates that higherlevels of self-reported exercise, physical activity, as well as cardio-respiratory fitness (i.e., objective assessment of exercise exposure)are inversely associated with the primary incidence of severalforms of cancer. This evidence base is summarized by severalexcellent systematic reviews and meta-analyses (6–9). For exam-ple, exercise participation consistent with the national guidelines(i.e., 150 minutes of moderate-intensity or 75 minutes of vigor-ous-intensity exercise per week) is associated, on average, with25%, and 30% to 40% risk reductions in breast and colon cancers,respectively, compared with inactivity. There is also evidence of alinear dose–response relationship in prevention of breast andcolon cancer. On this basis, the evidence for the exercise–preven-tion relationship is categorized as "convincing" for breast andcolon cancer by several national agencies, and regarding as"encouraging" or "promising" for the prevention of prostate,lung, and endometrial cancers (10, 11). On the basis of this data,several phase II randomized controlled trials (RCT)were initiated,predominantly in breast cancer prevention, to investigate theeffects of highly structured exercise onmodulation of host-relatedfactors (e.g., adiposity, circulating factors including sex-steroidand metabolic sex hormones, and the immune–inflammatoryaxis) that may underpin the exercise–cancer prevention relation-ship (6, 12–14). In general, exercise was associated with modestchanges in markers of adiposity and select circulating factors(6, 12, 13). Whether the observed alterations are of biologic orclinical importance remains to be determined, as only one trial to

1Duke University Medical Center, Durham, North Carolina. 2Massachu-setts General Hospital, Boston, Massachusetts. 3Memorial Sloan Ket-tering Cancer Center, New York, New York.

Note: Supplementary data for this article are available at Cancer ResearchOnline (http://cancerres.aacrjournals.org/).

M.W. Dewhirst and L.W. Jones contributed equally to this article.

CorrespondingAuthors:LeeW. Jones, Department ofMedicine,Memorial SloanKettering Cancer Center, 485 Lexington Avenue, New York, NY 10017. Phone:646-888-8103; Fax: 646-888-4588; E-mail: [email protected]; and Mark W.Dewhirst, Department of Radiation Oncology, Duke University Medical Center,Box 3455, Medical Sciences Research Building 1, Room 201, Durham, NC 27710.Phone: 919-684-4180; E-mail: [email protected]

doi: 10.1158/0008-5472.CAN-16-0887

�2016 American Association for Cancer Research.

CancerResearch

Cancer Res; 76(14) July 15, 20164032

on January 31, 2021. © 2016 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

Published OnlineFirst July 5, 2016; DOI: 10.1158/0008-5472.CAN-16-0887

http://cancerres.aacrjournals.org/

date has investigated the exercise-induced changes in circulatingfactors occuring in conjunction with changes in factors/pathwaysin the organ/tissue of primary interest (i.e., colon crypts; ref. 15).Whether exercise reduces cancer incidence or modulates estab-lished surrogate markers of cancer incidence has not beeninvestigated.

In patients with cancer, a steadily growing and ever diversifyingseries of studies indicate that, in general, exercise is a tolerableadjunct therapy associated with significant benefit across a widerange of symptom control variables both during and after primaryadjuvant therapy (5, 16, 17). These data combined with thepowerful inverse relationships with primary cancer incidence hasled researchers to investigate whether exercise influences diseaseoutcomes after diagnosis (18, 19). Although not nearly as matureas the evidence in the prevention setting, emerging observationaldata suggest that regular exercise exposure is associated withbetween a 10%–50% reduction in the risk of recurrence andcancer-specific death in patients with colorectal, breast, andprostate cancer (reviewed in ref. 20), compared with inactivity.

In the development of potential drug candidates, data fromobservational studies is insufficient to support the initiation ofhuman trials; appropriate preclinical evidence is first requiredprior to human testing (21). While exercise is not a drug andexhibits a markedly different safety profile than most anticanceragents, the use of preclinical models are of critical importance toconfirm the biological plausibility, establish the therapeutic win-dow of efficacy, a biologically effective dose, and identify pre-dictors of response (22). This evidence, combined with data fromepidemiologic and molecular epidemiologic studies facilitatesthe design of early "signal-seeking" clinical studies and ultimatelydefinitive RCTs. Accordingly, we conducted a critical systematicreview of in vivo preclinical studies across the cancer continuum(i.e., prevention throughmetastasis). A secondary purpose was toprovide recommendations to facilitate the standardization of theconduct of in vivo exercise–oncology studies as well as directionsfor future research.

Materials and MethodsSearch strategy and inclusion criteria

A systematic literature search was conducted usingOVIDMED-LINE (1950 to May 2015), PUBMED (1962 to May 2015), andWEB OF SCIENCE (1950 to May 2015) with MeSH terms andkeywords related to exercise, cancer, and animals. Text wordsweresearched and appropriate MeSH terms were found (Supplemen-tary Table S1).When possible, Boolean logic was usedwithMeSHterms to build searches. All results and reference lists weresearched manually. Peer-reviewed research articles involving ani-mals with cancer and exposed to chronic exercise (repeated boutsof more than 3 sessions) adopting either forced (i.e., treadmillrunning or swimming) endurance (aerobic) training or physicalactivity (i.e., voluntary wheel running) paradigms were consid-ered eligible. All types of animal models of solid tumors wereconsidered eligible including genetically predisposed models[transgenic, genetically engineered mouse models (GEMM)],orthotopic, subcutaneous, and intravenous injections, tumortransplant, and spontaneous or carcinogen-induced solid tumormodels. Studies that included multiple treatments, such as studyarms with dietary restrictions, were eligible, as long as it waspossible to compare sedentary (control) and exercise alonegroups. Studies that evaluated preneoplastic lesions (e.g., aberrant

crypt foci, ApcMin), or hematopoietic and ascites tumors wereexcluded. Only mouse and rat studies were included. Articlesunavailable in English were excluded.

Study selection and classificationFour authors (K.A. Ashcraft, R.M. Peace, A.S. Betof, and L.W.

Jones) assessed study eligibility by reviewing the titles andabstracts of all potential citations according to the inclusioncriteria. K.A. Ashcraft, R.M. Peace, M.W. Dewhirst, and A.S. Betofextracted and interpreted data from published articles. Whennecessary, effort was made to contact authors and acquire pub-lications for evaluation. Studies are summarized by type ofexercise model and method of tumor initiation. Exercise char-acteristics are described using common prescription elements:modality, frequency, duration, intensity, and total length ofintervention.

Tumor initiation versus growthArticles were classified by the endpoints reported in the indi-

vidual studies: (i) "Incidence" (tumor presence or multiplicity),(ii) "Growth" (data on tumor growth, latency or survival), and(iii) "Metastasis" (evaluation of tumors distinct from the primarytumor or developing following the commonmetastasis model ofintravenous tumor cell injection). Study categorization was notalways mutually exclusive; thus, studies that included multipleendpoints applicable to more than one categorization wereincluded in both.

Analysis of mechanistic findingsFor evaluation of mechanistic findings, an alternative classifi-

cation was applied on the basis of the initiation of the exerciseintervention relative to the time of tumor cell transplant orapplication of carcinogens. "Prevention" was defined as exerciseinitiated prior to tumor transplant/induction. "Progression" wasdefined as exercise initiated �3 days post-transplant/induction.Studies involving GEMMswere categorized as prevention studies.Distinguishing between exercise initiation and tumor cell inoc-ulation is important because exercise-induced adaptations priorto tumor injection could "prime" the host and/or tissue micro-environment, making it physiologic or biologically distinct fromtumor inoculation into a sedentary host. Mechanistic findingswere classified as either intratumoral or systemic.

Interpretation and analysisStudies were assessed for changes in tumor growth (as well as

the related parameters of time to tumor-related endpoint, andtumor size/mass at the end of the study), incidence (tumorpresence), and multiplicity (number of tumors/metastases). Allstudy results that were reported to be "statistically significant"achieved P < 0.05 according to the authors of the original manu-scripts. Preliminary analysis of included studies indicated con-siderable methodologic heterogeneity in all aspects of studydesign, end points, and efficacy. As such, it was not possible tocompare the efficacy of exercise across cancer setting (i.e., inci-dence, progression, metastasis), cancer histology, exercise para-digm (i.e., forced vs. voluntary), or exercise dose.

ResultsA total of 426 potential citations were initially identified using

search terms. After secondary screening, 53 articles were deemed

Exercise in Cancer Initiation, Progression, and Metastasis

www.aacrjournals.org Cancer Res; 76(14) July 15, 2016 4033




eligible and underwent full review (Supplementary Fig. S1).Classification of articles was as follows: (i) incidence (n ¼ 24;45.3%; refs. 23–46), growth (n ¼ 33; 62.3%; refs. 24, 26, 34,37, 39, 40, 42, 44–69), andmetastasis (n¼ 10; 18.9%; refs. 53, 55,63, 64, 70–75).

Tumor models and exercise prescription characteristicsIncluded studies tested the effects of exercise on 15 different

tumor types/cell lines, using six different tumor initiationmethods (Supplementary Table S2). Details of the exerciseprescriptions are summarized in Tables 1, 2, and 3. The mostcommon modalities included voluntary running (n ¼ 22;41.5%; refs. 24–28, 31, 33, 35, 42, 43, 51, 52, 55, 57, 64–66, 70, 71, 73–75) forced running (n ¼ 25; 47.2%; refs. 26, 29,36–41, 44–46, 48, 49, 54, 56, 58–60, 63, 67–70, 72, 74), andswimming (n ¼ 10; 18.9%; refs. 23, 30, 32, 34, 47, 50, 53,54, 61, 62).

Effect of exercise on tumor outcomesIn incidence studies, 58% reported that exercise inhibited

tumor initiation or multiplicity (23–25, 27, 28, 31, 33, 35, 36,41, 43–46), 8% reported that exercise accelerated tumor inci-dence (26, 42), and 3% found null effects (29, 30, 32, 34, 37–40). In the growth category, exercise was associated with tumorinhibition in 64% of studies (24, 39, 47–54, 58–63, 65–69),while 21% (37, 40, 44, 55–57, 64) and 9% (26, 34, 42) ofstudies reported null and accelerated tumor growth, respective-ly. Finally, in the tumor metastasis category, three studiesutilized models in which metastases arose from a primarytumor; of these, two reported non-significant inhibition oftumor growth (55, 64), while the other found acceleratedtumor growth with exercise (53). Eight studies utilized intra-venously injected tumor cell model of metastases. MacNeil andHoffman-Goetz found that exercise did not alter retention oflung tumor cells, but increased the median number of lungmetastases (74). Conversely, Jadeski and Hoffman-Goetzreported that exercise decreased retention of lung tumor cells,but had no effect on the number of lung metastases (72). Oneadditional paper reported no difference in tumor cell retentionin the lungs (71), whereas three papers reported no effect ofexercise on lung metastasis (64, 70, 73). Two papers reportedthat exercise inhibited lung metastasis multiplicity (63) or totalvolume (75).

Effects on the intratumoral microenvironmentMechanistic findings are summarized in Table 4 and Fig. 1.

Studies were classified as prevention (n ¼ 20; 37.7%), progres-sion (n ¼ 26; 49.1%), or metastasis (n ¼ 7; 13.2%). Eightprevention studies (40%) reported significant effects of exercisein modulation of local immune response, tumor metabolism,and tumor physiology/angiogenesis. Ten progression studies(38.5%) examined mechanisms underlying the effects of exer-cise on tumor progression (32, 41, 42, 44, 52, 55, 57, 61, 68,69). The mechanisms examined included multiple differentfactors/pathways such as apoptosis, perfusion, and immunecell infiltration. Only one metastasis study examined changes intumor biology: Higgins and colleagues found that exercisefavored a proapoptotic environment (75), reflecting changesin immune cell populations/function, tumor physiology, andsignaling cascades.

Effects on systemic (host) pathwaysCorrelative systemic pathways examined are summarized

in Table 4. Ten prevention (24, 28, 29, 40, 46–49, 59, 62), sevenprogression (23, 31, 37, 42, 51, 55, 64, 76), and five metastasisstudies (70–72, 74, 75) reported significant effects of exercise onchanges in systemic effectors, predominantly changes in factorsinvolved in immune surveillance or metabolism.

DiscussionThe findings of this critical review indicate that the current

evidence base is plagued by heterogeneity in all aspects of studymethodology and data reporting. Unfortunately, such heteroge-neity precludes rigorous evaluation of essential questions such asthe biologically effective exercise dose tomodulate specific tumorpathways or inhibit tumor growth, the effects of manipulatingexercise intensity or duration or the differential impact of exerciseacross tumor subtypes (22). Nevertheless, our review did permitidentification of the most salient methodologic issues that pru-dent investigatorsmay consider when designing in vivo preclinicalexercise–oncology studies. These aspects are described in theproceeding sections and summarized in Table 5.

Heterogeneity in exercise prescriptionThe components of the exercise prescription being investigated

in preclinical studies shouldmirror, as closely as possible, exerciseprescription parameters tested in human studies (22). Key para-meters include: (i) modality/paradigm (i.e., forced vs. voluntary),(ii) dose (i.e., intensity, session duration, frequency of trainingsessions/week, and length of treatment), and (iii) schedule (i.e.,time of initiation).

Exercise modality (forced vs. voluntary paradigms). A foremostdecision is the use of forced versus voluntary exercise paradigms.An often overlooked key point is that voluntarywheel running is amodel of physical activity, whereas forced paradigms are a modelof exercise training (i.e., structured and purposeful physical activ-ity). Observational (epidemiologic) studies typically measureboth physical activity and exercise, whereas efficacy-based clinicaltrials largely examine highly structured exercise training. Thedecision of which exercise modality is selected should dependon whether the investigators envisage the study findings directlyinforming clinical translation or plausibility/mechanisms of aclinical observation.

An important caveat to consider in all exercise paradigms is thedegree of associated negative stress, as evidenced by exercise-induced increases in serumcorticosterone and fecal corticosteronemetabolites (77, 78), as observed in both voluntary and forcedexercise paradigms. Furthermore, voluntary runningmay result in"addictive behavior" with negative effects on the hypothalamic–pituitary–adrenal (HPA) axis and animal health (79). Humanstudies have taught us that exercise induces spikes in cortisol at thebeginning of exercise and immediately after bout of exerciseceases (80). Stress-induced activation of the HPA axis may accel-erate tumor growth (81), and have diverse effects on the immuneresponse (reviewed in ref. 82), thereby confounding the efficacy ofexercise on tumor growth characteristics. HPA-mediated changeson the immune response could contribute to discordancebetween studies with respect to immune function. For example,Zhu and colleagues reported a decrease in TNFa (43) whereasAbdalla and colleagues reported an increase (23).

Ashcraft et al.

Cancer Res; 76(14) July 15, 2016 Cancer Research4034




Table

1.Tum

orinciden

cestud

ies

Metho

ds

Exe

rciseprotoco

l

Stud

yReferen

ceRoden

tmodel

Tumortype/induc

tion

model

Exe

rcisemodality

Exe

rciseprescription

Freq/w

eek|Dur

|Intens

|Le

ngth

Exe

rciseinitiation

Tumorinciden

ceresults

And

rian

opouloset

al.,1987

255w

old

maleSprague

–

Daw

leyrats

Intestinal/D

MH,i.p.q

1wfor6w

Voluntarywhe

elrunn

ing

Whe

elrunn

ing

1wpriortofirstinjection

-Tum

ors

present

in18/20SEDrats

and6/11EX

rats

Red

dyet

al.,1988

33MaleF34

4rats

Intestinal/Sub

cutane

ous

AOM

15mg/kgBW,q

1w�

2wat

7wk

ofag

e.

Voluntarywhe

elrunn

ing

Whe

elrunn

ingfor38

wee

ks4dpost-A

OM

-EX#i

nciden

cean

dmultiplicityofco

lonan

dsm

allintestina

laden

ocarcinomas,a

ndliver

foci.

Sug

ieet

al.,1992

355w

old

F-344rats

Hep

atocellular/15

mg/kgAOM

s.c.q1w

for2w

Voluntarywhe

elrunn

ing

38w

4dpost-injection.

-Liver

tumors

notedin

7%ofAOM

trea

tedSED

only.

Ikuy

amaet

al.,1993

28Jc1:Wistarrats

Hep

atoma/0.0177g/day/kgBW

dietary

30-M

e-DABfor35

wee

ks.

Voluntarywhe

elrunn

ing

Whe

elrunn

ingfor62wee

ks,u

sing

foodas

arewardforachiev

ing

specified

distances

17w

priorto

dietary

30-

Me-DAB

-65%

reductionin

tumorinciden

ce.

Zhu

etal.,20

08

42

21dold

femaleSprague

–

Daw

leyrats

Mam

mary/25

or50

mg/kgMNU,

i.p.

Voluntarywhe

elrunn

ing

Voluntarywhe

elrunn

ingfor8w

1wpost-injection

-84.5%

inciden

cevs.9

8.1%

,(SEDvs.E

X)

Esser

etal.,20

09

27C3(1)Tag

mice

Prostate/tran

sgen

icmouse

model

Voluntarywhe

elrunn

ing

Whe

elrunn

ingfor10

wee

ks10w

ofag

e-18%(>5K)an

d55

%(<5K)ofa

nimalswithhigh

gradene

oplasiaat

20wee

ksDataan

alyzed

based

onmicethat

ran

>5Kor<5

Kaday

-57%

reductionin

inciden

ceofhighgrade

neoplasiain

>5Kvs.<

5Kmice

Alessioet

al.,20

09

243w

old

femaleSprague

–

Daw

leyrats

Spontan

eous

tumors

Voluntarywhe

elrunn

ingor

activity

box

Whe

el:e

very

other

day

,24haccess

throug

hout

anim

als'life.

Spontan

eous

tumors,

anim

alsfollo

wed

for

life.

-Duringwee

ks60–120

,38%

ofEXrats

were

tumor-bea

ring

anim

als(vs.42%

PArats

and

54%

SEDrata).

Activitybox(PA):1hin

largeactivity

boxtw

iceawee

kforlife.

-Atwee

k88,tum

ormultiplicitywas

0.69forEX

anim

als,0.75forPA,a

nd0.96forSED.

Colberte

tal.,20

09

26Fem

alehe

terozygous

(p53

þ/�):MMTV-W

nt-1

tran

sgen

icmice

Mam

mary/Transgen

icVoluntarywhe

elrunn

ingan

dforced

trea

dmillrunn

ing

Tread

millrunn

ing:

TREX1:5x

|45min|20m/m

inat

5%

grade|un

tilcompletion

TREX2:

5x|45min|24m/m

inat

5%

grade|un

tilcompletion

Voluntarywhe

elrunn

ingwith24

hour

access.

11w

ofag

e-Tum

orinciden

ce"i

nwhe

elrunn

ingmiceby

32%

Man

net

al.,20

1031

21dold

femaleSprague

–

Daw

leyrats

Mam

mary/50

mg/kgMNUi.p

.Voluntaryno

n-motorized

andmotorizedwhe

elrunn

ing

Voluntaryno

n-motorizedan

dmotorized(40m/m

in)whe

elrunn

ing

1wpost-injection

-96%,74%

and70

%inciden

cein

controls,n

on-

motorizedan

dmotorizedmice,

respective

ly

Zhu

etal.,20

1243

21dold

femaleSprague

–

Daw

leyrats

Mam

mary/50

mg/kgMNUi.p

.Voluntarywhe

elrunn

ingat

afixeddaily

distance

Three

leve

ls:W

R-H

igh:

maxim

um35

00m/d

WR-Low:m

axim

um1750

m/d.

SEDco

ntrol.

1wpost-injection

-97%

tumorinciden

cein

controls,8

0%

tumor

inciden

cein

WR-H

igh

-Can

notco

mpareWR-H

ighan

dWR-Low,

becau

sedietary

energyrestrictionwas

applied

toWR-Low

only

Tho

rlinget

al.,1993

365w

old

maleFischer

rats

Intestinal/15mg/kgAOM

s.c.on

Day

s1,4an

d8.

Forced

trea

dmillrunn

ing

5x|2

km/day|7

m/m

in|38w.

3dafterlast

injection

-EX#c

olonne

oplasiainciden

ce,53%

vs.78%in

SEDco

ntrols.

First

wee

kwas

acclim

atization.

Woodset

al.,1994

40

6w

old

maleC3H

/HeN

mice

Mam

mary/2.5�

105mam

mary

SCA-1cells

s.c.in

theback.

Forced

trea

dmillrunn

ing

Tread

millrunn

ing:M

oderate:

7x|30

min|18m/m

inat

5%grade|1w

.

3dpriorto

injection.

-Increaseintumorinciden

ceat

Day

7inboth

EX

group

s,but

nodifferences

inan

ysubseque

nttimepoints.

Exh

austive:7x|varied|18m/m

infor30

min,the

n3m/m

in"e

very

30min

untile

xhau

sted

|1w

Whittal

and

Parkh

ouse,1996

3821dold

femaleSprague

–

Daw

leyRats

Mam

mary/50

mg/kgNMUi.p

.at

50dofag

eForced

trea

dmillrunn

ing

Progressivetraining

to5x

|60min|18

m/m

inat

15%

grade|4w

21dofag

e(29dpriorto

injection)

-Inciden

ce/m

ultiplicityat

24w

post-N

MU:5

8tumors

inSEDrats,3

3tumors

inEXrats

-Nosignificant

differenceinlatencyorinciden

ce

(Continue

donthefollowingpag

e)






Table

1.Tum

orinciden

cestud

ies(Cont'd)

Metho

ds

Exe

rciseprotoco

l

Stud

yReferen

ceRoden

tmodel

Tumortype/induc

tion

model

Exe

rcisemodality

Exe

rciseprescription

Freq/w

eek|Dur

|Intens

|Le

ngth

Exe

rciseinitiation

Tumorinciden

ceresults

Whittal-Stran

ge

etal.,1998

3921dold

femaleSprague

–

Daw

leyrats

Mam

mary/37

.5mg/kgNMUi.p

.at

50dofag

e,(1day

afterlast

bout

ofEX)

Forced

trea

dmillrunn

ing

Progressivetraining

to5x

|60min|18

m/m

inat

15%

grade|4w

21dofag

e(29dpriorto

injection)

-Inciden

cesofcarcinomas,h

ighgradean

dlow

gradetumors

were29

.2%,10.4%,a

nd25

%in

SED,a

nd38

%,14.3%

and21.4%

inEX

Westerlindet

al.,

2003

3721dold

femaleSprague

–

Daw

leyrats

Mam

mary/25

or50

mg/kgMNU,

i.p.

Forced

trea

dmillrunn

ing

Wee

k1:5x

|10–15min|30m/m

in|1w.

1wpost-injection

-"La

tencyin

EX(35.8dvs.3

3.1d).

Wee

k2–9:5

x|30

min|23–

25m/

min|8w

-Nodifferencein

med

iantumor-free

survival

timewas

observed

intheEXve

rsus

sham

-EX

(SHAM),no

rweretherean

ydifferences

inmultiplicityat

either

ahighorm

oderatedose

of

MNU

Zielinskie

tal.,

2004

44

6–8

wold

femaleBALB

/cmice

Neo

plasticlympho

idcells/2

�10

7

EL-4cells

s.c.in

theback

beh

indthene

ck

Forced

trea

dmillrunn

ing

7x|3

horun

tilv

olitiona

l

fatigue

|gradua

llyincrea

sing

spee

d,

20–4

0m/m

in,5

%grade|5–

14d

First

session

immed

iately

before

injection.

-EX#t

umorap

pea

rance

Zhu

etal.,20

09

41

21dold

femaleSprague

–

Daw

leyrats

Mam

mary/50

mg/kgMNU,i.p.

Forced

whe

elrunn

ing

Motorizedrunn

ingwhe

el;d

etailsno

tprovided

1wpost-injection

-66.7%

and92.6%

inciden

cein

EXan

dSED

Katoet

al.,20

1129

5woldmaleFischer

344rats

Ren

al/5

mg/kgBW

Fe-NTAi.p

.onceaday

for7day

s,then

10mg/kgFe-NTA3x

/wkfor11w.

Forced

trea

dmillrunn

ing

Sho

rt-term:15m|8

m/m

in,0

%|12w

.Trainingdone

15m

before

each

injection

-Nodifferences

innu

mber

ofrats

withno

dules,

nodules/rat

ormea

narea

ofno

dules.

Long

-term:15m|8

m/m

in,0

%|12w

;

then

5x|30m|8m/m

in,0%|12w

fora

totalo

f24

wtraining

Exercise

continue

dun

til4

0wee

ks,b

utat

lower

intensityto

acco

untforthe

declinein

rathe

alth.

-Sho

rt-term

EX"r

atswithmicrocarcinomas,

karyomeg

aliccells

anddeg

enerativetubules

compared

toSED.

-Lo

ng-term

EX#r

atswithmicrocarcinomas,

karyomeg

aliccells

anddeg

enerativetubules

compared

toshort-term.

Malicka

etal.,20

1545

4w

old

femaleSprague

–

Daw

leyrats

Mam

mary/180mg/kgMNUi.p

.Forced

trea

dmillrunn

ing

Low

intensity(LIT):5x

|10–3

5

min|0.48–1.34km

/h|12w

Immed

iately

afterMNU

injection

-Inciden

ce64%,6

7%,4

0%an

d43%

inSED,LIT,

MIT

andHIT

group

s,respective

ly(N

ot

significant)

Moderateintensity(M

IT):5x

|10–3

5

min|0.6–1.68km

/h|12w

-Multiplicity:Ratswithtumorsha

dan

averag

eof

2.4,1.6,1

and1tumors

inSED,LIT,M

ITan

dHIT

group

s,respective

ly(Statisticsno

tperform

ed.)

Highintensity(H

IT):5x

|10–3

5

min|0.72–2.0km

/h|12w

Pigue

tet

al.,20

1546

7–9w

old

maleAlbCrePten

flox/floxmice

Hep

atocellularcarcinoma/

Transgen

icForced

trea

dmillrunn

ing

5wacclim

ationperiodfollo

wed

by:

5x|60m|12.5m/m

in|27w

7–9w

ofag

e-Tum

orinciden

ce100%

inSEDvs.7

1%in

EX

Lunz

etal.,20

08

3011w

old

maleWistarRats

Intestinal/4

s.c.injections

DMH3

day

sap

art.

Forced

swim

mingwith

Wee

k1–2:

5x|5–2

0min|-load

|2w

24hpost

firstinjection

-Nodifferencein

tumorinciden

ce

0%,2

%or4%

BW

load

Wee

k3–

5:5x

|5–2

0min|þ

load

|3w

Wee

k6-35

:5x|20

min|þ

load

|30w

-Aerobicsw

immingtraining

with2%

body

weight

ofload

protected

againsttheDMH-

induced

prene

oplasticco

lonlesions,b

utno

tag

ainsttumordev

elopmen

tin

therat

Pacelie

tal.,20

1232

AdultmaleBalb/c

mice

Lung

/1.5mg/kgBW

uretha

nei.p

.tw

ice,

2day

sap

art

Forced

swim

ming

Aerobic:4

x|20

m|–|19w

Withinawee

kafter

injection

-Nosignificant

effectsofae

robictraining

on

lung

cancer

inciden

ce.

Wee

k1:10

m/d

to50

min

5day

s-A

erobictraining

resulted

in8lung

nodules

per

anim

alvs.5

2in

theco

ntrol.Notsignificant.

Ana

erobic:3x|20

m(2

msw

imming/2

mresting)|progressiveload

ingof

5–20

%BW|20w

-Med

ianco

ntroln

odules

was

2.0,m

edian

aerobicco

ntroln

odules

was

0.0.N

ot

significant.

Abdallaet

al.,20

1323

8w

old

femaleBalb/c

mice

Mam

mary/1mg/m

LDMBAp.o.

oncewee

klyfor6wee

ksForced

swim

ming

5x|45m|–|8

wee

ksSam

eas

tumor

initiation

-EX#t

umorinciden

ce

Water

temperature30

�4� C

S� ae

zMdel

etal.,

2007

3450

dold

femaleSprague

–

Daw

leyrats

Mam

mary/5mg/w

DMBAgastric

intubationfor4w

Forced

swim

ming

30m/d,5

d/w

for38

–65d

.1d

afterap

pea

ranceof

firsttumor

-Nodifferencein

survival

timeortumor

multiplicity

Abbreviations:A

OM,a

zoxymetha

ne;B

W,b

odyweight;d

,day

DMBA,7

,12-dim

ethy

lben

z(a)an

thracene

;DMH,1,2-dim

ethy

lhyd

razine

;30 -Me-DAB,3

0 -methy

l-4-dim

ethy

laminoazoben

zene

;EX,e

xerciseoractivity

group

s;Fe-NTA,ferricnitrilo

triacetate;

MNU,1-m

ethy

l-1-nitrosourea

;NMU,n

itrosomethy

lurea;

q1w

,onceper

wee

k;SED,sed

entary

controls;w

,wee

ks.

Ashcraft et al.





Table

2.Tum

orgrowth

stud

ies

Metho

ds

Exe

rciseprotoco

l

Stud

yReferen

ceRoden

tmodel

Tumortype/induc

tionmodel

Exe

rcisemodality

Exe

rciseprescriptionFreq/w

eek|

Dur

|Intens

|Le

ngth

Exe

rciseinitiation

Tumorprogressionresults

Dan

eryd

etal.,1995

51Fem

aleWistar

Furth

rats

Leyd

igcell/1.5

mm

3injectionof

Leyd

igcellsarcoma(LTW)

Voluntarywhe

elrunn

ing

13d

Immed

iately

afterinjection

-EX#t

umorvo

lumeby34

%.

Dan

eryd

etal.,1995

52Fem

aleWistar

Furth

rats

Leyd

igcell/1.5

mm

3injectionof

Leyd

igcellsarcoma(LTW)or

Nitrosogua

nine

-ind

uced

aden

ocarcinomas.c.into

each

flan

k

Voluntarywhe

elrunn

ing

32d

Immed

iately

afterinjection

-13.4

gvs.16.4

gEXvs.S

EDfina

lLTW

weights

Zhu

etal.,20

08

42

21dold

female

Sprague

–Daw

ley

rats

Mam

mary/25

or50

mg/kgMNU,

i.p.

Voluntarywhe

elrunn

ing

Voluntarywhe

elrunn

ingfor8w

1wpost-injection

-Tum

orweight

0.62gvs.1.16

g(SEDvs.E

X)

Jone

set

al.,20

1057

3–4w

old

female

athy

mic

mice

Mam

mary/1�

106MDA-M

B-231

cells,injectedortho

topically

Voluntarywhe

elrunn

ing

Voluntarywhe

elrunn

ingfor41–48d

2dpost-implant

Nochan

gein

primarytumorgrowth

(EX"2

1%)

Yan

andDem

ars,20

1164

3wold

maleC57

BL/6

mice

Lung

/2.5

�10

5/50ml/mouse

Lewislung

carcinomacells

s.c.

lower

dorsal

region

Voluntarywhe

elrunn

ing

Primarytumors

excisedat

1cm

diameter,a

ccessto

whe

els

continue

dforad

ditiona

l2w.

9w

before

tumorim

plantation

-Nodifferenceintumorcross-sectiona

lareaan

dtumorvo

lume.

Jone

set

al.,20

1255

6–8

woldmaleC57

BL/6

mice

Prostate/5�

105mouseprostate

C-1cells,o

rtho

topically

Voluntarywhe

elrunn

ing

Whe

elrunn

ingfor8wee

ks14daftertumortran

splant

-Primarytumorgrowth

was

comparab

lebetwee

ngroup

s

Gohet

al.,20

1466

18m

old

Balb/cBymice

Mam

mary/1�

104cells

in4th

mam

maryfatpad

Voluntarywhe

elrunn

ing

Voluntarywhe

elrunn

ingfor90day

s60dayspriorto

tumor

tran

splant,follo

wed

by30

day

spost-transplant

-Inv

erse

relationshipbetwee

ndistancerunan

dfina

ltum

ormass

Betofet

al.,20

1565

Fem

aleBalb/c

or

femaleC57

Bl/6mice

Mam

mary/5�

1054T1-lucor2.5

�10

5E077

1cells

indorsal

mam

maryfatpad

Voluntarywhe

elrunn

ing

Voluntarywhe

elrunn

ingbeg

inning

either

9wee

kspriorto

tumor

tran

splant,o

rat

thetimeoftumor

tran

splant

SS:S

EDbefore

andafter

tran

splant

-Growth

ratesofSSan

dRSweresimilar,an

dgrowth

ratesofSRan

dRRweresimilar

RS:E

Xfor9wee

kspriorto

tran

splant;S

EDafter

tran

splant

-EXslowed

tumorgrowth

compared

toSED

(both

tumormodels)

SR:S

EDbefore

tran

splant;E

Xaftertran

splant

RR:E

X9wee

kspriorto

tran

splant,continuing

after

tran

splant

Alessio

etal.,20

09

243w

oldfemaleSprague

–

Daw

leyrats

Spontan

eous

tumors

Voluntarywhe

elrunn

ingoractivity

box

Whe

el:e

very

other

day

,24haccess

throug

hout

anim

als'life.

Spontan

eous

tumors,a

nimals

follo

wed

forlife.

-EX#tu

morgrowth

rate

Activitybox(PA):1hin

largeactivity

boxtw

iceawee

kforlife.

Colbertet

al.,20

09

26Fem

alehe

terozygous

(p53

þ/�):MMTV-

Wnt-1tran

sgen

icmice

Mam

mary/Transgen

icVoluntarywhe

elrunn

ingan

dforced

trea

dmillrunn

ing

Tread

millrunn

ing:TREX1:5x

|45

min|20m/m

inat

5%grade|un

til

completion

11w

ofag

e-Tim

eto

tumorsize

of1.5

cm:24.8d,13.8d,and

19.5din

control,TREX1an

dTREX2an

imals.

TREX2:

5x|45min|24m/m

inat

5%

grade|un

tilcompletion

Voluntarywhe

elrunn

ingwith24

hour

access.

-Tread

millrunn

ingledto

faster

tumorgrowth,

nodifferencedue

tovo

luntarywhe

elrunn

ing

-Tread

millrunn

ing#s

urviva

l

New

tonet

al.,1965

60

45d

old

Sprague

–

Daw

leyrats

Carcino

ma/Equa

lvolumes

of

Walker-25

6cells

s.c.into

the

right

flan

k.

Forced

trea

dmill

runn

ing

Pre-Tum

or:50

hove

r5d

at950

ft/hr.

5dbefore

tumor

implantation�

4dafter

tumorim

plantation

-EX#fi

naltum

orweight

vs.S

EDco

ntrol.

Post-Tum

or:138hove

r10dat

950

ft/hr.

-Early

lifeman

ipulationþ

EX#fi

naltum

or

weight

vs.E

Xalone

andSED.

Uhlen

bruck

andOrder,

1991

63

BALB

/cmice

Sarco

ma/2.4�

104L-1cells

s.c.

Forced

trea

dmill

runn

ing

7x|distances

of20

0m/400m/800

m|0.3

m/s|2w

4w

before

and2w

after

injection

-200m

group

#tum

orweight

(Continue

donthefollowingpag

e)






Table

2.Tum

orgrowth

stud

ies(Cont'd)

Metho

ds

Exe

rciseprotoco

l

Stud

yReferen

ceRoden

tmodel

Tumortype/induc

tionmodel

Exe

rcisemodality

Exe


eek|

Dur

|Intens

|Le

ngth

Exe

rciseinitiation


Woodset

al.,1994

40

6w

old

maleC3H

/HeN

mice

Mam

mary/2.5�

105mam

mary

SCA-1cells

s.c.in

theback.

Forced

trea

dmill

runn

ing

Tread

millrunn

ing:M

oderate:

7x|30

min|18m/m

inat

5%grade|1w

.

3dpriorto

injection.

Nodifferencein

growth

rate

oftumorsize

attimeofeu

than

asia

(twowee

ls)

Exh

austive:7x|varied|18m/m

infor30

min,the

n3m/m

in"e

very

30min

untile

xhau

sted

|1w

Whittal-Stran

geet

al.,

1998

3921dold

female

Sprague

–Daw

ley

rats

Mam

mary/37

.5mg/kgNMUi.p

.at

50dofag

e,(1day

afterlast

bout

ofEX)

Forced

trea

dmill

runn

ing

Progressivetraining

to5x

|60min|18

m/m

inat

15%

grade|4w

21dofag

e(29dpriorto

injection)

-Tum

orgrowth

rate

at22

wpost-N

MU:0

.043

g/day

inSEDvs.0

.107g/day

inEX

-Finaltumorweight:(3.2ginSEDvs.1.2ginEX

Bacurau

etal.,20

00

49

12woldmaleWistarrats

Carcino

ma/2�

107Walker-25

6cells

s.c.in

theflan

kForced

trea

dmill

runn

ing

5x|60min|60%

ofVO2pea

k|10w

8w

priorto

injection

-Day

15tumorweight

1.82%

vs.19%

ofBW

(EX

vs.S

ED)

-EXprolong

edsurvival

by1.9

fold

Westerlindet

al.,20

03

3721dold

female

Sprague

–Daw

ley

rats

Mam

mary/25

or50

mg/kgMNU,

i.p.

Forced

trea

dmill

runn

ing

Wee

k1:5x

|10–15min|30m/m

in|1w.

1wpost-injection

-"La

tencyin

EX(35.8dvs.3

3.1d).

Wee

k2–9:5

x|30

min|23–

25m/

min|8w

-Nodifferencein

med

iantumor-free

survival

timewas

observed

intheEXve

rsus

sham

-EX

(SHAM),no

rweretherean

ydifferences

inmultiplicityat

either

ahighorm

oderatedose

of

MNU

Zielinskie

tal.,20

04

44

6–8

woldfemaleBALB

/cmice

Neo

plasticlympho

idcells/2

�10

7

EL-4cells

s.c.in

theback

beh

indthene

ck

Forced

trea

dmill

runn

ing

7x|3

horun

tilv

olitiona

l

fatigue

|gradua

llyincrea

sing

spee

d,

20–4

0m/m

in,5

%grade|5–

14d

First

sessionim

med

iately

before

injection.

-Nodifferencein

tumorden

sity

Jone

set

al.,20

05

563–

4w

old

female

athy

mic

mice

Mam

mary/Flank

injectionof5�

106MDA-M

B-231

cells

Forced

trea

dmill

runn

ing

5d/w

|10m/m

infor10

minup

to18

m/

min

for45min|0%

grade|8w

14dpost-injection

-Nochan

gein

tumorgrowth.

Bacurau

etal.,20

07

48

8wold

maleWistarrats

Carcino

ma/2�

107Walker-25

6cells

s.c.in

theflan

kForced

trea

dmill

runn

ing

5x|30min|85%

ofVO2max|10w

8w

priorto

injection

-Survival:16dforSED,4

5dforEX

-EXtumors

were6.9%

offina

lbodymassvs.

17.33%

forSEDco

ntrol.

Lira

etal.,20

08

58MaleWistarrats

Carcino

ma/2�

107Walker-25

6cells

s.c.in

theflan

kForced

trea

dmill

runn

ing

5x|60min|60–6

5%ofVO2pea

k|10w

8w

priorto

injection

-Tum

orweight:17.2gin

SED;1.9

gin

EX

2wpre-trainingperiod:ratsran

progressivelyfrom

15to

60min

at10

m/m

in.R

unning

was

increa

sed

to20

m/m

infortw

owee

ksafter

injection.

Murphy

etal.,20

1159

4w

old

C3(1)SV40Tag

mice

Mam

mary/Transgen

ic(tum

ors

beg

andev

elopingat

12w

of

age).

Forced

trea

dmill

runn

ing

6x|60m|20m/m

inat

5%|20w

4w

ofag

e-Tum

orvo

lume:

#inEXat

21an

d22

w.

Gue

ritatet

al.,20

1469

10–12w

old

Copen

hagen

rats

Prostate/surgical

s.c.

implantationofR33

27Dun

ning

AT1tumorfrag

men

t

Forced

trea

dmill

runn

ing

5x|15–

60m|20–25m/m

in|5w

15daftertumorim

plantation

-EXrats

hadsm

allertumors

at14

and21

day

sco

mpared

toSEDco

ntrols

-Tum

ordoub

lingtimewas

significantly

slower

inEXvs.S

ED(6.19

dvs.8

.81d)

Sha

lamzariet

al.,20

1467

4–6

wold

Balb/c

mice

Mam

mary/1�

106MC4-L2s.c.in

theflan

kForced

trea

dmill

runn

ing

-|20

–40min|6–2

0m/m

in|15w

RTR:S

eden

tary

before

and

aftertran

splant

-ETEha

dsignificantlyslower

growth

compared

toRTR

RTE:E

Xaftertumortran

splant

only

-Nodifferenceinfina

ltum

orv

olumeofR

TEan

dETRgroup

sETR:E

Xbefore

tumor

tran

splant

only

ETE:E

Xbefore

andafter

tran

splant

9w

before

tumortran

splant,

and/or6w

aftertran

splant

(Continue

donthefollowingpag

e)

Ashcraft et al.





Table

2.Tum

orgrowth

stud

ies(Cont'd)

Metho

ds

Exe

rciseprotoco

l

Stud

yReferen

ceRoden

tmodel

Tumortype/induc

tionmodel

Exe

rcisemodality

Exe


eek|

Dur

|Intens

|Le

ngth

Exe

rciseinitiation


Ave

sehet

al.,20

1568

5wold

femaleBalb/c

mice

Mam

mary/1.2

�10

6MC4-L2cells

inright

dorsal

mam

maryfat

pad

Forced

trea

dmill

runn

ing

7x|20–5

5min|10–2

0m/m

in|7w

10daftertumortran

splant

-EXdecreased

tumorvo

lume

Malicka

etal.,20

1545

4w

old

female

Sprague

–Daw

ley

rats

Mam

mary/180mg/kgMNUi.p

.Forced

trea

dmill

runn

ing

Low

intensity(LIT):5x

|10–3

5

min|0.48–1.34km

/h|12w

Immed

iately

afterMNU

injection

-Nodifferencein

fina

lvolumeoftotaltum

or

volume

Moderateintensity(M

IT):5x

|10–3

5

min|0.6–1.68km

/h|12w

Highintensity(H

IT):5x

|10–3

5

min|0.72–2.0km

/h|12w

Pigue

tet

al.,20

1546

7–9w

old

male

AlbCrePtenflox/flox

mice

Hep

atocellularcarcinoma/

Transgen

icForced

trea

dmill

runn

ing

5wacclim

ationperiodfollo

wed

by:

5x|60m|12.5m/m

in|27w

7–9w

ofag

e-EXdecreased

totalv

olumeofliver

tumors

Hoffman

etal.,1962

54Wistarrats

Carcino

ma/2mLWalker25

6cell

suspen

sions.c.into

theright

thigh.

Continuo

usrunn

ingon

a20

ftrunw

ayþ

swim

mingþ

revo

lvingdrum

21dofEX,a

llEXdid

all3

modalities

each

day

:Run

way:c

ontinuo

usrunn

ingon20

ftrunw

ay,d

uration

andintensityno

tclea

r

Immed

iately

afterinjection

-97%

inhibitionoftumorgrowth.

Swim

ming:increasing20

min/day

to4

h/day

Rev

olvingdrum:5

.4miin12

h

-Tum

orweight

#inEXgroup

Gershbeinet

al.,1974

53Holtzm

anrats

Carcino

sarcoma/Walker-25

6tumori.m

.intoboth

hind

limbs.

Forced

swim

ming

10x|15

min|–|10d

Immed

iately

afterinjection.

-EX#t

umorsize.

-Nochan

gein

survival

rates.

Baracos,1989

50Sprague

–Daw

leyrats

Hep

atoma/20

uLMorris

hepatoma77

7s.c.

Forced

swim

ming

Low:5x|5min/d,increased

by5min/d

for3w

.

2Group

s-3w

ofsw

imming,tum

or

tran

splant,the

n3w

additiona

lswim

ming.

-EX#fi

naltum

orweight,b

oth

group

s.

Med

ium:5

x|10

min/d,increased

by10

min/d

for3w

.-3wofswim

mingbeg

inning

3dpost-transplant

High:5x

|15min/d,increased

by15min/

dfor3w

.

Rad

aket

al.,20

02

61

Adultfemalehy

brid

BDF1mice

Solid

leuk

emia/5

�10

6P-388

lympho

idleuk

emia

cells

s.c.

Forced

swim

ming

5x|60min|–|10w

10w

before

injection.

-ECan

imalsha

dslower

tumorgrowth

than

ET

andco

ntrol,(end

points

were�1

.24cm

3vs.2

cm3an

d2.4cm

3)

ET:trainingterm

inated

attumor

implantation.

EC:trainingco

ntinue

dfor18dafter

tumorim

plantation.

S� ae

zMdel

etal.,20

07

3450

dold

female

Sprague

–Daw

ley

rats

Mam

mary/5mg/w

DMBAgastric

intubationfor4w

Forced

swim

ming

30m/d,5

d/w

for38

–65d

.1d

afterap

pea

ranceoffirst

tumor

-EX"t

umorgrowth

by20

0%.

Alm

eidaet

al.,20

09

47

7wold

maleSwissmice

Carcino

ma/2�10

6Ehrlichtumor

cells

s.c.in

thedorsum

.Forced

swim

ming

5x|60min|50/80%

max

test|6w.

4w

before

injection

-50%

workload

#tum

orweight

andtumor

volume(0.18

mg/g

and0.11

mm

3)vs.control

(0.55mg/g

and0.48mm

3)

Progressiveload

test

beg

anafter1w

:load

increa

sedby2%

BW

every3

min

untile

xhau

stion.

-Tum

orvo

lumean

dweight

were27

0%

and

280%

"inSEDmice.

Sasva

riet

al.,20

1162

AdultfemaleBDF1m

ice

Sarco

ma/5�

106S-180cells

s.c.

injected

.Forced

swim

ming

5x|60m|–|10w

10w

before

tumor

implantation.

-ETC#fi

naltum

orweight

vs.S

EDco

ntrol.

ETT:cellsinjected

afterEX.

ETC:E

X(10w),cells

injected

,EX(18

additiona

lday

s)

Abbreviations:A

OM,azo

xymetha

ne;B

W,bodyweight;d,day

;DMBA,7,12

-dim

ethy

lben

z(a)an

thracene

;DMH,1,2-dim

ethy

lhyd

razine

;30 -Me-DAB,3

0 -methy

l-4-dim

ethy

laminoazoben

zene

;EX,exerciseoractivity

group

s;Fe-NTA,ferricnitrilo

triacetate;M

NU,1-

methy

l-1-nitrosourea

;NMU,n

itrosomethy

lurea;

SED,sed

entary

controls;w

,wee

ks.






Table

3.Tum

ormetastasisstud

ies

Metho

ds

Exe

rciseprotoco

l

Stud

yReferen

ceRoden

tmodel

Tumortype/induc

tionmodel

Exe

rcisemodality

Exe

rciseprescription

Freq/w

eek|Dur

|Intens

|Le

ngth

Exe

rciseinitiation

Tumormetastasisresults

Naturally

occurring

Gershbeinet

al.,

1974

53Holtzm

anrats

Carcino

sarcoma/Walker-25

6tumori.m

.intoboth

hind

limbs.

Forced

swim

ming

10x|15

min|–|10d

Immed

iatelyafterinjection.

-Older

EXrats

"lower

abdominal

andinguina

lseco

ndarytumorno

dules.

Yan

andDem

ars,

2011

64

3wold

male

C57

BL/6mice

Lung

/2.5�1

05/50ml/mouse

Lewislung

carcinomacells

s.c.

lower

dorsal

region

Voluntarywhe

elrunn

ing

Tum

ors

excisedat

1cm

diameter,a

ccessto

whe

els

continue

dforad

ditiona

l2w.

9w

before

tumor

implantation

-Trend

toinve

rserelationshipbetwee

nrunn

ing

distancean

dmetastatictumoryield

Jone

set

al.,20

1255

6–8

wold

male

C57

BL/6mice

Prostate/5�

105mouseprostate

C-1cells,o

rtho

topically

Voluntarywhe

elrunn

ing

Whe

elrunn

ingfor8wee

ks14daftertumortran

splant

-EX#t

umorno

dal

invo

lvem

entby36

%,

metastasesweight

by88%

andnu

mber

of

metastasesby34

%(N

one

weresignificant)

Artificial(intraveno

usinjectionof

tumor

cells)

Uhlen

bruck

and

Order,1991

63

BALB

/cmice

Sarco

ma/2.4�

104L-1cells

i.v.

Forced

trea

dmill

runn

ing

7x|predetermined

distances

of

200–8

50m|0.3–0

.5

m/s|4–6

w

4w

before

injection,

follo

wed

byeither

restor

anad

ditiona

l2wrunn

ing

-EXdecreased

lung

tumormultiplicity

-Differences

inrunn

ingprescriptions

makeit

difficultto

determineifexercise

cessationafter

tumorcelltran

splant

was

different

from

continuo

usexercise

MacNeila

ndHoffman

n-Goetz,1993a

744–5

wold

male

C3H

/Hemice

Transform

edfibroblasts/1.5

�10

6

CIRAS1tumorcells

i.v.v

iatail

vein.

Forced

treadm

illand

voluntarywheel

runn

ing

Tread

mill:5

x|30

min|15m/m

in,

0%|9w.

9w

before

injection

-Nosignificant

effect

ofactivity

onlung

tumor

retention.

VoluntaryWhe

el:24haccess

towhe

elfor9w.

-Significant

but

wea

kco

rrelationofd

istancerun

andmultiplicityoflung

metastases.

Allan

imalsremaine

dSEDafter

injectionfor3w

.-M

ediannu

mber

oflung

metastasesper

anim

alwas

greater

inEXmice(21vs.10SEDco

ntrol).

MacNeila

ndHoffman

n-Goetz,1993b

73C3H

/Hemice

Transform

edfibroblasts/3�

105

CIRAS1cells

i.v.

Voluntarywhe

elrunn

ing

3–12w.

9wpriorto

and/or3w

after

injection

-EXha

dno

effect

onlung

tumorden

sity

-EXpriorto

tumorinjection"i

nciden

cein

the

lowesttertile

oftumordistributionvs.S

ED

controls.

Hoffman

n-Goetz

etal.,1994a

71C3H

/He-bg2J/þ

andC3H

/HeJ

mice

Transform

edfibroblasts/5�

105

CIRAS1orCIRAS3

radiolabeled

tran

sform

edfibroblast

cells

i.v.viatailve

in.

Voluntarywhe

elrunn

ing

24haccess

torunn

ingwhe

elfor

9w.

9w

before

injection

-EX#r

eten

tionofradioactivity

inlung

s5min

and30

min

post-injection.

Hoffman

-Goetz

etal.,1994b

703w

old

female

BALB

/cmice

Mam

mary/La

teraltailv

ein

injectionof1�

104MMT66

cells

Forced

trea

dmill

runn

ingorvo

luntary

whe

elrunn

ing

Tread

millrunn

ing:5

x|30

min|18

m/m

inat

0%|8w

or3w

.

8w

prioror36

hafter

injectionfor3w

-NoEXeffect

onnu

mber

oflung

tumors.

Group

s:WS:

wheelmice,24

haccess

for8w

,thenSE

Dfor3w

.

-TTtend

edto

have

"tum

ormultiplicity.

TS:tread

millmice,then

SEDfor

3w.

TT/W

T:C

ontinuo

usEXfor11w

total.

STorSW:S

EDfor8w

then

trea

dmill(ST)orwhe

el(SW)

for3w

.SS:S

EDfor11w

total.

-STan

dSW

tend

edto

have

#tum

orm

ultiplicity.

Jadeski

and

Dem

ars,1996

724–9

wold

C3H

/He-bg2J/þ

andC3H

/HeJ

mice

Transform

edfibroblasts/5�

105

CIRAS1orCIRAS3

tran

sform

edfibroblastcells

i.v.

viatailve

in.

Forced

trea

dmill

runn

ing

5x|30min|20m/m

in,0

%|9w

9w

before

injection

-EX#t

umorcelllung

retention(44.2

vs.5

2.8%

control).

Acclim

atizationperiodof1

wee

k.-EX#l

ungretentionoftheless

aggressive

CIRAS1,no

differencein

CIRAS3cells.

-EXdid

notalterfina

ltum

orlung

metastases

numbers,(sub

group

evalua

ted3w

afterE

Xan

dinjection).

Yan

andDem

ars,

2011

64

3wold

male

C57

BL/6mice

Melan

oma/0.75�

105/200ml/

mouseB16BL/6cells

inlateral

tailve

in

Voluntarywhe

elrunn

ing

Melan

oma:

24haccess

towhe

els,co

ntinue

d2w

post-

implantation.

9w

before

tumor

implantation

-Nodifferencein

number

oflung

metastasis

Higginset

al.,

2014

756wold

malescid-

beigemice

Lung

/5�

105A54

9-luc-C8cells

i.v.v

iatailve

inVoluntarywhe

elrunn

ing

28d

After

lung

tumors

were

detectable

-EXdecreased

tumorvo

lume,as

mea

suredby

bioluminescent

imag

ing

Miceaverag

ed600–120

0m/day

Abbreviations:E

X,e

xerciseoractivity

group

s;SED,sed

entary

controls.

Ashcraft et al.





Table

4.Mecha

nistic

results

Mec

hanistic

find

ings

Stud

yReferen

ceTu

mortype

Exe

rcisemodality

Intratum

oral

System

icPotentialim

plications

Preve

ntion

Ikuy

ama

etal.,1993

28Carcino

gen

induced

hepatoma

Voluntarywhe

elrunn

ing

-None

reported

.-EX#g

amma-glutamyl

tran

spep

tidasean

d"

ALP

.Red

uced

liver

dam

age

Alessio

etal.,20

09

24Spontan

eous

tumors

Voluntarywhe

elrunn

ing

-None

reported

.-M

eanserum

prolactin

leve

lswere#i

nexercising

ratsan

d"inSEDratsat

24an

d52

wofag

e.

Prolactin

hasbee

nassociated

withtumor

growth

Gohet

al.,20

1466

Ortho

topicmam

marytumor

Voluntarywhe

elrunn

ing

-Inv

erse

correlationbetwee

ndistancerun

andmitoticindex

withintumors

-EXincrea

sedVO2an

drespiratory

exchan

ge

rate

Decreased

tumorcellproliferation

Betofet

al.,20

1565

Ortho

topicmam

marytumor

Voluntarywhe

elrunn

ing

-EXincreasedco

localizationofd

esminan

dCD31

anddecreased

tumorhy

poxiaan

dne

crosis

-None

reported

Increa

sedmicrove

ssel

den

sity

andmaturity,

which

lead

sto

improve

dtumorperfusion;

increa

sedtumorcellap

optosis

-EXincrea

sedexpressionofF

as,caspase8

andcleave

dcaspase3

Woodset

al.,1994

40

s.c.mam

marytumor

tran

splant

Forced

trea

dmill

runn

ing

-ModerateEX:"

pha

gocyticcells

-None

reported

Increa

sedtumoricidal

immun

eresponse

-Exh

austiveEX:#

totala

ndhighly

pha

gocyticcells

Bacurau

etal.,20

00

48

s.c.carcinomatran

splant

Forced

trea

dmill

runn

ing

-None

reported

-EX#g

luco

seco

nsum

ptionan

dproduction,

andlactateproductionan

d"g

lutamine

consum

ptionofmacropha

ges

Increa

sedtumoricidal

immun

eresponse

-EX#H

2O2productionbymacropha

ges,a

nd"

pha

gocytosis.

-EX"l

ympho

cyte

proliferation

Bacurau

etal.,20

07

49

s.c.carcinomatran

splant

Forced

trea

dmill

runn

ing

-EXim

pairs

tumorcellgluco

sean

dglutaminemetab

olism.

-EX,n

on-tumor"p

lasm

aco

rticosterone

vs.

control.

Modulationofphy

siology

-EXpreve

ntstumor-induced

reductionin

body

weight

andfoodintake,activationofg

lutamine

metab

olism

inmacropha

ges

andlympho

cytes.

Lira

etal.,20

08

58s.c.carcinomatran

splant

Forced

trea

dmill

runn

ing

-None

reported

.-EX#l

iver

triacylglycerol(TAG)co

nten

tco

mpared

toSED.

Associated

withreduced

cachexia

-SEDtumoran

imalsha

d"s

erum

andliver

TAG,

and#r

ateofVLD

Lsecretion,ap

oBexpression

andmicrosomal

TAGtran

sfer

protein

compared

toco

ntrol.

Murphy

etal.,20

1159

Transgen

icmam

mary

tumors

Forced

trea

dmill

runn

ing

-None

reported

.-#

spleen

weight

compared

towild

-typ

emice.

Increa

sedtumoricidal

immun

eresponse

-Nodifferencein

spleen

weight

due

toEX.

-EX#p

lasm

aIL-6

andMP-1.

Katoet

al.,20

1129

Carcino

gen

-ind

uced

rena

ltumors

Forced

trea

dmill

runn

ing

-None

reported

.-Long

-term

EXan

dFe-NTA#r

enal

brown

droplets

compared

toSED,"

adrena

lweight

compared

toboth

other

group

s.

Browndroplets

couldreflectrena

ldam

age

caused

bycarcinogen

applied.Increases

inad

rena

lweight

have

bee

nlinkedto

psychological

stress.

Sha

lamzariet

al.,20

1467

s.c.mam

marytumor

tran

splant

Forced

trea

dmill

runn

ing

-EXaftertumortran

splant

decreased

tumorIL-6

andVEGF

-None

reported

Red

uced

inflam

mationan

dsubseque

ntan

giogen

esis

-IL-6

andVEGFleve

lsinETRmicewereno

tdifferent

from

RTR(sed

entary)mice.

Pigue

tet

al.,20

1546

Transgen

iche

patocellular

carcinoma

Forced

trea

dmill

runn

ing

-EXdecreased

proliferation(Ki67staining

)in

tumorno

dules

>15mm

3.

-EXalteredgen

eexpressionoffattyacid

metab

olism

pathw

ays

Altered

lipogen

esis.S

omelip

ogen

esis

pathw

aysareprogno

sticindicatorsfollo

wing

HCCsurgical

remova

l

Malicka

etal.,20

1545

Carcino

gen

-ind

uced

mam

marytumor

Forced

trea

dmill

runn

ing

-EXincrea

sedTUNELpositive

cells

-None

reported

Alm

eidaet

al.,20

09

47

s.c.carcinomatran

splant

Swim

ming

-50%

workload

#macropha

geinfiltration

andne

utrophila

ccum

ulation.

-80%workload

induced

cardiachy

pertrophy

vs.

50%.

Altered

immun

eresponse;

future

analysisof

macropha

gesubsets

wouldbeben

eficial

tothefield

Sasva

riet

al.,20

1162

s.c.sarcomatran

splant

Swim

ming

-None

reported

.-EX#o

xidativemodificationofprotein

inthe

liver

asmea

suredbyprotein

carbony

ls.

Red

uced

oxidativestress

orim

prove

dan

ti-

oxidan

tactivity

(Continue

donthefollowingpag

e)






Table

4.Mecha

nistic

results(Cont'd)

Mec

hanistic

find

ings

Stud

yReferen

ceTu

mortype

Exe

rcisemodality

Intratum

oral

System

icPotentialim

plications

Progression

Dan

eryd

etal.,1995

51Carcino

gen

-ind

uced

ors.c.

leyd

igcelltran

splant

Voluntarywhe

elrunn

ing

-None

reported

-EXno

rmalized

insulin

sensitivityco

mpared

toSED

Refl

ects

metab

olic

adap

tations

topreve

nthy

po-orhy

perglycemia,w

hich

may

dev

elop

incancer

patients.

-EX"s

keletalm

usclemetab

olism

-EXattenu

ated

#ofreve

rsetriio

dothyronine

secretionbythethyroid

-EX"i

nsulin:glucagonratio

-EX#c

orticosterone

Dan

eryd

etal.,1995

52s.c.leyd

igcelltran

splant

Voluntarywhe

elrunn

ing

-EX1.3

1-fold

"intumorcellen

ergycharge

anduricacid

conten

t-N

one

reported

.Uricacid

hassincebee

nshownto

stim

ulate

den

driticcellactiva

tion,

andiselev

ated

intumors

withan

ti-tum

orim

mun

eresponses

Zhu

etal.,20

08

42

Carcino

gen

-ind

uced

mam

marytumor

Voluntarywhe

elrunn

ing

-EXactiva

tedAMPK

#Insulin,IGF-1,C

RP,lep

tinan

destrad

iol

EXincrea

sescellmetab

olism

andskew

sthe

BCL-2family

mem

ber

protein

profile

pro-

apoptotic.

-EX#V

EGF

"Corticosterone

-EX#B

cl-2,X

-linkedinhibitorofap

optosis

pathw

ay(XIAP)while

"Bax,a

poptosis

pep

tidase-activating

factor-1

Jone

set

al.,20

1057

Ortho

topicmam

marytumor

Voluntarywhe

elrunn

ing

-EX"p

erfusedve

sselsan

dHIF-1protein

leve

ls-N

one

reported

Improvedtumorperfusion,

oxygen

ation

Yan

andDem

ars,20

1164

s.c.lung

tumortran

splant

Voluntarywhe

elrunn

ing

-None

reported

.-Tum

orpresence"p

lasm

aVEGF,P

DGF-AB,

MCP-1.

VEGFexpressionha

sbee

nlinkedto

worse

outco

mein

patients,but

couldinstea

drepresent

improve

dmicrove

sselden

sity

and

vascular

norm

alizationin

tumors.

-Run

ning

:#plasm

ainsulin

andleptin,

"ad

ipone

ctin,"

plasm

aVEGF.

Jone

set

al.,20

1255

Ortho

topicprostatetumor

Voluntarywhe

elrunn

ing

-EX"v

ascularization,stab

ilizationofH

IF-1a

!40%

"regulationofVEGF

-"activity

ofproteinkina

seswithinMEK/M

APK

andPI3/m

TOR

Improvedtumorperfusion/oxygen

ation

-Exp

ressionofprometastaticgen

eswas

significantly

modulated

inexercising

anim

alswithashifttowardreduced

metastasis

Man

net

al.,20

1031

Carcino

gen

-ind

uced

mam

marytumor

Voluntaryno

n-motorizedor

motorizedwhe

elrunn

ing

-None

reported

-Ind

uced

citratesyntha

seactivity

Refl

ects

training

response

Zhu

etal.,20

1243

Carcino

gen

-ind

uced

mam

marytumor

Voluntarywhe

elrunn

ingat

afixed

daily

distance

-None

reported

-#Insulin-likegrowth

factor-1(IGF-1),insulin,

interleu

kin-6,serum

amyloid

protein,T

NFa

,an

dleptin

Increa

sedtumoricidal

immun

eresponse

-"IGF-bindingprotein

3(IGFBP-3)an

dad

ipone

ctin

Westerlindet

al.,20

03

37Carcino

gen

-ind

uced

mam

marytumor

Forced

trea

dmill

runn

ing

-None

reported

-"h

eartan

dsoleus

weights

Refl

ects

training

response

Zielinskie

tal.,20

04

44

s.c.ne

oplasticlympho

idcell

tran

splant

Forced

trea

dmill

runn

ing

-Nodifferenceinthefluidco

nten

toftum

or

-None

reported

Altered

immun

eresponse;

future

analysisof

macropha

gesubsets

wouldbeben

eficial

tothefield

-EX#i

nve

ssel

den

sity

-EX#i

nflam

matory

cells

(macropha

ges

andne

utrophils)but

increa

sed

lympho

cytes

Zhu

etal.,20

09

41

Carcino

gen

-ind

uced

mam

marytumor

Forced

whe

elrunn

ing

-Apoptosisinduced

viamitochond

rial

pathw

ayin

EX

-None

reported

EXpromotestumorcellap

optosisan

dpreve

nts

proliferations

andan

giogen

esis

-Cellcycleprogressionsuppressed

atG(1)/

Stran

sitionin

EX

-EX#b

loodve

ssel

den

sity.

(Continue

donthefollowingpag

e)

Ashcraft et al.





Table

4.Mecha

nistic

results(Cont'd)

Mec

hanistic

find

ings

Stud

yReferen

ceTu

mortype

Exe

rcisemodality

Intratum

oral

System

icPotentialim

plications

Gue

ritatet

al.,20

1469

s.c.prostatetumor

tran

splant

Forced

trea

dmill

runn

ing

-EXdecreased

tumorcellproliferation

(Ki67staining

),p-ERK/ERKratioan

d8-

OHdG

-None

reported

ERKpho

spho

rylationisincrea

sedbyoxidative

stress

-Nodifferencein

tumorSOD,p

rotein

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Although changes in glucocorticoids have been seen using allexercise modes and intensities, such considerations may be espe-cially important when investigating the effects of high-intensity orhigh-volume exercise treatment doses. This is relevant because, asreviewed here, studies have tested the effects of exhaustive exercisedoses (ref. 40; e.g., forced swimming for 4 hours followed by 12hours of physical activity; ref. 54), or forced swimming of animalsloaded with external weights (30, 32, 47). The latter exerciseparadigms may have additional safety and ethical concerns.Indeed, one study investigating the effect of forced swimmingreported four animal deaths due to drowning (30). Researchersshould also be cognizant of the impact of the exercise on theanimals' natural circadian rhythms. Fuss and colleagues demon-strated that voluntary wheel running occurs predominantly dur-ing the animals' dark cycle (78), therefore it would be prudent toconduct exercise training during the dark cycle. Regardless ofexercise prescription, corticosterone analysis would be helpful toinclude in all study designs; such levels could be correlated withtumor growth endpoints. In this review, three studies analyzedsystemic corticosterone levels (42, 48, 51); of these, two studies

reported increases in corticosterone levels, whereas the otherstudy reported a decrease. Interestingly, tumor growth was inhib-ited in all studies.

Exercise dose (intensity, session duration, frequency of training, andlength of treatment). Exercise at different intensities confersremarkably different physiologic and gene expression adaptationsin mammals (83); however, a key question is whether thesedifferences translate into differential effects on tumor outcomes.In clinical trials, the efficacy of different exercise intensities varyingfrom 50% to 100% of a patient-derived physiologic parameter(e.g., age-predictedmaximumheart rate,measured exercise capac-ity) have been investigated. Such an approach permits personal-ized exercise prescriptions, which is important because exerciseabilities (and therefore appropriate exercise intensity) vary con-siderably in patients with cancer (83). Animal-specific exerciseprescriptions are challenging to implement in preclinical studies,but could be important, as findings reviewed here suggest thatexercise intensity may differentially modulate tumor endpoints.For example, using a transgenic model of p53þ/� MMTV-Wnt-1,

© 2016 American Association for Cancer Research

Immune response: Altered phagocytic cell infiltrationand activity, depending on exercise intensity,decreased IL-6

Metabolism: Increased ALP, decreased GGT,serum prolactin, liver TAG, VLDL secretion,

ApoB and MTB; altered fatty acidmetabolism

Redox environment: Decreased proteinoxidation in the liver

Immune response: Decreased IL-6, TNFα;Increased lymphocyte IFNγ, IL-2, IL-12 TNFα,

TH1 phenotype,

Signal cascades: Increased MEK/MAPK pathwaykinases, decreased VEGF

Immune response: Increased splenic NKand LAK cell activity

Metabolism: Increased insulin:glucagon ratio,IGFBP-3, adiponectin, decreased insulin, IGF-1, CRP,

leptin, estradiol, adiponectin, serum amyloid protein,

Immune response: Decreased macrophageH2O2 production, increased macrophage

phagocytosis and lymphocyte proliferation,decreased serum IL-6 and MP-1

Metabolism: Impaired glucose and glutaminemetabolism

Tumor physiology: Increased MVD and vesselmaturity; increased VEGF; increased tumor cellapoptosis; decreased tumor cell proliferation

Signal cascades: Increased Bax, APAF-1,Ras, IκB, Bcl-2, XIAP., decreased pERK:ERKratio

Gene expression: Decreased prometastatic geneexpression

Signal cascades: Increased p53, Bax, Bakand cleaved caspase 3

Immune response: Increased lymphocytes,decreased macrophages and neutrophils

Tumor physiology: Increased activated AMPK,perfused vessels, Hif-1, 8-OHdG; decreasedcell cycle progression and MCT1 and CD147expression. VEGF reported as both increasedand decreased

Intratumoral Systemic

Metastasis

Progression

Prevention

Figure 1.

Postulated intratumoral and systemic mechanisms underlying exercise oncology across the cancer continuum. Note that few reports combined measurements intumor with systemic changes. The link between intratumoral changes and systemic changes is largely unknown.


Ashcraft et al.




Colbert and colleagues found that exposure to forced treadmilltraining of different intensities accelerated tumor growth ratecompared with sedentary controls, with the highest tumormultiplicity in the lowest intensity group (26). Conversely,Almeida and colleagues reported diminishing returns in thecontext of increasing exercise intensity using two differentswimming intensities (50% or 80% of maximal workload;CT50 and CT80, respectively, defined using a maximum loadtest conducted one week prior to exercise initiation; ref. 47).CT50 caused significant tumor growth inhibition, whereas CT80was ineffective. Using a model of forced treadmill running,Woods and colleagues compared the effects of "moderate"versus "exhaustive" exercise prescriptions, with no differencesin mammary tumor growth or overall incidence (40). In con-trast, Malicka and colleagues reported a trend towards a neg-ative correlation between exercise intensity [varied by progres-sively adjusting the speed of the treadmill (low: 0.48–1.34 km/h, moderate: 0.6–1.68 km/h, high: 0.72–2.0 km/h)] and tumorincidence and multiplicity, as well as an increase in tumor cellapoptosis across all exercise prescriptions, compared with con-

trols (45). Kato and colleagues examined duration of prescrip-tion of forced treadmill running using a nitrilotriacetate-induced renal carcinoma model. Rats were assigned to exerciseexposure for either 12 weeks or 40 weeks (29). Twelve weeks ofexercise increased microcarcinoma incidence and multiplicitycompared with sedentary controls with no differences (com-pared with control) in 40 weeks of exercise.

Schedule of exercise exposure.A critical question is whether exerciseexposure prior to diagnosis improves disease outcomes comparedwith inactivity (prior to diagnosis). Similarly, do previouslysedentary patients initiating exercise after diagnosis have superioroutcomes compared with those having sedentary or decreasingexercise levels after diagnosis? Exploratory findings from epide-miologic studies suggest that timing or initiation of exerciseexposure could be important (84). Two studies have empiricallyinvestigated this question: Betof and colleagues and Shalamzariand colleagues found that exercise initiated after tumor trans-plantation (equivalent to postdiagnosis setting) inhibitedtumor growth, independent of exposure to exercise prior to

© 2016 American Association for Cancer Research

Mediators of exerciseresponse

Implicated systemic ‘Host’pathways

Potential tumormicroenvironment targets

• Skeletal muscle• Bone marrow• Adipose tissue• Other organs (e.g., liver)

• Angiogenesis and vessel maturity• Apoptosis• Cell signaling• DNA synthesis and repair• Epithelial-mesenchymal transition and metastasis• Immune cell infiltration• Metabolism• Oxidative balance• Proliferation• Steroid receptors• Stromal interactions

• Metabolism (insulin, glucose, IGF-1, IGFBPs)• Oxidative balance (reactive oxygen species, NO)• Immune surveillance (NK cells, T-regs, macrophages)• Inflammation / cytokines (VEGF, Interleukins, SDF-1, TNFα)• Sex Hormones (estrogen, androgens)• Stress response (corticosteroids, catecholamines)

Figure 2.

Hypothesized pathways by which endurance exercise may impact tumor progression and metastasis. Key host tissues such as skeletal muscle, adipose tissue,bone marrow, and the liver mediate the effect of exercise on a variety of systemic pathways. Exercise-induced alterations in systemic and circulatingfactors, in turn, influences ligand availability in the tumor microenvironment, which alters cellular signaling modulating the hallmarks of cancer.






transplantation (65, 67). Similarly, Radak and colleagues foundslower tumor growth with exercise pre- as well as post-tumorimplantation in comparison with no exercise after transplant orsedentary control (61). Such findings stress the importance ofmaintaining exercise after diagnosis. Finally, whether the effects ofexercise are different across the steps in the metastatic cascade[altered adhesion (invasion); intravasation; survival in the circu-lation; extravasation, and seeding at a distant site (metastaticcolonization; ref. 85)] has not been investigated. Addressing thisquestion has significant clinical implications, and further researchin this area is warranted.

Common methodologic/experimental weaknessesSeveral salient methodologic issues across studies were iden-

tified (see Table 5). Of these, two common issues that requireparticular attention regarded selection of appropriate in vivotumor models, and lack of mechanistic studies.

In vivo tumor models. Preclinical oncology studies have generallyfocused on subcutaneous tumor implantation models. Thesemodels permit monitoring of tumor growth kinetics but do notaccurately recapitulate the tissuemicroenvironment of the ectopic(orthotopic) or distant organ or mimic the natural evolution ofcancer. In addition, blood flow to subcutaneous tumors may notreflect that of orthotopic tumors. As the benefits/risks of usingsubcutaneousmodels are beyond the scope of this review, herewewill simply caution investigators against using subcutaneoustumors. This model is not a perfect surrogate for spontaneouslyoccurring tumors.

The majority of studies reviewed herein investigated the effectsof exercise on tumor growth characteristics in the primary organsite. In contrast, studies ofmetastasis, the primary cause of cancer-related death, has received limited attention to date. In addition,73% of the metastasis studies we reviewed used an intravenous(tail-vein) injection of tumor cells as amodel ofmetastasis, whichevaluates the ability of tumor cells to survive in circulation and tocolonize an organ but does not enable investigation of the earlysteps in themetastatic cascade (86). Indeed, three studies reportedon tumor cell retention in the lungs following intravenous injec-tion (71, 72, 74), with two studies reporting a decrease in tumor

cell retention in exercising animals, but no change in the finalnumber of metastases. Interestingly, MacNeil and colleaguesreported that exercise did not affect tumor cell retention in thelung. These three studies differed with respect to type of exerciseand number of tumor cells injected; thus nomeaningful compar-isons canbemadebetween them. The impact of themethodologicdifferences can only be evaluated by completing the studies-side-by-side, comparing all combinations of exercise/tumor inocula-tion models.

An alternative, and arguablymore appropriatemodel ofmetas-tasis, is surgical excision of the primary tumor, which stimulatesspontaneous metastasis, predominantly to the lungs; only onestudy to date (Yan and colleagues) has adopted this model toexamine exercise effects (64) and they reported a trend towards aninverse relationship between distance run andmetastatic burden.Conversely, Jones and colleagues examined the metastasisresponse in a prostate cancer model by quantifying the mass of"non-contiguous external masses that were grossly visible inde-pendent from the primary prostate tissue." In this model, exercisewas not associated with a significant reduction in the number orweight of metastases (55).

Emerging technology has provided researchers with a consid-erable number of in vivomodels beyond cell line xenografts, suchas patient-derived xenografts (PDX), syngeneic allografts, andGEMMs (87), as well as nonrodent models (e.g., zebrafish,Drosophila). The advantages and disadvantages of each modelhave been reviewed elsewhere (88–91). Ultimately, no one in vivomodel will be appropriate to address all exercise–oncology ques-tions, with model selection being contingent on the scientificquestion at hand as well as translational importance.

The importance of appropriate control groups.Consideration of thenature of control (nonexercising) groups should not be over-looked. To the extent possible, control animals should be exposedto the same variables as exercise counterparts including aspectsrelated to housing, transportation to different facilities, or pro-cedures to reinforce exercise behavior (i.e., prodding, shock).Taken even further, animals could be housed in cages with lockedwheels, placed on stationary treadmills, or made to stand in veryshallow pools of water, depending upon the exercise regimens

Table 5. Recommendations for preclinical exercise oncology research

Concern Recommendation

Use of xenograft models in immunodeficit animals Orthotopic implantation of syngeneic tumor cell lines or induction of orthotopic tumors viatransgenic or chemical methods in immunocompetent animals

Poor description of exercise intervention characteristics Describe frequency, intensity, duration, and progression, as appropriate. Avoid vague terms suchas "exercise to exhaustion." Confirmation of "training" effect via muscle fiber or mitochondrialfunction analysis

Handling of control (sedentary) animals Handling, social interaction, and environment should be similar to animals randomized to exerciseconditions. This includes differences in cage size and social housing. If possible, animals shouldbe acclimated to exercise, or introduced to the activity gradually.

Tail vein models of metastasis Consider using orthotopic implantation of syngeneic tumor cell lines or transgenic models thatspontaneously develop metastasis. However, tail vein models of metastasis may still be usefulfor assessing the effects of exercise at later time points in the metastatic cascade.

Lack of assessment of systemic and molecular mechanisms Investigate effects on systemic mechanisms (metabolic and sex hormones, inflammation,immunity, andproducts of oxidation) postulated to underlie effects of exercise on tumorigenesisas well as potential mediating molecular mechanisms (e.g., cell signaling pathways,angiogenesis, metabolism, migration). Findings should be validated by the use of knock-out/knock-in transgenic animals.

Lack of assessment of tumor biology beyond tumorincidence, weight, or volume

Report on other common markers of the neoplastic phenotype (e.g., apoptosis, proliferation,microvessel density, necrosis, angiogenesis)

Lack of concern regarding the psychologic differencesbetween voluntary physical activity vs. forced exercise

Comprehensive study on hypothalamic–pituitary–adrenal axis activation in response to differentexercise prescriptions and the effects that associated hormones have on tumor progression/prevention in sedentary controls.

Ashcraft et al.





used. We stress that exposing control and experimental mice todifferent housing or environmental conditions is a study weak-ness. For example, one study housed control animals in unusuallysmall cages (5 inches in diameter and 6 inches high) to restrictactivity (54), whereas exercise treatment animals were not con-fined. The differences in housing size and daily movement couldhave either induced a stress response or altered the animals'resting metabolism, thereby affecting tumor growth. We adviseresearchers reviewing extant publications for planning of theirown exercise oncology studies to consider whether controls wereproperly handled beforemodeling their ownwork off of previousstudies.

Mechanistic studies/analyses. The majority of studies reviewedhere examined the effects of exercise on tumor growth char-acteristics as evaluated by tumor volume or growth rates. Whilesuch endpoints are clearly important, subtle but importantmodulations of intratumoral physiologic or biological altera-tions can be masked. For instance, our group observed differ-ences in perfusion and expression of key factors regulatingmetabolism and hypoxia, despite comparable primary tumorgrowth rates between exercised and sedentary animals (57).Elegant studies by McCollough and colleagues demonstratedthat exercise improved blood flow and oxygen delivery toorthotopic prostate tumors in rats, but not to the normalprostate tissue in either tumor-bearing or control rats (92).These changes were reflected by decreased hypoxia within thetumor during exercise. While in-depth explications of thesystemic or local molecular mechanisms underpinning theexercise–tumor prevention/progression relationship remainsin its infancy, studies such as this one may set the precedentfor future mechanistic studies in this field (Fig. 2). The currentworking hypothesis is that exercise modulates tumor progres-sion via modulation of the host–tumor interaction (19). Tumorprogression is regulated by complex, multifaceted interactionsbetween the systemic milieu (host), tumor microenvironment,and cancer cells (93). The microenvironments of primary andmetastatic tumors are subject to modulation by systemic andlocal growth/angiogenic factors, cytokines, hormones, and res-ident cells (94, 95). Factors such as hepatocyte growth factor(HGF), TNF, IL6, insulin, and leptin (96–98) have already beenassociated with higher risk of recurrence and cancer-specificmortality in a number of solid malignancies.(99) Clearly,manipulation of such factors by physical activity could alteraspects of the cancer continuum (100).

As reviewed here, multiple systemic factors are perturbed byexercise, including metabolism, inflammatory–immune, andreactive oxygen species–mediated pathways (101). The breadthof these factors likely contributes to the pleiotropic benefits ofexercise in health and disease (102, 103) and likely the poten-tial antitumor effects of exercise. (19) Notably, most cancerstudies investigate single pathways in isolation, without con-sideration of overlap/synergism between pathways. Because thehost–tumor interaction is modulated by numerous host-relatedfactors and multiple pathways (100), an ideal study approachwould be to investigate exercise effects on multiple pathwayssimultaneously (Fig. 2). This would fill in the missing gaps ofthe "multitargeted" effects of exercise. A recent analysis ofpreclinical exercise oncology studies by Pedersen and collea-gues reported that only 30.7% evaluated systemic changes inanimals (104). In addition, intratumoral signaling, and

changes in tumor vascularity were examined by only 29.5%and 6.8%, respectively (104).

Future recommendationsWith a view towards future studies, we encourage the exercise–

oncology field to consider certain guidelines for preclinical exer-cise–oncology research (see Table 5).However, we realize that it isimpractical for all exercise–oncology experiments to standardizeall study procedures. Nevertheless, it may behoove the field todevelop a means of quantifying the exercise prescription applied,which will then permit comparisons between studies. Such anapproach is readily used in the fields of radiation oncology [i.e.,the biologically equivalent dose (BED), which allows comparisonof different dose/fractionation schemes (105)] and hyperthermia[i.e., the cumulative equivalent minutes at 43�C (CEM43), whichstandardizes the thermal killing effect of hyperthermia, regardlessof variations in heating efficiencies between tumors (106)]. Estab-lishing a biological equivalent exercise dose (BEED) would facil-itate comparisons across studies as well as provide an opportunityto test elements of prescriptions such as different schedules,timing, and duration.

Exercise investigations should also strive to adopt the experi-mental procedures andmodels beingutilized in the general tumorbiology literature. Indeed, it appears that more recent studiesreviewed here have started to utilize clinically relevant tumormodels, favoring transgenic mice and orthotopic tumors overcarcinogen induction. The general cancer field is also starting tofavor the use of patient-derived xenograft (PDX) models. PDXhave certain weaknesses, including increased heterogeneity, and arequirement for immunocompromisedmice, but could representan important step towards personalized medicine. Furthermore,PDXs do not accrue additional mutations through in vitro cultureand tend to be slower growing than murine-derived tumor lines.Delayed growth curves may highlight slight changes in tumorgrowth followingmanipulations of exercise dose. GEMMs shouldalso be considered, especially in mechanistic studies. A secondtrend in cancer biology is use of biomarkers. The discovery ofblood, imaging, and/or genomic biomarker(s) to predict ormonitor exercise response is of obvious importance.

Finally, researchers must be cognizant of clinical care, anddesign studies that reflect the clinical scenario. For example, thevast majority of the current literature investigates the effects ofexercise as monotherapy. The majority of clinical scenarioswould be applying exercise as an adjuvant therapy to surgery,radiation, chemotherapy, or immunotherapies. As such, it isimportant for the next generation of preclinical studies aimingto study tumor progression to evaluate the interaction betweenexercise and the pharmacodynamic or pharmacokinetic activityof conventional and novel therapies to guide the design andinterpretation of clinical studies. We advise researchers toproceed with caution and carefully include all possible controlsgroups, because the additional therapies could introduce newconfounding factors that complicate data interpretations Con-versely, studies on tumor incidence may be strengthened byeliminating additional factors such as concomitant manipula-tion of dietary composition.

ConclusionA sound foundation of basic and translational studies will

optimize the therapeutic potential of exercise on symptom






control and clinical outcomes across the cancer continuum.Despite its importance, we found that the current evidencebase is plagued by considerable methodologic heterogeneity inall aspects of study design, endpoints, and efficacy therebyprecluding meaningful comparisons, and conclusions. To thisend, we have provided an overview of methodologic anddata reporting standards that we hope will set the platformfor the next generation of preclinical studies required for thecontinued development and progression of exercise–oncologyresearch.

Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed.

Grant SupportL.W. Jones is supported in part by grants from the National Cancer Institute,

AKTIVAgainst Cancer, and theMemorial SloanKetteringCancer Center SupportGrant/Core Grant (P30 CA008748). K.A. Ashcraft and M.W. Dewhirst aresupported by NIH CA40355.

Received April 19, 2016; accepted April 21, 2016; published OnlineFirstJuly 5, 2016.

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Ashcraft et al.




2016;76:4032-4050. Published OnlineFirst July 5, 2016.Cancer Res Kathleen A. Ashcraft, Ralph M. Peace, Allison S. Betof, et al.

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ﬁcacy and Mechanisms of Aerobic Exercise on Cancer Initiation, … · effects of exercise in cancer prevention and progression. Stud-ies were evaluated on the basis of tumor outcomes