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
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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
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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.
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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)
Exercise in Cancer Initiation, Progression, and Metastasis
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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
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.
Cancer Res; 76(14) July 15, 2016 Cancer Research4036
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
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)
Exercise in Cancer Initiation, Progression, and Metastasis
www.aacrjournals.org Cancer Res; 76(14) July 15, 2016 4037
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
Table
2.Tum
orgrowth
stud
ies(Cont'd)
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
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.
Cancer Res; 76(14) July 15, 2016 Cancer Research4038
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
Table
2.Tum
orgrowth
stud
ies(Cont'd)
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
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.
Exercise in Cancer Initiation, Progression, and Metastasis
www.aacrjournals.org Cancer Res; 76(14) July 15, 2016 4039
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
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.
Cancer Res; 76(14) July 15, 2016 Cancer Research4040
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
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)
Exercise in Cancer Initiation, Progression, and Metastasis
www.aacrjournals.org Cancer Res; 76(14) July 15, 2016 4041
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
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.
Cancer Res; 76(14) July 15, 2016 Cancer Research4042
on January 31, 2021. © 2016 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from
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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
carbony
lationorlip
idoxidattion
Ave
sehet
al.,20
1568
Ortho
topicmam
marytumor
Forced
trea
dmill
runn
ing
-EXshiftedtumorlactatedeh
ydrogen
ase
expressiontowardstheLD
H1isoen
zyme
-None
reported
AshifttowardsLD
H-1may
signa
lred
uced
lactateco
ncen
trations
inthetumor.La
ckof
MCT1may
resultin
thetumorcells
utilizing
gluco
seinstea
doflactose,a
ndev
entually
starving
thetumorcells.C
D147isrequiredfor
MCT1expression
-EXdecreased
tumormono
carboxylate
tran
sporter
1(M
CT1)an
dCD147
expression.
Rad
aket
al.,20
02
61
s.c.solid
leuk
emiatran
splant
Swim
ming
-ECtumorsha
d"R
asproteinco
mpared
toco
ntrol.
-None
reported
May
beassociated
withlympho
cyte
proliferationan
dactivity,b
utad
ditiona
lan
alyses
arene
eded
-ECtumors
had"I-kBproteinthan
ETan
dco
ntrol.
Abdalla
etal.,20
1323
Carcino
gen
-ind
uced
mam
marytumor
Swim
ming
-None
reported
.-Phy
sicalactivity"lym
pho
cytesproducingIFN-
g,IL-2,
IL-12,
andTNFa.
Increa
sedtumoricidal
immun
eresponse
-Phy
sicala
ctivitypromotedim
mun
esystem
polarizationtowardan
antitumorTh1
response
pattern
profile.
Metastasis
MacNeil
etal.,1993a
74i.v.injectionoftran
sform
edfibroblasts
Forced
trea
dmillor
voluntarywhe
elrunn
ing
-None
reported
.-W
heelgroup
"splenicNKresponsevs.control.
Increa
sedtumoricidal
immun
eresponse
Hoffman
n-Goetzet
al.,
1994a
71i.v.injectionoftran
sform
edfibroblasts
Voluntarywhe
elrunn
ing
-None
reported
.-Run
ning
#reco
very
ofradioactivity
from
liver,
spleen
andkidne
yat
30min
and90min
post-
injection.
May
reflectdecreased
retentionofcirculating
tumorcells
inorgan
s,thereb
yloweringthe
risk
ofmetastasis.
Hoffman
-Goetzet
al.,
1994b
70i.v.injectionofmam
mary
tumorcells
Forced
trea
dmill
runn
ingorvo
luntary
whe
elrunn
ing
-None
reported
-Pre-tum
orEX"L
AKcellactivity.
Increa
sedtumoricidal
immun
eresponse
-NKactivity
lower
inan
imalsthat
stopped
EXat
tumorinjection.
Jadeski
andHoffman
-Goetz,1996
72i.v.injectionoftran
sform
edfibroblasts
Forced
trea
dmill
runn
ing
-None
reported
-EX"c
itrate
syntha
seactivity
inthesoleus.
Indicates
atraining
effect
dev
eloped
Higgins
etal.,20
1475
i.v.injectionoflung
tumor
cells
Voluntarywhe
elrunn
ing
-EXtumorsha
dincrea
sedleve
lsofp
53,Bax
andBak.
-EXincrea
sedserum
BUNan
ddecreased
ALT
,but
both
werestillwithinno
rmal
rang
esSup
portsincrea
sedap
optosisoftumorcells
-EXtumors
hadincrea
sedstaining
for
clea
vedcaspase-3
Exercise in Cancer Initiation, Progression, and Metastasis
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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.
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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.
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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.
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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
Exercise in Cancer Initiation, Progression, and Metastasis
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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.
References1. Booth FW, Gordon SE, Carlson CJ, HamiltonMT.Waging war onmodern
chronic diseases: primary prevention through exercise biology. J ApplPhysiol 2000;88:774–87.
2. Giannuzzi P,Mezzani A, Saner H, BjornstadH, Fioretti P, MendesM, et al.Physical activity for primary and secondary prevention. Position paper ofthe Working Group on Cardiac Rehabilitation and Exercise Physiology ofthe European Society of Cardiology. Eur J Cardiovasc Prev Rehabil2003;10:319–27.
3. Hawley JA, Hargreaves M, Joyner MJ, Zierath JR. Integrative biology ofexercise. Cell 2014;159:738–49.
4. Warburton DE, Nicol CW, Bredin SS. Health benefits of physical activity:the evidence. CMAJ 2006;174:801–9.
5. Jones LW, Alfano CM. Exercise-oncology research: past, present, andfuture. Acta oncologica 2013;52:195–215.
6. FriedenreichCM,WoolcottCG,McTiernanA,Ballard-BarbashR, Brant RF,Stanczyk FZ, et al. Alberta physical activity and breast cancer preventiontrial: sex hormone changes in a year-long exercise intervention amongpostmenopausal women. J Clin Oncol 2010;28:1458–66.
7. Lynch BM, Friedenreich CM, Winkler EA, Healy GN, Vallance JK, EakinEG, et al. Associations of objectively assessed physical activity andsedentary time with biomarkers of breast cancer risk in postmenopausalwomen: findings from NHANES (2003–2006). Breast Cancer Res Treat2011;130:183–94.
8. Gammon MD, Schoenberg JB, Britton JA, Kelsey JL, Coates RJ, Brogan D,et al. Recreational physical activity and breast cancer risk among womenunder age 45 years. Am J Epidemiol 1998;147:273–80.
9. Bernstein L, Henderson BE, Hanisch R, Sullivan-Halley J, Ross RK.Physical exercise and reduced risk of breast cancer in young women.J Natl Cancer Inst 1994;86:1403–8.
10. Byers T, Nestle M, McTiernan A, Doyle C, Currie-Williams A, Gansler T,et al. American Cancer Society guidelines on nutrition and physicalactivity for cancer prevention: Reducing the risk of cancer with healthyfood choices and physical activity. CA Cancer J Clin 2002;52:92–119.
11. Kushi LH, Doyle C, McCullough M, Rock CL, Demark-Wahnefried W,Bandera EV, et al. American Cancer Society Guidelines on nutritionand physical activity for cancer prevention: reducing the risk of cancerwith healthy food choices and physical activity. CA Cancer J Clin2012;62:30–67.
12. Friedenreich CM, Neilson HK, O'Reilly R, Duha A, Yasui Y, Morielli AR,et al. Effects of a high vs.moderate volumeof aerobic exercise on adiposityoutcomes in postmenopausal women: a randomized clinical trial. JAMAOncol 2015;1:766–76.
13. Irwin ML, Yasui Y, Ulrich CM, Bowen D, Rudolph RE, Schwartz RS,et al. Effect of exercise on total and intra-abdominal body fat inpostmenopausal women: a randomized controlled trial. JAMA 2003;289:323–30.
14. McTiernan A, Ulrich CM, Yancey D, Slate S, Nakamura H, Oestreicher N,et al. The Physical Activity for Total Health (PATH) Study: rationale anddesign. Med Sci Sports Exerc 1999;31:1307–12.
15. Campbell KL, McTiernan A, Li SS, Sorensen BE, Yasui Y, Lampe JW, et al.Effect of a 12-month exercise intervention on the apoptotic regulatingproteins Bax and Bcl-2 in colon crypts: a randomized controlled trial.Cancer Epidemiol Biomarkers Prev 2007;16:1767–74.
16. Mishra SI, Scherer RW, Geigle PM, Berlanstein DR, Topaloglu O, GotayCC, et al. Exercise interventions on health-related quality of life for cancersurvivors. Cochrane Database Syst Rev 2012;8:CD007566.
17. Schmitz KH, Holtzman J, Courneya KS, Masse LC, Duval S, Kane R.Controlled physical activity trials in cancer survivors: a systematicreview and meta-analysis. Cancer Epidemiol Biomarkers Prev 2005;14:1588–95.
18. Jones LW,DewhirstMW. Therapeutic properties of aerobic training after acancer diagnosis: more than a one-trick pony? J Natl Cancer Inst 2014;106:dju042.
19. Betof AS, Dewhirst MW, Jones LW. Effects and potential mechanisms ofexercise training on cancer progression: a translational perspective. BrainBehav Immun 2013;30Suppl:S75–87.
20. Ballard-BarbashR, FriedenreichCM,CourneyaKS, Siddiqi SM,McTiernanA, Alfano CM. Physical activity, biomarkers, and disease outcomes incancer survivors: a systematic review. JNatl Cancer Inst 2012;104:815–40.
21. Gorski DH. Integrative oncology: really the best of both worlds? Nat RevCancer 2014;14:692–700.
22. Jones LW. Precision oncology framework for investigation of exercise astreatment for cancer. J Clin Oncol 2015;33:4134–7.
23. Abdalla DR, Murta EF, Michelin MA. The influence of physical activity onthe profile of immune response cells and cytokine synthesis in mice withexperimental breast tumors induced by 7,12-dimethylbenzanthracene.Eur J Cancer Prev 2013;22:251–8.
24. Alessio HM, Schweitzer NB, Snedden AM, Callahan P, Hagerman AE.Revisiting influences on tumor development focusing on laboratoryhousing. J Am Assoc Lab Anim Sci 2009;48:258–62.
25. Andrianopoulos G, Nelson RL, Bombeck CT, Souza G. The influence ofphysical activity in 1,2 dimethylhydrazine induced colon carcinogenesisin the rat. Anticancer Res 1987;7:849–52.
26. Colbert LH, Westerlind KC, Perkins SN, Haines DC, Berrigan D, Done-hower LA, et al. Exercise effects on tumorigenesis in a p53-deficientmousemodel of breast cancer. Med Sci Sports Exerc 2009;41:1597–605.
27. Esser KA, Harpole CE, Prins GS, Diamond AM. Physical activityreduces prostate carcinogenesis in a transgenic model. Prostate 2009;69:1372–7.
28. Ikuyama T, Watanabe T, Minegishi Y, Osanai H. Effect of voluntaryexercise on 30-methyl-4-dimethylaminoazobenzene-induced hepatomasin male Jc1:Wistar rats. Proc Soc Exp Biol Med 1993;204:211–5.
29. Kato T, Kawaguchi H, Miyoshi N, Aoyama K, Komatsu M, Horiuchi M,et al. Effect of habitual exercise on renal carcinogenesis by ferric nitrilo-triacetate. Environ Health Prev Med 2011;16:232–8.
30. Lunz W, Peluzio MC, Dias CM, Moreira AP, Natali AJ. Long-term aerobicswimming training by rats reduces the number of aberrant crypt foci in1,2-dimethylhydrazine-induced colon cancer. Braz J Med Biol Res2008;41:1000–4.
31. Mann PB, Jiang W, Zhu Z, Wolfe P, McTiernan A, Thompson HJ. Wheelrunning, skeletal muscle aerobic capacity and 1-methyl-1-nitrosoureainduced mammary carcinogenesis in the rat. Carcinogenesis 2010;31:1279–83.
32. Paceli RB, Cal RN, dos Santos CH, Cordeiro JA, Neiva CM, Nagamine KK,et al. The influence of physical activity in the progression of experimentallung cancer in mice. Pathol Res Pract 2012;208:377–81.
Ashcraft et al.
Cancer Res; 76(14) July 15, 2016 Cancer Research4048
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
33. Reddy BS, Sugie S, Lowenfels A. Effect of voluntary exercise on azoxy-methane-induced colon carcinogenesis in male F344 rats. Cancer Res1988;48:7079–81.
34. Saez Mdel C, Barriga C, Garcia JJ, Rodriguez AB, Ortega E. Exercise-induced stress enhances mammary tumor growth in rats: beneficial effectof the hormone melatonin. Mol Cell Biochem 2007;294:19–24.
35. Sugie S, Reddy BS, Lowenfels A, Tanaka T, Mori H. Effect of voluntaryexercise on azoxymethane-induced hepatocarcinogenesis in male F344rats. Cancer Lett 1992;63:67–72.
36. Thorling EB, Jacobsen NO, Overvad K. Effect of exercise on intestinaltumour development in the male Fischer rat after exposure to azoxy-methane. Eur J Cancer Prev 1993;2:77–82.
37. Westerlind KC, McCarty HL, Schultheiss PC, Story R, Reed AH, Baier ML,et al. Moderate exercise training slows mammary tumour growth inadolescent rats. Eur J Cancer Prev 2003;12:281–7.
38. Whittal KS, Parkhouse WS. Exercise during adolescence and its effects onmammary gland development, proliferation, and nitrosomethylurea(NMU) induced tumorigenesis in rats. Breast Cancer Res Treat 1996;37:21–7.
39. Whittal-Strange KS, Chadan S, Parkhouse WS. Exercise during pubertyand NMU induced mammary tumorigenesis in rats. Breast Cancer ResTreat 1998;47:1–8.
40. Woods JA, Davis JM, Kohut ML, Ghaffar A, Mayer EP, Pate RR. Effects ofexercise on the immune response to cancer. Med Sci Sports Exerc 1994;26:1109–15.
41. Zhu Z, Jiang W, McGinley JN, Thompson HJ. Energetics and mammarycarcinogenesis: effects of moderate-intensity running and energy intakeon cellular processes and molecular mechanisms in rats. J Appl Physiol2009;106:911–8.
42. Zhu Z, Jiang W, Sells JL, Neil ES, McGinley JN, Thompson HJ. Effect ofnonmotorized wheel running on mammary carcinogenesis: circulatingbiomarkers, cellular processes, andmolecularmechanisms in rats. CancerEpidemiol Biomarkers Prev 2008;17:1920–9.
43. Zhu Z, Jiang W, Zacher JH, Neil ES, McGinley JN, Thompson HJ. Effectsof energy restriction and wheel running on mammary carcinogenesisand host systemic factors in a rat model. Cancer Prev Res 2012;5:414–22.
44. Zielinski MR, Muenchow M, Wallig MA, Horn PL, Woods JA. Exercisedelays allogeneic tumor growth and reduces intratumoral inflammationand vascularization. J Appl Physiol 2004;96:2249–56.
45. Malicka I, Siewierska K, Pula B, Kobierzycki C, Haus D, Paslawska U, et al.The effect of physical training on the N-methyl-N-nitrosourea-inducedmammary carcinogenesis of Sprague-Dawley rats. Exp Biol Med2015;240:1408–15.
46. Piguet AC, Saran U, Simillion C, Keller I, Terracciano L, Reeves HL, et al.Regular exercise decreases liver tumors development in hepatocyte-spe-cific PTEN-deficient mice independently of steatosis. J Hepatol2015;62:1296–303.
47. Almeida PW, Gomes-Filho A, Ferreira AJ, Rodrigues CE, Dias-PeixotoMF,Russo RC, et al. Swim training suppresses tumor growth in mice. J ApplPhysiol 2009;107:261–5.
48. Bacurau AV, Belmonte MA, Navarro F, Moraes MR, Pontes FLJr, PesqueroJL, et al. Effect of a high-intensity exercise training on themetabolism andfunction of macrophages and lymphocytes of walker 256 tumor bearingrats. Exp Biol Med (Maywood) 2007;232:1289–99.
49. Bacurau RF, Belmonte MA, Seelaender MC, Costa Rosa LF. Effect of amoderate intensity exercise training protocol on the metabolism ofmacrophages and lymphocytes of tumour-bearing rats. Cell BiochemFunct 2000;18:249–58.
50. Baracos VE. Exercise inhibits progressive growth of the Morris hepatoma7777 inmale and female rats. Can J Physiol Pharmacol 1989;67:864–70.
51. Daneryd P, Hafstrom L, Svanberg E, Karlberg I. Insulin sensitivity, hor-monal levels and skeletal muscle protein metabolism in tumour-bearingexercising rats. Eur J Cancer 1995;31A:97–103.
52. Daneryd P,Westin T, EdstromS, Soussi B. Tumour purine nucleotides andcell proliferation in response to exercise in rats. Eur J Cancer1995;31a:2309–12.
53. Gershbein LL, Benuck I, Shurrager PS. Influence of stress of lesion growthand on survival of animals bearing parenteral and intracerebral leukemiaL1210 and Walker tumors. Oncology 1974;30:429–35.
54. Hoffman SA, Paschkis KE, Debias DA, Cantarow A, Williams TL. Theinfluence of exercise on the growth of transplanted rat tumors. Cancer Res1962;22:597–9.
55. Jones LW, Antonelli J, Masko EM, Broadwater G, Lascola CD, Fels D, et al.Exercise modulation of the host-tumor interaction in an orthotopicmodel of murine prostate cancer. J Appl Physiol 2012;113:263–72.
56. Jones LW, Eves ND, Courneya KS, Chiu BK, Baracos VE, Hanson J, et al.Effects of exercise training on antitumor efficacy of doxorubicin in MDA-MB-231 breast cancer xenografts. Clin Cancer Res 2005;11:6695–8.
57. Jones LW, Viglianti BL, Tashjian JA, Kothadia SM, Keir ST, Freedland SJ,et al. Effect of aerobic exercise on tumor physiology in an animalmodel ofhuman breast cancer. J Appl Physiol 2010;108:343–8.
58. Lira FS, Tavares FL, Yamashita AS, Koyama CH, Alves MJ, Caperuto EC,et al. Effect of endurance training upon lipid metabolism in the liver ofcachectic tumour-bearing rats. Cell Biochem Funct 2008;26:701–8.
59. Murphy EA, Davis JM, Barrilleaux TL,McClellan JL, Steiner JL, CarmichaelMD, et al. Benefits of exercise training on breast cancer progression andinflammation in C3(1)SV40Tag mice. Cytokine 2011;55:274–9.
60. Newton G. Tumor susceptibility in rats: role of infantile manipulationand later exercise. Psychol Rep 1965;16:127–32.
61. Radak Z, Gaal D, Taylor AW, Kaneko T, Tahara S, Nakamoto H, et al.Attenuation of the development of murine solid leukemia tumor byphysical exercise. Antioxid Redox Signal 2002;4:213–9.
62. Sasvari M, Taylor AW, Gaal D, Radak Z. The effect of regular exercise ondevelopment of sarcoma tumor and oxidative damage in mice liver.J Sports Sci Med 2011;10:93–6.
63. Uhlenbruck G, Order U. Can endurance sports stimulate immunemechanisms against cancer and metastasis? Int J Sports Med1991;12Suppl 1:S63–8.
64. Yan L, Demars LC. Effects of non-motorized voluntary running onexperimental and spontaneous metastasis in mice. Anticancer Res2011;31:3337–44.
65. BetofAS, LascolaCD,WeitzelD, LandonC, ScarbroughPM,DeviGR, et al.Modulation of murine breast tumor vascularity, hypoxia and chemother-apeutic response by exercise. J Natl Cancer Inst 2015;107:djv040. doi:10.1093/jnci/djv040.
66. Goh J, Endicott E, Ladiges WC. Pre-tumor exercise decreases breast cancerin old mice in a distance-dependent manner. Am J Cancer Res 2014;4:378–84.
67. Shalamzari SA, Agha-Alinejad H, Alizadeh S, Shahbazi S, Khatib ZK,Kazemi A, et al. The effect of exercise training on the level of tissue IL-6 andvascular endothelial growth factor in breast cancer bearing mice. Iran JBasic Med Sci 2014;17:231–58.
68. Aveseh M, Nikooie R, Aminaie M. Exercise-induced changes in tumourLDH-B and MCT1 expression are modulated by oestrogen-related receptoralpha in breast cancer-bearing BALB/c mice. J Physiol 2015;593:2635–48.
69. Gueritat J, Lefeuvre-Orfila L, Vincent S, Cretual A, Ravanat JL, Gratas-Delamarche A, et al. Exercise training combined with antioxidant sup-plementation prevents the antiproliferative activity of their single treat-ment in prostate cancer through inhibition of redox adaptation. FreeRadic Biol Med 2014;77:95–105.
70. Hoffman-Goetz L, May KM, Arumugam Y. Exercise training and mousemammary tumour metastasis. Anticancer Res 1994;14:2627–31.
71. Hoffmann-Goetz L, MacNeil B, Arumugam Y. Tissue distribution ofradiolabelled tumor cells in wheel exercised and sedentary mice. Int JSports Med 1994;15:249–53.
72. Jadeski L, Hoffman-Goetz L. Exercise and invivo natural cytotoxicityagainst tumour cells of varying metastatic capacity. Clin Exp Metastasis1996;14:138–44.
73. MacNeil B, Hoffman-Goetz L. Exercise training and tumour metastasisin mice: influence of time of exercise onset. Anticancer Res 1993;13:2085–8.
74. MacNeil B,Hoffman-Goetz L. Effect of exercise onnatural cytotoxicity andpulmonary tumor metastases in mice. Med Sci Sports Exerc 1993;25:922–8.
75. Higgins KA, Park D, Lee GY, Curran WJ, Deng X. Exercise-induced lungcancer regression: mechanistic findings from a mouse model. Cancer2014;120:3302–10.
76. Zhao G, Zhou S, Davie A, Su Q. Effects of moderate and high intensityexercise on T1/T2 balance. Exerc Immunol Rev 2012;18:98–114.
Exercise in Cancer Initiation, Progression, and Metastasis
www.aacrjournals.org Cancer Res; 76(14) July 15, 2016 4049
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
77. Roberts CJ, Stuhr KL, Hillard CJ. Swim stress differentially affects limbiccontents of 2-arachidonoylglycerol and 2-oleoylglycerol. Neuroscience2012;204:74–82.
78. Fuss J, Ben Abdallah NM, Vogt MA, Touma C, Pacifici PG, Palme R, et al.Voluntary exercise induces anxiety-like behavior in adult C57BL/6J micecorrelatingwithhippocampalneurogenesis.Hippocampus2010;20:364–76.
79. Richter SH, Gass P, Fuss J. Resting is rusting: a critical view on rodentwheel-running behavior. Neuroscientist 2014;20:313–25.
80. Hackney AC, Viru A. Twenty-four-hour cortisol response tomultiple dailyexercise sessions of moderate and high intensity. Clin Physiol 1999;19:178–82.
81. Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, et al.Chronic stress promotes tumor growth and angiogenesis in a mousemodel of ovarian carcinoma. Nat Med 2006;12:939–44.
82. Zen M, Canova M, Campana C, Bettio S, Nalotto L, Rampudda M, et al.The kaleidoscope of glucorticoid effects on immune system. AutoimmunRev 2011;10:305–10.
83. Sasso JP, Eves ND, Christensen JF, Koelwyn GJ, Scott J, Jones LW. Aframework for prescription in exercise-oncology research. J CachexiaSarcopenia Muscle 2015;6:115–24.
84. IrwinML, Smith AW,McTiernanA, Ballard-Barbash R, Cronin K,GillilandFD, et al. Influence of pre- andpostdiagnosis physical activity onmortalityin breast cancer survivors: the health, eating, activity, and lifestyle study.J Clin Oncol 2008;26:3958–64.
85. Mina LA, Sledge GWJr. Rethinking the metastatic cascade as a therapeutictarget. Nat Rev Clin Oncol 2011;8:325–32.
86. Chambers AF, Groom AC, MacDonald IC. Dissemination and growth ofcancer cells in metastatic sites. Nat Rev Cancer 2002;2:563–72.
87. Day CP,Merlino G, VanDyke T. Preclinical mouse cancer models: a mazeof opportunities and challenges. Cell 2015;163:39–53.
88. Gonzalez C. Drosophilamelanogaster: a model and a tool to investigatemalignancy and identify new therapeutics. Nat RevCancer 2013;13:172–83.
89. Gould SE, Junttila MR, de Sauvage FJ. Translational value of mousemodels in oncology drug development. Nat Med 2015;21:431–9.
90. Sharpless NE, Depinho RA. The mighty mouse: genetically engineeredmouse models in cancer drug development. Nat Rev Drug Discov2006;5:741–54.
91. White R, Rose K, Zon L. Zebrafish cancer: the state of the art and the pathforward. Nat Rev Cancer 2013;13:624–36.
92. McCullough DJ, Stabley JN, Siemann DW, Behnke BJ. Modulation ofblood flow, hypoxia, and vascular function in orthotopic prostate tumorsduring exercise. J Natl Cancer Inst 2014;106:dju036.
93. Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, et al.Tumour micro-environment elicits innate resistance to RAF inhibitorsthrough HGF secretion. Nature 2012;487:500–4.
94. McAllister SS, Gifford AM, Greiner AL, Kelleher SP, Saelzler MP, Ince TA,et al. Systemic endocrine instigation of indolent tumor growth requiresosteopontin. Cell 2008;133:994–1005.
95. McAllister SS, Weinberg RA. Tumor-host interactions: a far-reachingrelationship. J Clin Oncol 2010;28:4022–8.
96. Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Taylor SK, et al.Insulin- and obesity-related variables in early-stage breast cancer: correla-tions and time course of prognostic associations. J Clin Oncol2012;30:164–71.
97. Sheen-Chen SM, Chen WJ, Eng HL, Chou FF. Serum concentration oftumor necrosis factor in patients with breast cancer. Breast Cancer ResTreat 1997;43:211–5.
98. Sheen-Chen SM, Liu YW, Eng HL, Chou FF. Serum levels of hepatocytegrowth factor in patients with breast cancer. Cancer Epidemiol Biomar-kers Prev 2005;14:715–7.
99. Hursting SD, Berger NA. Energy balance, host-related factors, and cancerprogression. J Clin Oncol 2010;28:4058–65.
100. Glass OK, Inman BA, Broadwater G, Courneya KS, Mackey JR, Goruk S,et al. Effect of aerobic training on the host systemicmilieu in patients withsolid tumours: an exploratory correlative study. Br J Cancer 2015;112:825–31.
101. Joyner MJ, Green DJ. Exercise protects the cardiovascular system: effectsbeyond traditional risk factors. J Physiol 2009;587:5551–8.
102. Kodama S, Saito K, Tanaka S, Maki M, Yachi Y, Asumi M, et al. Cardio-respiratory fitness as a quantitative predictor of all-cause mortality andcardiovascular events in healthy men and women: a meta-analysis. JAMA2009;301:2024–35.
103. Lee IM, Shiroma EJ, Lobelo F, Puska P, Blair SN, Katzmarzyk PT, et al.Effect of physical inactivity onmajor non-communicable diseases world-wide: an analysis of burden of disease and life expectancy. Lancet2012;380:219–29.
104. Pedersen L, Christensen JF, Hojman P. Effects of exercise on tumorphysiology and metabolism. Cancer J 2015;21:111–6.
105. Fowler JF. 21 years of biologically effective dose. Br J Radiol 2010;83:554–68.
106. Dewhirst MW, Viglianti BL, Lora-Michiels M, Hanson M, Hoopes PJ.Basic principles of thermal dosimetry and thermal thresholds fortissue damage from hyperthermia. Int J Hyperthermia 2003;19:267–94.
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