associations between physical activity and susceptibility to cancer

Associations Between Physical Activityand Susceptibility to CancerPossible Mechanisms

Roy J. Shephard1,2 and Pang N. Shek2

1 Faculty of Physical Education and Health and Faculty of Medicine, University of Toronto, Ontario, Canada

2 Defence and Civil Institute of Environmental Medicine, North York, Ontario, Canada

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2941. Indirect Associations Between Cancer and Sedentary Living . . . . . . . . . . . . . . . . . . . . . 295

1.1 Effects of Pre-Existing Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2951.2 Constitutional Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2951.3 Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296

2. Gender and the Relationship Between Cancer and Sedentary Living . . . . . . . . . . . . . . . . 2973. Body Build . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

3.1 Height . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2973.2 Body Fat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298

4. Dietary Influences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2994.1 Overall Food Intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2994.2 Minerals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3004.3 Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3004.4 Counter-Regulatory Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3004.5 Megadoses of Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3014.6 Nonsteroidal Anti-Inflammatory Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3014.7 Dietary Fibre and Colon Transit Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3014.8 Protein Intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3014.9 Fat Intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

5. Other Aspects of Lifestyle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3025.1 Smoking Behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3025.2 Pulmonary Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3035.3 Socioeconomic Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303

6. Hormonal Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3046.1 Growth Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3046.2 Cortisol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3046.3 Prostaglandins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3046.4 Sex Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304

7. Immune Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3057.1 Tumour Initiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3077.2 Natural Killer Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3077.3 Cytolytic T Lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3077.4 Macrophages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3077.5 Neutrophils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3087.6 Acute-Phase Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308

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7.7 Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3087.8 Overall Assessment of Immune Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

8. Areas Requiring Further Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3099. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

Abstract Physical activity is associated with a reduced risk of all-cause and coloniccancers, and it seems to exert a weaker effect on the risk of breast, lung andreproductive tract tumours. This review examines possible mechanisms behindthe observed associations. Restriction of physical activity by pre-existing diseasemay contribute to the association with lung cancers, but seems a less likelyexplanation for other types of tumour. Indirect associations through activity-related differences in body build or susceptibility to trauma seem of minor im-portance.

Potential dietary influences include overall energy balance and energy expen-diture, the intake and/or bioavailability of minerals, antioxidant vitamins andfibre, and the relative proportions of protein and fat ingested.

Links between regular exercise and other facets of lifestyle that influencecancer risks are not very strong, although endurance athletes are not usuallysmokers, and regular leisure activity is associated with a high socioeconomicstatus which tends to reduce exposure to airborne carcinogens, both at work andat home. Overall susceptibility to cancer shows a ‘U’-shaped relationship to bodymass index (mass/height2) reflecting, in part, the adverse influences of cigarettesmoking and a tall body build for those with low body mass indices and, in part,the adverse effect of obesity at the opposite end of the body mass index dis-tribution. Obesity seems a major component in the exercise-cancer relationship,with a particular influence on reproductive tract tumours; it alters the pathwaysof estradiol metabolism, decreases estradiol binding and facilitates the synthesisof estrogens.

Among the hormonal influences on cancer risk, insulin-like growth factorspromote tumour development and exercise-mediated increases in cortisol andprostaglandin levels may depress cellular components of immune function. How-ever, the most important change is probably the suppression of the gonadotropicaxis. Apparent gender differences in the benefits associated with regular exercisereflect gender differences in the hormonal milieu and also a failure to adaptactivity questionnaires to traditional patterns of physical activity in females.

The immune system is active at various stages of tumour initiation, growthand metastasis. However, acute and chronic changes in immune response inducedby moderate exercise are rather small, and their practical importance remainsdebatable. At present, the oncologist is confronted by a plethora of interestinghypotheses, and further research is needed to decide which are of practical im-portance.

A growing number of epidemiological studieshave demonstrated an association between regularoccupational or leisure activity and a reduced over-all incidence of cancer.[1-9] There is strong and con-

sistent evidence that regular physical activity isassociated with a moderate reduction in susceptibil-ity to colonic tumours.[2,10,11] There is also growingevidence that it may protect against tumours of the

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breast and female reproductive tract,[12-16] the pros-tate (reported by Oliveria and Lee[17] but not byLee[2]), the testes,[18] the lungs[19] and other tis-sues.[20]

From the standpoint of public health policy, thekey issue is the influence of physical activity on theoverall cancer rate, but in terms of mechanisms itmay be important to distinguish the various typesof tumour. It remains unclear what factors are re-sponsible for the observed benefits of exercise(potential mechanisms are listed in table I) and howfar common physical activity–related mechanismsinfluence vulnerability to the various types of ma-lignancy. The goals of this review are thus: (i) toexclude any apparent benefits that arise, indirectly,from associations between habitual physical activ-ity and pre-existing disease, constitutional factorsor an unusual prevalence of trauma; (ii) to exploreapparent gender differences in the influence of phys-ical activity upon cancer risks; and (iii) to examinepotential mechanisms whereby regular physical ac-tivity could have a direct role in reducing the riskof developing various types of tumour. In particu-lar, this article explores whether active individualshave common underlying patterns of body build,diet, lifestyle and hormonal or immune responsesto physical activity.

Melanomas are probably as common in passivesunbathers as among individuals who exercise inthe sun without adequate screening of the skin.[21]

This category of neoplasm has been excluded fromour analysis. However, other potentially negativeeffects of vigorous physical activity, such as an in-creased production of free radicals and immuno-suppression, are discussed.

1. Indirect Associations BetweenCancer and Sedentary Living

A spurious correlation between 2 variables ariseswhen each is closely related to a third factor. Po-tential sources of such an indirect association be-tween a sedentary lifestyle and a high overall riskof cancer were discussed in earlier reviews.[6,22] Anindividual may have curtailed their patterns of ha-bitual physical activity because of symptoms asso-

ciated with pre-existing disease. Constitutionalfactors may not only predispose to athletic successbut also modify an individual’s risk for certaintypes of cancer. Finally, the incidence of traumaand thus exposure to x-rays may differ betweenathletes and the general population.

1.1 Effects of Pre-Existing Disease

An indirect association between sedentary liv-ing and a high risk of a given type of cancer couldarise if a person’s habitual physical activity wasalready curbed by manifestations of incipient orassociated disease at the time of their initial activityassessment. Such an effect seems unlikely in thecase of mammary or prostatic tumours. Neverthe-less, it could be a significant factor in the lung, wherecigarette smoking or occupational carcinogen ex-posure initially causes chronic obstructive lungdisease that seriously restricts the individual’s po-tential for physical activity, but at the same time islinked to an increased risk of future lung cancer.

Given the long initiation period and the slowprogression of some tumours, it is difficult to com-pletely exclude the effects of incipient disease onactivity patterns. Thune and Lund[19] provided somecontrol for this factor by demonstrating that theincreased risk of lung cancer among individualswith a sedentary lifestyle was unchanged, if theyexcluded from their analyses data for which phys-ical activity had been determined with less than 1-,2- or 4-years’ follow-up.[19]

1.2 Constitutional Factors

Genetic factors contribute to the risk of devel-oping various types of cancer, including tumoursof the colon[23] and breast.[24] Up to 10% of casesof breast cancer are attributable to genetic predis-position; one-third of these reflect a mutation in theBRCA1 gene on chromosome 17.[25] It might thusbe argued that common inherited characteristicspredispose to both the regular pursuit of physicalactivity[26] and the development of cancer.[27,28]

However, this is a relatively unlikely scenario,since athletes and non-athletes usually give a sim-ilar family history of susceptibility to cancer.[14] A

Physical Activity and Cancer 295


further possibility is that some inherited feature ofbody build, hormonal balance or personality influ-ences both athletic selection and the risk of cancer,as discussed in sections 3 and 6.

Since migrant populations quickly reflect thecancer profile of their adopted country, any influ-ence of constitution upon cancer risk must be rela-tively weak and easily outweighed by environmen-tal influences.[29]

1.3 Trauma

Trauma has been suggested to increase the riskof certain tumours, including meningiomas[30,31]

and testicular seminomas.[32] Various mechanismscould link trauma to an increased incidence of tu-mours.[33] In the short term, the process of sepsis,exacerbated by exercise,[34] could lead to an impair-ment of immune function with a resulting depres-

Table I. Potential explanations for associations between physical activity and an altered susceptibility to cancera

Indirect associationsEffects of pre-existing disease predispose to cancer and decrease physical activity*Common constitutional factors influence athletic selection or interest in physical activity and susceptibility to cancer*High incidence of trauma in athletes stimulates cell growth or increases exposure to x-rays, increasing risk of tumours at injury site*

Differences in body buildTallness of some athletes reflects increased number of stem cells or increased exposure to insulin-like growth factors, increasing tumour risk†

Body fat content reflects physical activity and smoking history;† smoking increases risk of many tumours Increase of body fat increases estrogen exposure and thus cancer risk†

Differences in dietOverall food intake influences cumulative exposure to colonic carcinogens* and reactive species†

Energy balance influences obesity (see Differences in body build, above)†

Minerals: low iron stores of endurance athlete reduce colon cancer risk;† selenium intake increases induction of antioxidant enzymes*Antioxidants: generation of free radicals during exercise increases cancer risk* but is countered by upregulation of antioxidant enzymes†

and (in many athletes) by increased intake of retinol, ascorbic acid and tocopherol (vitamins A, C and E)*Nonsteroidal anti-inflammatory drugs intake is greater in athletes, enhancing NK cell function and decreasing cancer risk*Increased fibre intake binds bile acids,* alters gastrointestinal flora* and speeds gastrointestinal transit,† reducing cancer riskHigh protein intake increases lymphocyte proliferation,* reducing risk, but it is also associated with decreases in intake of fibre,* n-3 andn-6 fatty acids* and antioxidant vitamins*High fat intake increases secretion of bile acids and prolactin,* increasing risk of colonic and breast tumours, respectively

Differences in lifestyleHealth-conscious individuals conduct self-examination of potential tumour sites,* reducing riskEndurance athletes are less likely to smoke,† reducing risk of many tumoursLung volumes and airflow patterns are modified by regular exercise,* allowing greater penetration of airborne carcinogens into the lungs

Differences in hormonal milieuStimulation of IGF promotes tumour growth*Cortisol secretion induced by exercise and associated stress depresses immune function,* increasing cancer riskProstaglandins liberated by microtrauma influence gastrointestinal motility† (beneficial effect)Sex hormones: suppression of gonadotropic axis by heavy exercise;† reduction of body fat also modifies estrogen synthesis, transportand catabolism,† both reducing cancer risk

Differences in immune functionAcute exercise depresses but regular exercise enhances NK cell function,* reducing cancer riskEnhanced macrophage chemotaxis and phagocytic and lysozymal enzymic activity postexercise* reduce cancer riskExercise modifies levels of IL-1, TNF, and IFN-α,* reducing cancer riska Arbitrary classification of importance of the various potential mechanisms.IFN = interferon; IGF = insulin-like growth factor; IL = interleukin; NK = natural killer; TNF = tumour necrosis factor; * = possible factor;† = probable factor.

296 Shephard & Shek


sion of natural killer (NK) cell function.[35] Alter-natively, an increased rate of cell division sub-sequent to injury might increase the chances ofmetaplasia. The diagnosis of many injuries in-volves the use of x-rays. Finally, it is possible thatthe development of a tumour may merely triggeran individual’s ability to remember previous inju-ries to the affected body part.[33]

An increased risk of musculoskeletal injuries isassociated with certain vigorous athletic pursuits,and as such could increase the risk of specific tu-mours such as meningiomas. However, it seemsunlikely to be a factor in the moderate daily activ-ities that are linked to a reduced overall risk ofcancer.

2. Gender and the RelationshipBetween Cancer and Sedentary Living

Since many important types of cancer developin the reproductive tract, it is hardly surprising thatthere are gender differences in the influence of sed-entary living upon the overall risk of neoplasia. Anumber of studies have suggested that, comparedwith women, regular physical activity also offersmen greater protection against cancer in variousparts of the body other than the reproductivetract.[19,36]

It may be that men have a greater risk of expo-sure to occupational co-carcinogens, and thusgreater scope to demonstrate a protective effectfrom habitual physical activity. Moreover, therehave been temporal differences in the smokinghabits of men and women. Reported gender differ-ences in the benefits of physical activity may relatemore to inadequacies in the methods used to assessphysical activity patterns in women[5] than to anytrue gender difference in susceptibility to the vari-ous forms of cancer. Few women engage in signif-icant physical activity at work,[19] thus limiting thepossibility of demonstrating a protective effect ofoccupational activity in women. Most question-naires on leisure activity were designed to explorethe habits of men rather than women. Typically, thequestions asked fail to cover the energy spent incaring for children and aging relatives. Although

some women report undertaking as much as 40hours of household work per week,[11] White et al.concluded that domestic activity did not influencethe risk of colon cancer; they admitted, neverthe-less, the need for a better instrument to assess suchtypes of physical activity.

Many questionnaires have excluded certain lei-sure activities, such as dancing and gymnastics,which are more popular among women than men.[36]

Much of the reduced risk of breast and reproductivetract tumours that women derive from an activelifestyle may be related to a reduction in the life-time number of ovulatory cycles.[37-40] The latentperiod for the development of most types of tu-mour is very long, and it is thus important in bothmen and women to examine patterns of physicalactivity which have been adopted over the entirespan of adult life, rather than focusing on the life-style adopted during the most recent 5 or 10years.[12]

3. Body Build

There is quite a strong association between aperson’s body build and the likelihood of their se-lection for particular types of athletic event.[41,42]

The well-established influence of interindividualdifferences in height and percentage body fat onthe risk of certain types of neoplasm thus offers apotential mechanism to explain some of the ob-served associations between a high level of habit-ual physical activity and an altered risk of carcino-genesis.

3.1 Height

Body size has long been recognised as a riskfactor for lung tumours in experimental animals.[43]

Likewise, tallness seems to be a risk factor for co-lon cancer in humans.[10,44,45] It may simply be thattall people have a longer colon, and thus more stemcells at risk of carcinomatous change.[46] Alterna-tively, tall people may produce more insulin-likegrowth factors, promoting the development of tu-mours, or they may have differences in the recep-tors and binding proteins that promote tumourgrowth.



Certain types of athlete such as basketball play-ers are very tall. As yet, there has been no study oftumour risk in this population. However, thereseems no reason to suppose that the average partic-ipant in moderate occupational or leisure activityis of an unusual height.

3.2 Body Fat

The body mass index (mass/height2) is a com-monly used measure of body fat, and humans tendto show a ‘J’- or ‘U’-shaped relationship betweenthis index and the overall risk of neoplasia. A lowbody mass index tends to increase the risk for sometumours, such as lung cancers, in part because ofthe adverse experience of tall people (see section3.1), and in part because heavy smoking is oftenassociated with a low body mass.[47] On the otherhand, a low body fat content leads to depression of

the gonadal axis: in men, levels of testosterone arereduced; and in women there may be delayed men-arche, irregular menstrual cycling or amenorrhoea,a reduction in the total number of menstrual cy-cles,[48,49] and thus a decrease in a woman’s life-time exposure to estrogens, all of which can reducesusceptibility to reproductive tract cancers.

A high body mass index is a well-establishedrisk factor for several types of cancer. A high ratioalters the pathways of estradiol metabolism (fig. 1),decreases estradiol binding and facilitates thesynthesis of estrogens from androstenedione.[50]

Obesity is also associated with high insulin levels,which promote tumour growth (see section 6.1).

Empirical data show that in rats treated with thecarcinogen N-nitrosomethylurea, the subsequentincidence of tumours is diminished by regularexercise. Moreover, this benefit seems to be linked

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Fig. 1. Pathways of estrogen metabolism.

298 Shephard & Shek


to a decrease in the body fat content of the ani-mals.[51]

In humans, too few epidemiological studies ofphysical activity and cancer have controlled for theobesity of participants.[52] An excess body massincreases the risk of both endometrial[53,54] and coloncancer,[55] but apparently does not influence the riskof prostatic cancer.[56] Some authors have found norelationship between the risk of breast cancer inpremenopausal women and such surrogate meas-ures of body fat as Quetelet’s index.[12] Other in-vestigators have even suggested that body fat canprotect against breast tumours prior to the meno-pause,[40,57-59] although perhaps because of linkagesto diabetes or to decreased levels of estradiol-binding protein, a centripetal type of fat distributionincreases the risk of cancer both before and afterthe menopause.[60,61]

Several of the above mechanisms could influ-ence susceptibility not only to tumour initiationand progression, but also to recurrence after surgicalor chemotherapeutic treatment. One report foundan adverse effect of a high body mass index on themortality of patients who were being treated forbreast cancer, both before and after the meno-pause,[62] although this could reflect in part thegreater difficulty of completing surgical removalof the tumour in obese individuals.

4. Dietary Influences

The diet of an active individual differs from thatof a more sedentary person in many respects.Given a good mixed diet, the active person is likelyto have a greater intake of trace minerals and anti-oxidants than a sedentary individual. The overallenergy intake is also larger in an active person, andindeed some observers have explored the influenceof physical activity upon cancer simply in terms ofthe resulting changes in energy balance and theaccumulation of body fat. Most active individualsachieve an appropriate balance between energyintake and expenditure, and they are thus lesslikely to be obese than their sedentary peers. In afew sports disciplines in which weight categoriesare imposed or success is, in part, gauged on phys-

ical appearance, participants may even show a neg-ative energy balance, with specific implications forthe gonadal axis and the risk of reproductive tracttumours.

A person who deliberately undertakes regularphysical activity tends to be more health consciousthan someone who is sedentary. Those participat-ing in recreational exercise often choose a diet thathas a high content of fibre,[63] fruit and grains,[64]

but is low in animal fat. In contrast, participants insome types of team sport, such as American foot-ball, tend to have a high consumption of animalprotein and saturated fat.

There seem to be good theoretical reasons whythe quantity and type of diet could influence over-all and specific risks of cancer, but several epide-miological studies that have controlled for diethave found little or no effect from this variable.[52,65]

Possibly, any effect has been masked by the use ofrelatively crude instruments to assess dietary pat-terns. However, it is also worth noting that in moststudies the protection against cancer has been greaterfor occupational than for recreational activity, andthere is little evidence that people employed inheavy industry adopt a particularly favourable diet.

4.1 Overall Food Intake

The influence of total food intake upon healthis quite complex. Some of the influences of phys-ical activity have at least a potential for harm. Be-cause active people eat more, they are necessarilyexposed to larger quantities of any toxins and car-cinogens that are contained in common foods. Inaddition, the production of reactive species is nor-mally proportional to the quantity of food metabo-lised.[66] At least in experimental animals, dietaryrestriction helps to conserve immune function.[67]

Empirical data underline the negative consequencesof an increased intake of food. The lifespan of ratsis extended by restricting food intake,[68] and thereis an associated reduction in the incidence of tu-mours.[69] Likewise, human studies that have com-pared the incidence of tumours in different partsof the world suggest that differences in the totalenergy intake or composition of the food ingested



may influence the overall risk of carcinogene-sis.[70] In animals, the voluntary exercise of wheelrunning partially negates the beneficial influenceof dietary restriction on lifespan[68] and tumouri-genesis.[71]

Food restriction limits the accumulation of bodyfat (see section 3.2) and (of potential interest in thecontext of carcinogenesis) it may shift the physio-logical state of the body from cellular proliferationand reproduction to maintenance and repair.[72] Inthe context of moderate physical activity (perhaps0.5 to 1 MJ/day), the positive consequence of re-duced fat storage probably outweighs the potentialnegative influences from the increased amount offood ingested.

Diet composition has been suggested to be arisk factor for intestinal cancer.[73] Epidemiologi-cal data suggest that the intake of alcohol, retinol(vitamin A), fat and fibre affect this risk,[74] andhealth-conscious individuals undertaking recrea-tional exercise may vary the intake of each of thesedietary components. Adequate plasma levels ofbranched-chain amino acids seem to be importantfor the proliferation of lymphocytes,[75] and fat in-take also affects the function of NK cells.[76] Inaddition, there have been suggestions that a highintake of saturated fat decreases the incidence ofcertain types of tumour. For instance, dietary cho-lesterol inhibits mammary tumourigenesis.[77] Onthe other hand, a diet low in saturated fat enhancesthe resistance to colonic and ovarian tumours.[55,78]

4.2 Minerals

Iron is a catalyst in the production of oxygenradicals and it may also be a rate-limiting nutrientfor the growth of some types of tumour cell. Thus,there have been suggestions that physical activitymay reduce the risk of colon cancer in part by re-ducing body iron stores.[79,80] Such a mechanismcould well operate in endurance athletes who en-gage in rigorous training but it seems an unlikelyconsequence of moderate occupational or leisureactivity.

The intake of trace minerals such as seleniumincreases with energy intake. Experimental studies

are difficult to perform because these minerals arewidely and inconsistently distributed in variousfood products. Selenium is thought to protectagainst cancer by inducing the antioxidant enzymescatalase and dismutase[81,82] but it can also be toxicif it is administered in large doses.[83] Again, thisfactor may operate in endurance athletes, becausea greater quantity of food is ingested, but it is un-likely to be important in those undertaking moder-ate exercise.

4.3 Antioxidants

Free radicals can play a role in the initiation oftumours by ionising radiation, foreign bodies, met-als and chemical carcinogens.[84] It is probable thatfree radicals cause strand breakages in DNA[85,86]

and form specific bases such as 8-hydroxyguaninewhich cause polymerase-induced miscoding oftranscribed DNA.[87] Given the likely role of reac-tive species, protection might be anticipated fromthe administration of antioxidants, and low serumlevels of retinol have been linked to an increasedincidence of cancer.[88]

Vigorous physical activity has the negativeconsequence of causing a substantial increase inmitochondrial generation and/or leakage of super-oxide and hydrogen peroxide, sometimes with anassociated reduction in the tocopherol (vitamin E)content of both muscle and liver.[89] Animal studieshave demonstrated that moderate to intense physi-cal activity has increased the risk of carcinogene-sis. For example, Thompson et al.[90,91] found thatexercise could accelerate the development of mam-mary tumours in rats, and they linked this to anexercise-induced increase of oxidant productionby demonstrating increased levels of oxidisedthiols in the exercised animals.[92]

4.4 Counter-Regulatory Mechanisms

The potential for an increase in oxidative stressin athletes who are engaged in heavy training[93] isnormally offset by exercise-induced increases inthe activity of antioxidant enzymes[94,95] and thecoenzyme Q content of various tissues.[96] Inges-

300 Shephard & Shek


tion of coenzyme Q may help to protect the exer-cising individual against oxidant damage.[82]

4.5 Megadoses of Vitamins

Many regularly exercising individuals are suf-ficiently health conscious to take megadoses ofascorbic acid and tocopherol (vitamins C and E) ona regular basis;[97] this probably accounts for thehigh α-tocopherol content of erythrocytes ob-served in runners.[95] Supplements of β-carotene,tocopherol and selenium have reduced the inci-dence of gastric carcinomas in a Chinese popula-tion,[98] but critics of this study point out that thestudy population was unusual in terms of havingboth a high base rate of cancer and a low intake ofantioxidant vitamins.[83] In North Americans, theprotective influence of megadose vitamin therapyremains to be established and the incidence ofcolon cancer seems to be unrelated to the intake ofvitamin supplements.[11]

4.6 Nonsteroidal Anti-Inflammatory Drugs

The minor muscle injuries sustained by athletesoften lead to an increased use of aspirin and othernonsteroidal anti-inflammatory drugs (NSAIDs).Such agents could exert some protective effect, par-ticularly against colorectal tumours,[99-103] althoughthe mechanism – a reversal of the depressant actionof prostaglandins on NK cell activity, an inhibitionof cell proliferation or a blocking of tumour pro-moters – remains obscure.[104]

The mechanism behind the effects of NSAIDsis unlikely to explain the protective effect of mod-erate occupational or leisure activity.

4.7 Dietary Fibre and Colon Transit Time

It has been suggested that dietary fibre reducesthe risk of cancer by 1 of 3 mechanisms: (i) bindingcarcinogens and cancer promoters such as bileacids;[105] (ii) altering the gastrointestinal flora; or(iii) increasing the speed of gastrointestinal tran-sit.[106]

Despite strong advocacy of a high fibre diet, anybenefit appears to depend heavily on the type of

fibre that is consumed, and some studies havefound little influence of fibre intake on the riskof colonic cancer.[11] Cereal-derived fibre has littleeffect but benefit has been observed with fruit- andvegetable-derived fibre.[83] This suggests that anyprotective effect of the fruit and vegetables ismediated by constituents other than fibre, possiblyby their content of antioxidant vitamins.

Data on bile acid concentrations and physicalactivity are conflicting. One study found lowerfaecal bile acid concentrations in athletes than insedentary controls,[107] although an earlier reportfound an increase rather than a decrease in the pro-duction of bile acids after an acute bout of exer-cise.[108]

In the very sedentary person, an increase ofphysical activity probably does increase colonicmotility[109-112] but there seems little change in theoverall intestinal transit time once a low thresholdof daily energy expenditure is reached.[113-117]

Some proponents of benefit from an increase incolonic motility have claimed that exercise accel-erates colonic rather than overall transit, or that anactive person shows increased local segmentationwithin the large intestine. There may also be a de-liberate choice of high fibre diets among individu-als who engage in recreational exercise.

4.8 Protein Intake

Competitors in some sporting disciplines con-sume large quantities of animal protein; intakes aslarge as 2 g/kg body mass per day have beenthought beneficial to the synthesis of muscle pro-tein during periods of very intensive training.[66] Ahigh-protein intake may facilitate lymphocyteproliferation by providing essential branched-chain amino acids.[75] In contrast, the glutaminedepletion associated with prolonged enduranceexercise can depress lymphocyte proliferation. Never-theless, dietary animal proteins seem to increasethe risk of tumours. Vegetarians have only about60% the risk of cancer observed in meat-eaters,[118,119]

although a part of this benefit may reflect otherunmeasured differences in lifestyle between the 2groups. The benefits of a vegetarian diet are ob-



served mainly with respect to tumours of the respi-ratory system and digestive tract, and the dietarycomposition has little influence on susceptibility tohormone-related cancers.[83]

Evidence that nitrite additives in meat enhanceintestinal nitrosamine formation[120] is not very con-vincing.[121] The described reduced risk of cancerof vegetarians probably reflects a combination ofsuch associated factors as a high intake of dietaryfibre, n-3 and n-6 fatty acids and antioxidant vita-mins. The estrogens used to fatten livestock maybe a further hazard associated with a high-proteindiet (see section 6.4).

4.9 Fat Intake

Following administration of N-nitrosomethyl-urea, the incidence of mammary tumours in seden-tary rats is greater in animals receiving high- (20%)or medium-fat (10%) than in those receiving a low-fat (5%) diet.[122] Likewise, in humans, epidemio-logical data suggest a correlation between fat in-take and the overall risk of cancer.[70,123] It has beenestimated that a 60% reduction in fat intake wouldlead to a 4-fold reduction in the incidence of breastcancer.[124] Possibly, fat stimulates the secretion ofbile acids, and a bacterial formation of secondarybile acids then serves to promote cancer.[106]

Exercise seems to protect against the risks asso-ciated with a high fat intake. Faecal bile acid con-centrations are lower in distance runners than insedentary individuals.[107] In small mammals, vol-untary (wheel) exercise can reduce the overall can-cer risk associated with a high-fat diet to that of alow-fat diet in animals that do not exercise.[122]

Likewise, although a high fat intake appears to in-crease the risk of colonic cancers, and possiblyprostatic cancers in humans, physical activity con-tinues to protect against such tumours after control-ling for various dietary factors.[46,125-127]

The effect of fat intake on the incidence ofbreast cancer remains controversial.[13,83,106,128-130]

In theory, fat could affect the proliferation of breasttissue by encouraging prolactin secretion, but inpractice no changes in prolactin levels have beenobserved in response to changes in dietary fat

intake.[122] Analysis of interactions between exer-cise and fat intake is complicated, and there is someevidence that women who begin athletic trainingat an early age eat less fat than their sedentarypeers.[131]

5. Other Aspects of Lifestyle

Relationships between regular physical activityand the adoption of other desirable types of healthbehaviour are not particularly strong.[132-134] Withregard to preventive examinations such as mam-mography, conflicting reports suggest that womenwho exercise regularly are less well informedabout breast cancer than their sedentary counter-parts,[135] but they are more likely to undertakeself-examination of the breast to detect possibletumours.[136]

Participation in some types of exercise such asrunning, jogging and walking is associated with alow prevalence of obesity and cigarette smoking.Both obesity and smoking substantially augmentthe risk of carcinogenesis. Risks may also vary be-cause physical exercise affects pulmonary functionor because lifestyle is influenced by socioeconomicstatus.

5.1 Smoking Behaviour

There is a strong probability that those whoare endurance athletes will be nonsmokers,[137,138]

although sometimes the cessation of smoking an-tedates regular involvement in athletic train-ing.[97,139] In contrast, former participants in teamsports have a greater likelihood of being cigarettesmokers than do their non-athletic peers.[140]

Smoking behaviour affects susceptibility tomany types of cancer, including tumours of the re-productive tract,[141] but it is most important as acovariate when examining the influence of physicalactivity on the risk of pulmonary tumours. Manyrecent epidemiological studies of physical activityand cancer risk have covaried for smoking behavi-our,[19,142] but the influence of tobacco-derivedcarcinogens is so powerful that it remains uncertainwhether statistical manipulation of the data pro-vides adequate protection against the influence of

302 Shephard & Shek


smoking. Some analyses have made only a limitedclassification of smoking habits (for example,smokers versus nonsmokers). In their study of lungcancer, Thune and Lund[19] made much more com-prehensive adjustments for current and formersmoking behaviour, the number of cigarettes smokedand years of current smoking. Nevertheless, evenafter completing such analyses, there remained po-tential influences from the type of cigarettesmoked, the number of ‘puffs’ per cigarette and thedepth of smoke inhalation. Perhaps the most con-vincing evidence that the effect of physical activityis independent of smoking behaviour is the dem-onstration of benefit even in those who are cur-rently smoking 15 or more cigarettes per day.[19]

A second important argument for an inde-pendent effect of physical activity is that protectionagainst pulmonary neoplasms is not restricted tothose types of tumour cell most strongly influencedby smoking behaviour.[19] Physical activity appar-ently protects most strongly against small cell car-cinoma (the risk of which is influenced by smok-ing). It is less protective against adenocarcinoma(where the effect of smoking is weak) and it is ofno benefit in squamous cell carcinoma (where theeffect of smoking is greatest). Nevertheless, theseobservations do not provide as strong evidenceagainst a residual effect of smoking as might at firstappear, since the accuracy of histological classifi-cation of tumours at routine postmortem examina-tion is quite limited. Further study is thereforeneeded before we can exclude an influence ofsmoking on the exercise–lung cancer relationship.

5.2 Pulmonary Function

Competitors in sports such as swimming havelarge vital capacities, although it remains unclearhow far this is due to athletic training and how farto the selection process. A large vital capacity couldpotentially augment the incidence of tumours bothby increasing the number of epithelial cells and byaltering patterns of airflow.

Tumours of the bronchial tree arise most com-monly at sites of particle deposition (for example,the bifurcation of the bronchi[143,144]). Vigorous

physical activity modifies the patterns of respira-tory airflow, and this could increase the depositionof carcinogenic particles, whether cigarette smoke,occupational pollutants or urban contaminants. Inparticular, it encourages mouth-breathing, thus by-passing the normal filtration mechanisms of thenose.[145] The increased rate of airflow also augmentsturbulence in the airstream,[146] with a greater ten-dency for the impaction and deposition of suspendedparticulate matter. Such factors could have someinfluence on prognosis in athletes, but are unlikelyto be important in the context of moderate occupa-tional and leisure activity.

In a few instances, athletes may have been ex-posed to asbestos fibres, because this material wasused in the construction of older gymnasia andswimming pools.[147] However, the importance ofthis risk remains highly debatable.

5.3 Socioeconomic Status

The influence of socioeconomic status upon theoverall risk of cancer is mediated largely by asso-ciated differences in lifestyle, including not onlypatterns of habitual physical activity but also diet,smoking and reproductive and sexual habits.[148] Inparticular, there is a strong positive association be-tween habitual physical activity and socioeconomicstatus.[149] The person who has an active leisure iswealthier, tends to live in a less polluted area of acity and is much less likely to be employed in anoccupation where there is exposure to carcinogens.Physically demanding occupations sometimes in-volve exposure to work-related carcinogens, andthe observed benefit of occupational activity mightbe increased if data were to be adjusted to allowfor this hazard.

Paradoxically, the incidence of breast cancer ishigh in affluent women.[150] This may reflect thepostponement of childbearing by the use of oralcontraceptives,[25] or it may merely be an artifactof earlier and more complete diagnosis in thosewho can afford sophisticated medical care.



6. Hormonal Factors

6.1 Growth Factors

Insulin is a growth promoter for breast[58] andcolon cancer cells.[151-153] Insulin levels are stronglyinfluenced by physical activity, obesity and the dis-tribution of body fat. Exercise-induced changes inthe expression of insulin receptors may also mod-ify macrophage activity (see section 7.4). Regularphysical activity could also influence the develop-ment of tumours through an action on blood levelsof vascular endothelial growth factor and thus thedevelopment of the blood supply to a tumour,[154,155]

although this issue remains to be explored.

6.2 Cortisol

A single bout of stressful exercise leads to thesecretion of cortisol. This has a transient depressantaction on many aspects of immune function. Incontrast, training decreases resting cortisol levels.[156]

Cortisol-induced suppression of lymphocyte pro-liferation and NK cell activity could depress natu-ral cytotoxicity toward tumour cells (see section7.2). Perhaps for this reason, the administration ofglucocorticoids promotes the induction of skin tu-mours and activates mammary tumour virus inmice.[157]

Somewhat surprisingly, Woods et al.[158] observedthat the increased levels of cortisol postexercisehad no effect on the cytotoxicity of inflammatorymacrophages. They acknowledged that fully acti-vated macrophages were sensitive to glucocortic-oid inhibition[159] but speculated that such effectshad been negated by other upregulating influences.

6.3 Prostaglandins

Prostaglandins are liberated as a consequence ofexercise-induced microtrauma. Secretion is greaterwith eccentric than with concentric activity, andchanges in output of this hormone are more likelyto occur with athletic than with moderate occupa-tional or recreational activity. Prostaglandins mayincrease gastrointestinal motility,[160,161] and couldthus reduce the risk of colon cancer. Prostaglandins

suppress NK cell function by influencing secondmessenger levels,[162] and they can also affect theproliferation of epithelial cells.[163] Further, in lungtumours, prostaglandin E2 enhances the metastaticphenotype of the tumour cell.[164]

6.4 Sex Hormones

It is well known that a bout of heavy exerciseinduces a temporary suppression of the gonadalaxis, with decreases in plasma testosterone and es-trogen levels in men and women, respectively.[165]

The gonadal hormones promote the growth and de-velopment of reproductive tissues, and it is thuslogical to infer that exercise-induced reductions inplasma levels of these hormones should reduce therisk of carcinogenesis. In addition, there is someevidence that estradiol has a suppressant effect onNK cells.[166]

In women, the total number of menstrual cyclesseems to be an important risk factor for cancer.[38,167]

Participants in a heavy athletic training programmemay show a delayed menarche[168,169] and their to-tal lifetime number of menstrual cycles is substan-tially reduced, thereby decreasing their risk ofcancer.

The postmenopausal administration of estrogenis recognised as increasing the risk of endometrialcancer,[170] and long term use of estrogen for con-traception[171] or therapeutic use of diethylstilbo-estrol can augment the risk of breast cancer.[172]

Moreover, a recent prospective study has confirmedan association between normal serum levels of freeestrogen and the incidence of breast cancer.[173]

There have been suggestions that the periods ofanovulation observed in athletes may predispose toendometrial hyperplasia, adenocarcinoma and breastcancer because of the unopposed action of estro-gens,[165,174,175] although the risks are probably lessthan with exogenous estrogen administration sinceexercise also suppresses estrogen production.

Suppression of the gonadal axis is unlikely to bea major factor affecting cancer risk in athletes whoare training very hard. However, a part of the effectof such exercise is mediated through changes in thebody fat, which modifies estradiol metabolism,

304 Shephard & Shek


estradiol binding and the synthesis of estrogensfrom androstenedione. This mechanism may thushave greater general applicability to the extent thatmoderate physical activity influences body fat.

6.4.1 Estradiol MetabolismBoth estradiol and progesterone play important

roles in tumourigenesis and the subsequent growthof breast tumours. The target cells show substantialdifferences in their expression of estrogen and pro-gesterone receptors, and thus their response toexercise, diet and pharmaceutically induced ma-nipulations of plasma estrogen levels.[176,177]

Naturally occurring estrogens, in ascending or-der of potency, are estriol, estrone and estradiol.Interrelationships between these compounds areillustrated in figure 1. In premenopausal, nonpreg-nant women, the ovaries are the main source ofestrogens (largely estradiol). Estradiol forms a re-versible redox system with estrone and is then met-abolised along 2 alternative pathways: 2-hydroxyl-ation and 16-hydroxylation.[178] The former pathwayis normally the more important, and it becomesdominant in individuals with a low body fat con-tent; this metabolic route leads to the formation of2-hydroxyestrone and thus 2-methoxyestrone. How-ever, obesity may cause a predominance of the 16-hydroxy products, with a resulting increase in therisk of cancer.[179,180] Probably because they have lessbody fat, athletes metabolise a greater proportionof estrogen to catecholestrogens. These changeswere thought to reduce the risk of estrogen-depend-ent tumours in both the breast and the female re-productive tract among active individuals.[14,181]

6.4.2 Estradiol BindingNormally, only about 2 to 3% of estradiol cir-

culates in the biologically active, unbound form.However, bioavailability is increased after themenopause,[182] particularly in obese individuals,because they have low levels of the predominantcarrier for estradiol, sex-hormone binding globu-lin.[16] The adverse effect of obesity upon estradiolbinding is especially marked in women with thecentral type of obesity.[183] Moreover, increasedcirculating levels of triglycerides competitivelydisplace estradiol from sex-hormone binding glob-

ulin to albumin, where it is much less securelybound.[16]

6.4.3 Synthesis of Estrone from AndrostenedioneFat is thought to provide the major site where

androstenedione, secreted by the adrenal glands,can undergo aromatisation to the much more potentcarcinogen estrone.[184,185]

6.4.4 Effects of Sex Hormones in MenProlonged endurance exercise depresses circu-

lating levels of sex hormones in men,[186,187] withthe likelihood of depressing the risk for tumours ofthe reproductive tract. In particular, testosteroneseems to regulate prostatic growth.[188] There havebeen reports that men in sedentary occupationshave an increased risk of testicular cancer,[189-191]

whereas vigorous exercise (15 hours or more perweek) halves this risk,[18] with no change in thisestimate after adjustment for the effects of socio-economic status. For prostatic cancer, evidence ofa benefit from an increase of physical activity isinconsistent; nevertheless, 9 out of 17 studies havesuggested that regular physical activity protectsagainst prostatic cancer.[17]

Androgens contribute to aggressive behaviour,and it is possible that some types of sport attractthose with an aggressive personality and high andro-gen levels. However, the incidence of prostaticcancer seems to be unrelated to a ‘masculine’ bodybuild.[56] ‘Doping’ with anabolic steroids gives atleast a small increase in the risk of hepatic tumoursamong certain classes of athlete.[192-195] At least 14cases of androgen-induced tumours have beencited in the literature.[192,195]

7. Immune Response

Tumour formation is essentially a 2-stage pro-cess. A stem cell first gives rise to an abnormal,precancerous cell. Further changes in genetic cod-ing during subsequent division produce a cancer-ous cell that is capable of rapid replication. Theimmune system can address the early geneticchanges and also modulate the likelihood of sub-sequent tumour formation by inhibiting subsequentgrowth of the cell or countering the action of tumour



growth promoters. Thus, a stimulation of immunefunction by regular moderate physical activity[196]

could reduce the risk of cancer, and any depressionof immune function induced by a single bout of ex-hausting exercise or by a period of excessive train-ing[196-198] could enhance risk (table II). In turn,some by-products of tumour cells have a negativeinfluence on immune responses.[199]

There have been suggestions that human cancersare nonimmunogeneic but there is now good evi-dence that tumour cells are susceptible to macro-phages, NK cells, lymphokine-activated killer(LAK) cells and cytolytic T cells, together with thecytokines and eicosanoids secreted by thesecells.[200-202] The tumour antigens are first pro-cessed and presented to T cells by monocytes and

macrophages. Activation of CD4+ T cells causes asecretion of various cytokines that stimulate thecytolytic activity of CD8+ T cells, LAK cells, NKcells, macrophages and neutrophils. B cells, in col-laboration with CD4+ T cells, also produce anti-bodies that counter tumour antigens, and certaincytokines exert a cytostatic or cytotoxic effect intheir own right.[203]

The primary example of carcinogenesis associ-ated with sustained immunodepression is in pa-tients with HIV infection. In this condition, partic-ular types of tumour such as lymphomas andKaposi’s sarcoma develop. There is some anecdotalevidence that athletes who train extremely hard de-velop a general immunodepression, with similarrisks.[34,196] The effect of exercise-induced immune

Table II. Immune functions that can influence tumour initiation or progression, and their modification by acute and chronic exercise

Component Function Effect of acute exercise Effect of chronic exerciseNK cells Kill most tumour cells Immediate increase in cell count and

cytolytic activity (depressed for 2 to 24hpostexercise)

Increase in resting NK cell countand activity, both in blood andspleen

Lymphocytes Cytolytic cells kill tumour cells,helper cells produce ILs

Vigorous activity causes transientdepression of cell proliferationModerate activity enhances cellproliferation

Regular moderate activityenhances cytolytic activity(?Greater production of or greaterrate of cell proliferation)

Macrophages Antigen-presenting, initialsources of IL-1 and TNF andpossess cytostatic andphagocytic activity

Immediate increase in monocyte countAdherence unchangedIncreased cytostatic and/or cytolytic activityIncreased phagocytosis with moderateexercise, decreased with heavy exerciseNo effect on tumour incidence orprogression

Resting monocyte countunchanged?Adherence reduced

Neutrophils Destroy tumour cells byproducing peroxides and freeradicals

Large and sustained increase

Acute-phase proteins Make tumour cells morevulnerable to phagocytosis

Increased C-reactive protein for several days

IL-1 Cytotoxic, promotes adhesionof tumour cells, enhancesactivity of cytotoxic cells

Production increased Resting levels increased

IFNs IFN-α is cytostatic and activatesmacrophages and NK cells,IFN-γ enhances cytotoxicfunction of macrophages

Increased

TNFα stimulates phagocytosis andgranulocyte adherence,cytostatic and cytotoxic,reduces tumour blood flow,induces cachexia

Increased

IFN = interferon; IL = interleukin; NK = natural killer; TNF = tumour necrosis factor.

306 Shephard & Shek


changes on susceptibility to other types of tumouris less certain.

7.1 Tumour Initiation

Cytotoxic T cells, NK cells, LAK cells, and mono-cyte/macrophages all play a ‘surveillance’ role,killing abnormal cells that are induced by activeradicals, ionising radiation and exogenous or en-dogenous carcinogens, and reducing the likelihoodof subsequent metastases.[7,15,199,204]

There is evidence that regular, moderate physi-cal activity enhances the proliferation of lympho-cytes, increases the number of NK cells and in-creases LAK cell activity.[196] It remains unclearwhether the underlying mechanism for the en-hanced LAK activity is a change in the levels ofcytokines such as interleukin (IL)-1 and IL-2 oran upregulation of IL-2 receptors on NK/LAKcells.[205]

The main problem of experimental studies todate has been that the acute, exercise-inducedchanges of immune function are very short-livedand do not appear to cause parallel changes incancer incidence or progression in animal models.

7.2 Natural Killer Cells

NK cells play an important surveillance role andare able to attack most (but not all) types of tumourcell.[206] Their usefulness in this respect is demon-strated by the low frequency of tumour metastasisin strains of mice with a high NK count,[207] a highrate of tumour growth in mice with poor NK cellfunction[208] and enhanced metastasis with sup-pression of NK cell activity.[209] However, the effec-tiveness of NK cells apparently diminishes as a tu-mour grows,[210,211] probably because by-productsof the tumour have a negative effect on NK cellfunction.[212]

A single bout of vigorous exercise increases theimmediate count of circulating NK cells, with aparallel increment in cytolytic activity.[196,213]

Regular exercise increases the cytotoxicity of bothcirculating[214-216] and splenic NK cells.[205] Trainedmice also have a higher NK cell activity, and thisis linked to a greater lung clearance of tumour

cells and a lower incidence of tumours.[217,218]

Training also increases resting NK cell activity inhumans.[196,216,219]

7.3 Cytolytic T Lymphocytes

The cytolytic T cells probably play an importantrole against cancer, and there is some preliminaryevidence that their activity is enhanced by regularmoderate physical activity,[220] whether through agreater production of IL-1 or increased cell prolif-eration.[196,216,219] However, excessive physicalactivity has a negative influence on lymphocyteproliferation.[198]

7.4 Macrophages

Macrophages play a dominant role in cancerprevention, as initial phagocytic agents, as antigen-presenting cells and as initial sources of IL-1 andtumour necrosis factor (TNF). They directly pro-tect against spontaneously arising malignant cellsand also exert a potent nonspecific antitumour cyto-toxicity by stimulating other components of theimmune defences.

Macrophages resident in the tissues normallyhave a low functional activity but they can beprimed by inflammatory signals to become ‘inflam-matory macrophages’. A second signal [usuallylipopolysaccharide or interferon (IFN)-γ] is neededfor full activation, and this step is indispensable forthe cells to develop tumouricidal activity. Themicrotrauma associated with physical activity mayhave a priming effect on macrophages.[159,204,221]

7.4.1 Phagocytic ActivityPhagocytic activity depends on adherence,

chemotaxis and the mechanical act of phagocyto-sis, followed by a respiratory burst and the releaseof toxic products. Acute exercise has no effect onthe adherence of monocytes but in trained individ-uals adherence is apparently somewhat reduced.[222]

Perhaps because of differences in their surface re-ceptors, fully differentiated macrophages from hu-man connective tissue show a contrasting response:increased chemotaxis and phagocytic and lysozy-



mal enzymic activity following an exhausting15km run.[223]

7.4.2 Cell NumbersAcute exercise may lead to a transient increase in

circulating monocyte/macrophage numbers.[196] Mod-erate physical activity has little effect on the numberof monocyte/macrophages elicited by inflammatoryagents, but exhausting exercise dramatically reducesthe intraperitoneal response to a heat-killed suspen-sion of Propioniebacterium acnes,[159,204,221] probablybecause of the exercise-induced release of cortisol.By analogy, cortisol secretion may also limit the in-flammatory response to tumour cells. Training haslittle effect on the macrophage count.[196]

7.4.3 Cytostatic and Cytolytic ActivityWhen mice run to exhaustion, both resident and

inflammatory macrophages from the peritoneumshow enhanced cytostatic but not cytolytic activi-ties against tumour cells in vitro.[4] Phagocytic,chemotactic and enzymatic activities are all enhancedby exercise.[223,224] As confirmation of these obser-vations, both moderate and exhausting exercise en-hance the in vitro antitumour cytostatic or cytotoxicactivity of murine inflammatory macrophages, asmeasured by the incorporation of radioactivethymidine.[158,204] This effect is unrelated to thenumber of macrophages per unit volume of bloodor to the macrophage production of IL-1β, reactivenitrogen or oxygen intermediates. However, thebenefit is reduced by neutralising the increasedlevels of TNFα.

Moderate exercise increases the number of in-sulin receptors on macrophages[225] but receptordensity is decreased after exhausting exercise.[226]

Other potential factors enhancing macrophage activ-ity include changes in blood levels of growth hor-mone, prolactin, neurotensin and dynorphin.[158]

Prostaglandin E2, whether derived from the tumouror produced by exhausting exercise, reduces cyto-lytic activity.[227]

7.4.4 Effect of Exercise on Tumour PhagocytosisA recent study investigated phagocytic activity

within the tumour mass.[221] Moderate, but not ex-haustive, exercise was observed to enhance intra-

tumour phagocytic activity; however, this appar-ently had no influence on either tumour incidenceor progression. It is unclear whether the absence ofresponse in vivo was due to a lack of effect of ex-ercise on the macrophages, whether the period ofobservation was too short or whether an upregula-tion of macrophage activity was countered by somehormonal or metabolic change, or an inhibition oflymphocyte proliferation or NK cell activity.

7.5 Neutrophils

Neutrophils can destroy tumour cells by produc-ing peroxides and free radicals. Physical activityproduces a large increase in the neutrophil count[196]

but it is less clearly established whether there is acorresponding increase in cytotoxic activity. Indeed,such activity appears to be lower in athletes than inthe general population.[228]

7.6 Acute-Phase Proteins

Many of the processes relevant to ‘immuno-surveillance’ are influenced by the acute-phase re-action, the septic inflammatory response to tissuedamage. The main acute-phase protein, C-reactiveprotein, probably binds with the surface protein ofsome tumour cells, making them more vulnerableto phagocytosis by monocytes.[229] C-reactive pro-tein is also a chemotactic agent, modifying the dis-tribution of macrophages within the body. A singlesession of exhausting physical activity can increaselevels of C-reactive protein by as much as 6-foldfor several days.[230]

7.7 Cytokines

Several cytokines produced by macrophages(IL-1, TNF and IFN) all have direct cytostatic orcytotoxic effects, thus enhancing resistance to tu-mours.[231-233] Along with IL-6, they also modifythe antitumour activity of other immune cells.

7.7.1 Interleukin-1IL-1 may have a direct cytotoxic effect early in

the course of neoplasia,[234] although metastasisingcells later become resistant to this cytokine.[235] Italso enhances the activity of the various cytotoxic

308 Shephard & Shek


cells but if the tumour is metastasising, it has thedisadvantage of promoting the adherence of tumourcells to the vascular endothelium and their sub-sequent penetration into the tissues.[236] An acutebout of exercise augments production of IL-1 andlevels also tend to be higher subsequent to train-ing.[196]

7.7.2 InterferonsIFN-α inhibits the growth and division of tu-

mour cells and it also exerts indirect effects by ac-tivating macrophages and NK cells.[237] It is widelyused in treating various types of cancer, includingKaposi’s sarcoma.[238] Interferon-γ also has an in-direct effect, enhancing the cytotoxic function ofmacrophages (see section 7.4). There has been rel-atively little study of the effects of exercise on in-terferons. However, a 2-fold increase in IFN-α hasbeen noted[239,240] after 1 hour of cycling at 70% ofmaximal aerobic power.[241]

7.7.3 Tumour Necrosis Factors (TNFs)TNFα stimulates phagocytosis and granulocyte

adherence, and induces the cachexia associatedwith neoplasms. It also has important cytostaticand cytotoxic effects against tumour cells,[231,233,242]

in part because it causes vascular damage, restrict-ing blood flow to the tumour.[154,155] Several stud-ies have shown increased levels of TNFα follow-ing sustained bouts of endurance exercise.[196,243-245]

7.8 Overall Assessment of Immune Changes

In general, there appears to be evidence for theimmune system to contribute to a ‘J’-shaped rela-tionship between physical activity and susceptibil-ity to neoplasia, but this relationship requires fur-ther investigation. Future studies may look at thetiming of physical activity relative to tumour initi-ation, the optimal ‘dose’ of activity and the com-ponents of the immune system that make the majorcontribution to any benefit.

8. Areas Requiring Further Study

Reasons have been suggested as to why theremight be a ‘J’- or ‘U’-shaped relationship betweeninvolvement in physical activity and susceptibility

to the initiation and progression of tumours. How-ever, most analyses to date have focused simply ona 2-way categorisation of individuals as being ei-ther active or inactive. Demonstration of a ‘dose’-response relationship would strengthen the infer-ence of a causal association and would help todefine the optimal ‘dose’ of physical activity. Indi-vidual laboratories seem unlikely to accumulatesufficient data to develop satisfactory ‘dose’-responsecurves, and it will be necessary to explore this issueby combining information from the better epide-miological surveys, using the techniques of meta-analysis. Particular attention should be directed to-wards surveys that have measured physical activityover the many years needed for tumour initiationand have accumulated adequate data on importantcovariates.

From the viewpoint of health policy, the mainissue is the influence of various quantities of phys-ical activity on overall cancer rates, but scientistswill also wish to move beyond the areas whichhave so far been explored (the colon, lung, breastand male and female reproductive tracts), lookingat the influence of physical activity on susceptibil-ity to tumours in other sites such as the brain andthe lymphatic system. There is also a dearth of in-formation concerning the influence of physical ac-tivity on the progression of tumours and its valuein preventing recurrence following surgical orchemotherapeutic treatment.

The contribution of the immune system to theobserved benefits of physical activity remains tobe defined. In particular, there is a need to examinethe time at which physical activity has a maximaleffect in relation to tumour initiation and progres-sion, and to determine which of the many compo-nents of the immune system is implicated in theprotective process.

9. Conclusions

Various reasons have been suggested for indi-rect associations between physical activity and analtered overall risk of neoplasia, including linkagesof vigorous exercise with certain types of bodybuild, adoption of an overall healthy lifestyle and



modification of habitual patterns of physical activ-ity by associated or undetected disease. Neverthe-less, both animal experimentation and human epi-demiological studies support the view that regularmoderate physical activity can have a more directfavourable influence on susceptibility to varioustypes of cancer. A wide variety of mechanisms hasbeen proposed, including modifications of diet,body fat content, hormone levels and immunefunction. The extent of body fat stores and associ-ated variation in gonadal function seem to be majorinfluences, particularly with respect to tumours ofthe reproductive tract. Much further research isneeded to determine which are the dominant under-lying mechanisms for the different types of tumour.Nevertheless, the influence of habitual physical ac-tivity upon overall susceptibility is sufficient thatwe can already recommend regular moderate phys-ical activity as a significant component of publichealth policy aimed at reducing the incidence ofneoplasms.

Acknowledgements

Dr Shephard’s research is supported by grants from theDefence and Civil Institute of Environmental Medicine andCanadian Tire Acceptance Limited.

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Correspondence and reprints: Dr Roy J. Shephard, P.O. Box521, Brackendale, British Columbia V0N 1H0, Canada.E-mail: [email protected]



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