A perspective on nonmutagenic mechanisms in carcinogenesis.

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A

Perspective

on

Nonmutagenic

Mechanisms

in

Carcinogenesis

by

Raymond W. Tennant

Although there is compelling evidencefor multiple mutageniceventsinthe inductionofcancers,there is also

substantial evidence in support of nonmutagenic mechanisms. It is proposed that the genetic basis of noninducedor spontaneous tumors, aswellascancersinduced bynonmutagens,involves heritable changes in theregulation ofgeneexpression.

Introduction

Cancer isadisease ofenvironment andgenetics. There

is a strong scientific consensus, codified by the

Interna-tional Agencyfor Research on Cancer

[IARC

(1)], that

environmentalfactors such assmoking, exposure to

sun-light, exposure to certain organic chemicals, and other

occupational and environmental factors establish a solid

basis foranenvironmental component in theinduction of cancers. Data derived from epidemiological studies have

identified differences in the prevalence andtypes of

cer-taintumorsbetweengeographicalareas.Also, differences

in the rate or frequency of the development of specific cancers in migrant populations provides support for an

environmental component(2,3).

Likewise, there is compelling evidence for a genetic

basis ofhumancancer.Thisincludes evidence forheritable

susceptibilities between populations ofhumans, for

exam-ple, skin cancer among fair skinned Anglo-Saxons and

evidenceforgenetic mechanisms ininduced carcinogene-sis. Theroleofgeneticmechanisms incarcinogenesiswas

firstproposed by Theodore Boveri in 1924 (4), who articu-lated the earliest version of the somatic mutation hypoth-esis.Subsequently,otherevidence for the role ofmutagenic changes in carcinogenesis have come from a variety of

sources.These lines of evidence include the chromosomal

alterations thathave been identifled in manyrodent and

human tumors. Infact, most human and rodent tumors that have been examined showgeneralized chromosomal damage as well as specific chromosomal mutations or

translocations(5). Also,overthepastdecade, evidencehas

emerged associating up to ahundred different dominant

genes (i.e., oncogenes) with carcinogenesis. The role of mutations in the activation ofthese geneshasprovideda

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Tri-angle Park,NC 27709.

genetic basis for bothinitiating andpromoting events in tumor development (6). Subsequently, evidence has emerged for anti-oncogenes or tumor-suppressor genes, which have an importantregulatoryrole incontrollingthe

expression or function of oncogenes (7). The function of these suppressor genes can be lost through mutation or translocation. Subsequent observations have provided a

schemeinwhichmultiple genetic changescanbe identified

and associated with sequential alterations giving rise to tumorsinhumans(8).

These observations represent a very brief and only a

partiallist of the data that areavailableto support arole forspecificgenes incarcinogenesisand forspecific altera-tions ormutations inthose genes that initiate or promote the carcinogenic process. Inthe face of such compelling data,it isdifficult to consider thepossibilitythatthere may be alternativemechanisms ofcarcinogenesis.

Evidence

Supporting

Nonmutagenic

Mechanisms

One of the strongest lines of evidence in support of nonmutagenicmechanisms arethechemicals that demon-strate no consistent mutagenic properties, yet have the

capacity to induce tumors in rodent bioassays (9). Our

operational definition of a nonmutagen is a chemical or

substancethat doesnotdemonstrateevidence of one of the structural alerts associated with electrophilic potential

and that the chemical does not induce mutations in the Salmonella assay nor induce chromosomal effects when measured in vivo(eitherinduction ofchromosome aberra-tionsormicronuclei).Althoughother mechanisms of geno-toxicity or mutagenesis exist, for example, interference with chromosomal metabolism or the mechanics of chro-mosomesegregation,therehave beennoassaysidentified

yet that arecapableofresolvingthosespecific properties

(2)

operational definition that we use, therefore, may miss someproportion ofincipient orindirectmutagens, butit provides the highest degree of specificity for carcinogen

identification. We believe that this operational definition

definesthechemicalgroupswith the highest probability of direct interaction with and damage to DNA. Chemicals that lack these properties comprise a very structurally

diversegroup(Table1).

Iable 1. Nonmutageniccarcinogens.a Chemical Aldrin Allyl isovalerate 11-Aminoundecanoic acid Benzaldehyde Benzene Benzofuran Benzyl acetate Butyl benzyl phthalate C.I. Vatyellow4

Chlordane(technical grade) Chlorendic acid

Chlorinatedparaffins:C12,60%chlorine Chlorinatedparaffins: C23,43%chlorine Chlorobenzilate Chlorothalonil Cinnamylanthranilate Decabromodiphenyl oxide Di(2-ethylhexyl) adipate Di(2-ethylhexyl) phthalate 1,4-Dichlorobenzene(p-dichlorobenzene) p,'-Dichlorodiphenyldichloroethylene Dicofol N,N'-Diethylthiourea 1,4-Dioxane Furfural Furosemide Heptachlor Hexachloroethane Hydroquinone Isophorone d-Limonene

Malonaldehyde, sodium salt Melamine

Mereaptobenzothiazole

a-Methylbenzylalcohol Monuron

Nalidixic acid

Nitrilotriacetic acid(NTA) N-Nitrosodiphenylamine Pentachloroethane Pentachlorophenol Phenylbutazone Piperonylsulfoxide

Polybrominated biphenyl mixture (Firemaster FF-1) Reserpine 2,3,7,8-Tetrachlorodibenzo-p-dioxin 1,1,1,2,-Tetrachloroethane 1,1,2,2-Tetrachloroethane Tetrachloroethylene 1,1,2-Trichloroethane

Trichloroethylene(withoutepichlorohydrin) 2,4,6-Trichlorophenol

Trimethylthiourea

Tris(2-ethylhexyl)phosphate

Zearalenone

aAll chemicals listed are negative for structural alerts and were

negativeinSalmonella.

Genetic

Basis for

Spontaneous

Tumors

Anotherline of evidence thatsupports a nonmutagenic originofsome cancers canbe derived fromthe occurrence

ofspontaneous tumors. Virtually all mammalian species

have demonstrated evidence of tumors when older

indi-vidualshave been examined. The best dataonthe incidence and patterns of spontaneous tumors are derived from studies with inbred mouse and rat strains. Among the

mostcomplete data availablearethose derivedfromthe 2 yearrodentbioassays conducted bythe National Toxicol-ogyProgram[NTP(10,11)]. Intheprotocolusedto assess

carcinogenicityin rodents, thereare concurrent controls of50miceorratsof each sexthatareheld fora104-week

exposure period and subsequently undergo complete

postmortem evaluation. The thousands of animals that

have been studied have demonstrated fairly consistent patterns of spontaneous tumor development, which has been maintained over manygenerations. Both mice (i.e., B6C3F1 hybrid) and rats (i.e., F344 strain) are housed

underhighly controlled conditions, andthedietsthey are

fed are well characterized and contain known, but extremelynegligible,amounts ofpotentially carcinogenic substances. The highly defined and controlled environ-mentprovides few,if any, sourcesofcarcinogens.Thus, the

constancyof thepatternoftumordevelopment within each

sexand species indicatesthat there areparticular genetic determinants that are responsible for theoccurrence of

spontaneous tumors.

The actual frequency of tumors developed at certain sitesdofluctuateand overtime;for example, the incidence

of mammary tumors or leukemia in rats has tended to increase. The increase in these latter tumors has been associated with improvementinmaintenance conditions,

thatis,areductioninendogenousviruses andbacteriathat

could decrease the health of the animals and also attributed to improved dietary conditions that result in

relatively high weightgain (11). Thus, there are

environ-mental factors that can influence the incidence of spon-taneous tumors but do not significantly influence the pattern with which these tumors develop. The origin of spontaneoustumorsis unclear. Aspecific genetic influence hasidentified thehigh frequency of livertumorsoccurring

in

B6C3F1

mice that isattributedto alocuscalledHcs(12). The genetic basis ofother types of spontaneous tumors

has not been well studied, but crosses between strains

showing high tissue-specific tumor incidence and other strains showing low tumor incidence at the same site, generally results in an intermediate level of tumor

expression in the F1 progeny,

suggesting

that in most casestheexpressionof spontaneoustumorsisdominantor

semidominant (13).

Among various ideas proposed to account for spon-taneoustumorigenesisisthe concept of DNAdamage of

endogenous origin. That is, mutations that could occur either as a consequence ofmistakes in DNArepair and

replicationmechanisms(14)orfromdamagethatoccurs as a consequence of normal metabolism

through

which

(3)

variousradicals ofoxygen,such assuperoxideorhydroxyl,

aregenerated (15-17). However, it is difficultto reconcile

these hypotheses with the spontaneous tumor patterns that develop inthe B6C3F1 mice and F344 rats because

neither can account for the tissue specificity of spon-taneous tumor incidence. If generalized DNA replication

orrepair errors oroxidative damagewereresponsible for the spontaneous tumors, onewould expect a more

gener-alized pattern of spontaneous tumor development that would be relatedtoeither'the tissues with the highest level ofendogenous cellular proliferationor tothose tissues that

have the highest levels of endogenous oxidative metabo-lism.Thepatternoftumorsobserved donotreflectthese patterns(10),andothermechanisms by which suchtumors

could arise should be considered.

It also has been proposed thattissues inwhich spon-taneous tumors arise undergo a higher level of spon-taneous initiation and that the action of nonmutagenic carcinogens may involve only the promotion or clonal expansion of suchspontaneously initiated cells. To evaluate this hypothesis, we have looked at the sites of

tumori-genesis that have been associated with exposure to 154

chemicalsidentifiedascarcinogensintheNTPbioassays

(9). As shown in Figure1, the carcinogens have induced

tumorsinabout30 tissuesites,butthe majority of chemi-calscanbe foundtobeactiveatapproximately10different

sites. These frequencies of induced tumorigenesis were thencomparedtothe sites of spontaneous tumorigenesis demonstrated in control animals. One example, male

Fischer rats (Fig. 2), shows a high level ofspontaneous

200 F 180 120 100 0

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20 0

tumorigenesisinthe hematopoieticsystem,whichis asite of relativelyhighcellproliferation. However,the hemato-poieticsystemiscomparabletothe adrenal glandinboth

spontaneousandinducedtumorincidence,but the level of endogenous cellularproliferation issignificantly lowerin

adrenal tissue. Another site of relatively high endogenous cell proliferationisthe skin, which showssignificantly less

spontaneous tumorigenesis andwas not asite oftumors

induced bynonmutagenic carcinogens.Sites ofthe highest

levels of inducedtumors were the liver and kidney, which

differconsiderablyinboth levels ofendogenous oxidative metabolism and spontaneous tumorincidence.

Theseresults,therefore,suggestthefollowing: a)notall sites inthebodyareequallyatriskfor chemical-induced tumorigenesis, b) the sites of induced tumors are not

directly related to the level ofendogenous cellular

pro-liferation,c)thespontaneous patternsof tumorigenesisdo not appear to dramatically influence the sites oftumor

induction by exogenous chemicals and, d) the genetic

influence on spontaneous tumors appears tobe the

pre-dominant factorintheirexpression. Ifindirectmutations

of oncogenes are involved in the development of spon-taneous tumors, the source ofthose spontaneous muta-tions is also unclear, and relatively little information is

available. The only extensive studies that have been

con-ducted involve the liverinthe B6C3F1 mouse.Spontaneous

mutations involving the 12th or13th codon of the v-H-ras genehave beenidentifiedinmany spontaneousandinduced

tumors (12), but mutated or translocated forms of other

oncogeneshavenotbeen studiedas

etensively.

_ Male p Rat _ Female Rat Male Mouse _Female Mouse

FIGURE 1.Occurrence oftumorsitesinducedby154carcinogenstestedby the NTPaccordingtosexandspecies. See Ashbyand Tennant(9)forkeyto

sites.

S LU CS MS IIC SP BD HG N PTG K L HS P C LS E PAG OST

ZG SB CG SK U TV 0 PG MG IS UB TG AG SV UT B OC MT

(4)

CIRCULATORY KIDNEY Spontaneous SI Nonmutagenic Carcinogens LIVER LUNG MAMMARY SKIN(S.C.) PANCREAS PREPUTIAL | THYROID PITUITARY ADRENAL

FIGLURE 2.Thefrequencies of inducedtumorigenesisbynonmutagenic carcinogenscomparedtothespontaneous ratesfor controlanimals.

Mechanisms of

Nonmutagenic

Carcinogenesis

The theories proposed to account forthe carcinogeni-city ofnonmutagenic chemicalscanbe combined intotwo

major groups: indirect mutagenesis and altered gene

expression. They arenotmutually exclusive mechanisms.

It isverypossible thatsomechemicals involvea

combina-tion of the two mechanisms, and there are even data to

suggest thatamong the mutagenic carcinogens, indirect

mutagenesis oralterationsintheexpression of important

target genes can be critical components in the

carcino-genic processes (19).

Indirect

Mutagenesis

Currently,themostintensespeculationabout nonmuta-genic carcinogensconcerns therelationship between tox-icity, sustained tissue damage, and induced cellular proliferation ormitogenesis (20).Cellproliferation

gener-ally referstocompensatoryorreparative celldivisionthat is a consequence of toxicity, whereas mitogenesis

gener-ally refers to the capacity ofachemical or substance to

directly elicit cell division. Investigations by Totter (15), Ceruti(16),and Amesand Gold(17)haveproposedthat by-products of the normal oxidative metabolism of cells gives rise to relatively high levels of free radicals such as

superoxide orhydroxyl that have the capacityto damage

DNAand to induce mutations. Ames and Gold (17) have

focused on chemicals that induce toxicity and suggest that reparative processes associated with toxic injury such as the infiltration ofmacrophages canincrease the level of

oxyradicals. They propose that toxic injury sustains cell proliferation and can promotethe development of tumors

by providingfor the clonalexpansionof cells damaged by oxyradicals. Evidence in support of this mechanism has been offeredbytheidentificationof8-hydroxyguanosine.

This is an altered DNA base that occurs as a result of

oxyradical-induced DNA damage. However, there is no way to determine whether such altered bases occur in healthy cells that are dividing and have the capacity to repair suchdamageorwhethertheyoccurpredominantly

in cells that are irreversibly injured by toxicity and thus could not contribute to eithertheproliferativeprocessor to subsequent developmentoftumors.

Asecond mechanism by which endogenous sources of DNAdamage could arise has been summarized byLoeb (14). He has proposed that lesions induced in DNA by

mistakes inreplicationandrepairprocessesinduce spon-taneous mutations and that such mutational events could accountforasignificant proportionofendogenously initi-ated cells.

Themajorargumentagainst the

amplification

orclonal expansion ofendogenousDNAdamagedcellsormutated cells (the "mitogenesis and mutagenesis" theory) come from two lines of evidence. The first is derived from an extensive evaluation ofanumber of chemicals that induce

(5)

Toxicitythat issustained for much of the 104-week period of chemical exposure in these bioassays can result in

proliferativeresponsessuchasinductionof hyperplasiain

specifictissues.Such changescanoccurintheabsence of

neoplasia (19). The bioassays are carried out for 2 years,

whichrepresentsapproximately60%of the lifespanof the animal. The animalsundergo completepostmortem exam-ination at theend ofthebioassay period, andthere is little

basis for arguing that tumors might be detected ifthe injury was sustained longer or if the animals were

observed longer.

The second line of

evidence

isbased on the pattern of spontaneous tumorsthatoccursinthemiceandratsused

inthe bioassay. As discussed previously, the data do not support generalized induction ofspontaneously initiated cells either by errors in proliferation and repair or by oxidativedamage. Comparisons of the sites of spontane-ous tumorswiththesitesofhighest levelsofendogenous cellularproliferationorof oxidativemetabolism show very

little relationship to the pattern ofspontaneous tumors. Therefore, it appears unlikely that the spontaneously occurringtumorsinrodentscanbedirectly accounted for by indirect mutagenesis mechanisms.These datado sup-portthe conceptthat the spontaneous tumorsarise as a

result of specific genetic determinantsintheanimal. This does not exclude thepossibilitythat somechemicals may

have the capacitytoinduce indirect oxidative damageor to increasethe level of cellular and repairproliferation

mis-takes, andtosubsequently clonallyamplify these mistakes whentheyoccurinanoncogeneorsuppressor gene.Itis a plausible mechanism for some tumorigenesis, but it is

unlikely to account for the full range of carcinogenic effects observedamongthelarge numberofnonmutagenic carcinogens.

Altered

Gene Expression

Ifthe clonal amplification ofspontaneous orindirectly initiated cells is not a common mechanism of

carcino-genesis, then howmay

proliferative

processesgive riseto

tumors? Thereare different linesofevidence thatcanbe

interpretedto

.support

arole for alterationsinthe expres-sion of one or more of the critical proto-oncogenes or proto-suppressor genes, that is, theendogenous formsof

theoncogenes or suppressor genesplay critical rolesinthe complex regulatory pathways that control normal cell

functions.Ananalogycanbe drawn from theprocessesof differentiation wherein sequential changes in the

expression ofgenes andthe responses ofdifferentiating

cellstothe geneproductsresultinheritablealterationsin the patternofgeneexpression. Suchchangesareacquired by,and oftenmodifiedin,progenycells.When appropriate

stages of differentiation arereached,the patternofgene

expression canbecome fixed and

subsequently

inherited by daughter cells arisinginthose tissues.Therefore,it is

possiblethat somechemicalsorenvironmentalagentscan actby

altering

theexpression of thesecriticalregulatory

genesandgiverisetoprogenycells in which theheritable phenotypic change provides a growth advantage. The

development of tumors in response to so-called

"solid-state" carcinogens, such as plastic strips, films, or calculi

could involve suchamechanism. The cells adapttogrowth

inthepresenceof, or on the foreign objects. Progressively, moredysregulatedcells can emerge with a growth advan-tagethateventuallybecomesa tumorphenotype(21). The

question of whether mutations are induced in critical targetsin such cells has notbeen addressed.Therefore,it is inadequate to assume that mutations are required to

elicitneoplasticgrowth under these conditions.

Hormonal carcinogenesisprovidesasecond line of

evi-dence.The profound changes on normal regulatory pro-cessesinduced by hormones involve complex interactions with surfaceorintracellularreceptors and the transduc-tion of signals to the nucleus where changes in gene

expressionareaffected by theactionofvarious

transcrip-tion factors. Oncogenesthatplayroles in these processes have beenidentified byvirtueof the mutatedforms of the genesthat existinandweretransducedbyretroviruses. However,there arenormal cellularcounterpartsforsuch genes. For example, the erbA protein functions as an intracellular receptorforthyroid hormone (T3) and func-tions as a negative regulator of transcription (22). The

mutatedform of erbA has beendemonstratedtoplay a role in tumorigenic processes. However, constitutive expres-sionof the endogenousc-erbA proto-oncogenecan plausi-blyresultin similar events. Forexample, ifachemicalcan

functionasaligand for the thyroid hormonereceptorand significant levels of the chemical are present for

pro-tracted periods of time, it is possible that the normal regulatory functions ofthe receptor willbe subverted and

thatthe erbAgene product would be constitutively

pro-duced. Theconsequencecouldbeadysregulatedpatternof cellular proliferation because there is selection for more

rapidlyproliferating cell populations. Daughter cells also requiredtoexist inthepresenceofthechemical would also possess the altered phenotype. Such

dysregulated

pro-liferating cells would provide a fertile environment in whichsubsequent genetic changes couldoccurand leadto amalignantphenotype. Thus, the proliferationofthyroid cellsmaybefundamentally differentinthepresenceof a

nonmutagenicchemical that canalterthe process of gene

expression.

Pathways suchasthatproposed for the erbAoncogene

provideabasis for viewing the emergence of some cancers as an adaptive process. In this hypothesis it is not the direct actionofthechemical thatinduces

specific

changes

in cells, but rather that the chemical elicits adaptive

responses on the part of cells that lead to deregulated growthpatternsandtheemergenceof neoplasticvariants

(21).While this may seemtobeaminordistinction between

the actions of somenonmutagenic chemicals,ithas

impor-tantimplications. Forexample,the adaptiveprocess may

beintrinsicallymorereversiblethan the inductive process. In the absence of the chemical, reversion to a normal

phenotypemaybepossible. Numerousexamples of rever-sion orremodeling have beenseeninstudiesof hepatocar-cinogenesis andintheneoplastic transformationof cells in

(6)

are aproduct thatcanbe studiedandquantitated farmore readily than can changes in the patterns of gene tran-scription. It is necessary to explore further the complex

molecular interactionsoftranscription factors with DNA

binding sites and to determine ifspecific chemicals can

dysregulate the expression of critical control genes in ways that do notinvolve changesin DNA sequence (23).

Thus, I am proposing that at least some portion of

cancers are diseases of transcription that arise through mistakesinthe complexprocessof transcriptional

regula-tion and that some chemicals have the capacity to illicit such changes independent of their ability to stimulate

cellularproliferation. Induced cellular proliferation, there-fore,maybeanessentialcomponentallowingforthe clonal amplification of transcriptionally altered cells. However,

chemicals that can induce cellular proliferation directly throughamitogeniceffect,orindirectlythrough elicitinga compensatory response tothetoxiceffects of the chemical,

are not necessarily carcinogenic. Other properties ofthe

chemical, related to their ability to specifically interfere with the transcriptional process, may be the important property that distinguishes this class of nonmutagenic carcinogen from both other nonmutagens andmutagens that arecarcinogens.

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