Carcinogenesis in mouse and human cells: parallels and paradoxes

Allan Balmain1 and Curtis C.Harris2

UCSF Cancer Center, 2340 Sutter Street, San Francisco, CA 94115, USA and
2 Laboratory of Human Carcinogenesis, Building 37 Room 2C05, 37 Convent Drive, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA


    Abstract
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 Abstract
 Similarities between mouse and...
 Cause-effect relationship...
 Contribution of p53 mutation...
 Stage-specific action of...
 Individual genetic...
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It has been known since the last century that genetic changes are important in carcinogenesis [Boveri,T. (1914) Zur Frage der Erstehung Maligner Tumoren. Gustav Fischer, Jena]. Observations of tumor cells growing in tissue culture led to the prediction, even before the true nature of the genetic material was known, that alterations at the chromosomal level were critically involved in the process of neoplastic development. The past 20 years have seen the transition of carcinogenesis studies from the purely observational to the molecular genetic level. Although much more needs to be done, it is nevertheless gratifying to be able to piece together the sequence of events from carcinogen exposure, metabolism of the carcinogen to the activated form, formation of specific carcinogen–DNA adducts, misrepair leading to the fixation of mutations in particular target genes, and the resulting selective outgrowth of neoplastic cells. The nature of many of these steps has been clarified only in the relatively recent past, and only for a small number of specific target genes, but the fact that we can say with confidence that such processes occur and are causal changes in tumorigenesis represents a tremendous advance over the situation pertaining 20 years ago. The purpose of this review is to summarize the advances over this time period in our understanding of some of the genetic alterations that contribute to neoplasia, with particular emphasis on chemical carcinogenesis in rodents and the parallels with transformation of human cells.

Abbreviations: AFB1, aflatoxin B1; B[a]P, benzo[a]pyrene; DMBA, dimethylbenzanthracene.


    Similarities between mouse and human cancers
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 Similarities between mouse and...
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Although much has been written about the discrepancies between mouse and human carcinogenesis, particularly with regard to the deficiencies in animal models for detection of carcinogens or prediction of risk, one of the most surprising results from research over the past 20 years has been the degree of genetic and biological similarity between the processes of neoplastic development in mouse and human systems. Although mice are small animals with a high metabolic rate and short life span, they develop tumors in the same tissues and in most cases with a remarkably similar histopathological course to that observed in humans. The step-wise nature of tumor progression from benign to malignant, has been amply demonstrated in both rodent (24) and human cancers (5). The particular genetic spectrum of events in human cancers is, with a few exceptions, surprisingly conserved in mice. In both species, point mutations lead to activation of ras gene family members, with the added similarity that squamous carcinomas predominantly have H-ras mutations, while adenocarcinomas of the lung or colon exhibit preferentially Ki-ras mutations, and haematopoietic malignancies are more likely to have N-ras mutations (68). The control of proliferation and growth of human intestinal epithelial cells is stimulated by loss-of-function mutations in the Apc gene or gain of function mutations in ß-catenin, and this again is reproduced in animal models of colon cancer (911). Tumors of the mouse undergo sequential genetic events similar to those detected in human tumors, including low-level amplification leading to increased expression of cyclin D1 (12), mitotic recombinations and non-disjunction events leading to loss of heterozygosity (LOH) on several chromosomes (1316), LOH and mutation in p53 (1721) and Rb (16), and p16INK4 homozygous deletions (2226). Given this exceptional conservation in cell-cycle control and in the signalling pathways leading to uncontrolled growth of specific cell types, it is indeed remarkable that mice can develop very malignant tumors showing multiple genetic alterations within a relatively short time period (6–18 months) while aggressive solid tumors in humans may take many years to reach the equivalent life-threatening stage.

Why should there be such an apparent speeding up of the whole process of carcinogenesis in mice? Although the mutation frequency is thought to be similar in mouse and human cells, cells of rodent origin are in general much easier to transform in culture, either by treatment with exogenous chemicals or by oncogene transfection. It has been speculated that the difference may be due to less efficient DNA repair, poorer control of genetic stability, or altered control of gene expression through processes such as DNA methylation (for review, see ref. 27).

Another possible explanation for mouse–human differences lies in the mechanisms by which cells become immortalized. Both mouse and human primary cells undergo senescence and die after a defined number of population doublings in vitro, but the frequency with which mouse cells escape from this death pathway is much higher than for human cells (28). A critical component of the immortalization process in human cells is the enzyme telomerase, a recently cloned enzyme that maintains the length of telomeres and helps to maintain chromosome integrity after repeated rounds of cell division (2931). It has been demonstrated that in the absence of a mechanism to repair chromosome ends, each round of cell division leads to loss of a small number of nucleotides, causing progressive erosion of genetic material at the end of each chromosome. Although telomerase exists in both mouse and human cells, there is evidence that control is more leaky in the mouse, providing a possible explanation for the ease with which rodent cells can become immortalized (32,33). The function of telomerase in transformation of mouse cells in vivo has been tested in elegant experiments involving the knockout of the gene encoding the essential mouse RNA component of telomerase activity. Although these animals are viable, they begin to show signs of neuronal and other tissue dysfunction after about six generations of breeding, at which point the telomeres have reached a critical length. Interestingly, telomerase negative mice appeared to be more resistant to the development of tumors on a p16/Ink4A null background (34), supporting the notion of a positive role for telomerase in cell transformation. On the other hand, the progressive loss of telomeres in the telomerase null mice seemed to lead to genetic instability that provoked an increase in spontaneous tumor formation (35). A similar picture emerged from a study of crosses between animals deficient in telomerase and the p53 tumor suppressor gene. The authors showed that p53 is activated by telomere shortening, leading to the apoptosis of cells with very short telomeres. In the absence of p53, these cells survive and go on to acquire additional genetic changes leading to malignancy (36). Presumably, although the vast majority of human tumors have increased telomerase activity, and telomerase has been shown to play a positive role in in vitro transformation of human cells (37), alternative mechanisms must have enabled the transformed cells of telomerase-deficient mice to escape the restriction of ever-shortening telomeres. Some human cells have also been shown to become immortalized in the absence of any detectable telomerase activity (38).

In spite of these substantial advances, many questions remain to be answered with regard to telomerase function in transformation, and the story is clearly more complicated than this simple scenario would suggest. Telomeres of mouse chromosomes are, in general, substantially longer than human telomeres, suggesting that more cell divisions would normally be required before the chromosome ends reach the stage where p53 and the telomerase enzyme are activated. By this scenario, mouse cells might take longer, in terms of population doublings, to activate the suicide response stimulated by short telomeres. The evolution of short telomeres in human cells may be a protective mechanism designed to eliminate cells that acquire unrestricted growth capacity during the relatively long human life span. Since mice only live for 1–2 years, they presumably have less of a requirement for such stringent control mechanisms to avoid tumor development. Telomere length can, however, also vary between mouse strains and species, and mice of the species Mus spretus have telomeres that are similar in length to those of human cells (39,40). Interestingly, these animals are relatively resistant to the development of cancers in most tissues that have been investigated (15,41,42; H.Nagase and A.Balmain, unpublished results), but any connection between this resistance and either telomere length or telomerase activity remains to be established. It is possible that the relatively high levels and uncontrolled expression of telomerase in Mus musculus may positively contribute to the ease of transformation of mouse cells, as recently demonstrated by in vitro transfection of mouse (43) and human (37) cells. The telomerase enzyme may have additional functions in transformation yet to be revealed (44), and the results of genetic manipulation of this important locus in mice are eagerly awaited.


    Cause–effect relationship between carcinogen exposure and genetic change
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 Similarities between mouse and...
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One of the major advantages of mouse models of carcinogenesis is in providing proof of the cause–effect relationship between carcinogen exposure, genetic alterations and biological events leading to neoplasia. If the mechanism of mutagenesis used by a particular carcinogen can be sufficiently well defined that it can be used as a `signature' for that class of agent, there would then emerge the possibility of using this molecular signature to establish the causal nature between particular genetic events in tumors and carcinogen exposure (the `smoking gun'). This would have major implications for pinpointing the exogenous causes of human cancers, and for the design of specific strategies to minimize exposure or introduce preventive measures. Early studies using the ras gene family members as `targets' for the action of carcinogens suggested that this might be a successful approach. Studies on skin carcinogenesis provided evidence that the same ras gene target is consistently activated in vivo by the classical initiation–promotion regimen for tumor induction (45) and demonstrated that activating mutations are already present at the early benign tumor stage (46). The strongest evidence that ras gene point mutations were directly induced by the initiating carcinogen came from sequencing the mutant alleles of rat mammary carcinomas and mouse skin tumors initiated either by polycyclic hydrocarbons or by alkylating agents. Mammary tumors induced by exposure to methylnitrosourea (MNU) had G->A mutations at codon 12, compatible with the proposed mechanism of action of methylating carcinogens (47,48). The same mutation was not detected in similar tumors induced by exposure to dimethylbenzanthracene (DMBA) (48), suggesting that the mutation was directly caused by carcinogen exposure. Mouse skin tumors initiated with DMBA showed predominantly mutations at the middle adenosine residue of H-ras codon 61 (CAA) which resulted in conversion to thymidine (CTA) and the introduction of an activating missense mutation (49,50). The same mutation was not seen in tumors induced by initiation with the alkylating agents MNU or N-methyl-N'-nitro-N-nitroso-guanidine, and these were subsequently shown to have the expected G->A mutations in the same target gene (51). A critical observation that helped to rationalize the mechanism of action of DMBA was reported by Dipple and co-workers, who had previously demonstrated that the diol epoxide resulting from metabolic activation of DMBA formed adducts primarily with adenosine residues (52,53). This observation explained the high frequency of mutations at the adenosine residues of codon 61 (CAA) of the H-ras gene in DMBA-initiated tumors. Many additional studies have been carried out to identify `mutation spectra' in a variety of putative target genes, including ras, p53 or transgenes such as the lacI gene, as a consequence of exposure to particular carcinogens in vivo. These have confirmed the preferred mechanism of mutation induction by DMBA and other polycyclic hydrocarbons (54,55) and have demonstrated the induction of different mutation types by other carcinogens (56,57).

A number of other model systems and target genes have now been studied and several putative carcinogen-specific mutations have been identified. Space does not allow a comprehensive review of all of this data, but striking examples of the `smoking gun' concept are the mutations in the p53 tumor suppressor gene in skin tumors induced by UV light, in colon carcinomas associated with carcinogenic pyrolysis products of proteins in cooked food, or in liver tumors induced by aflatoxin. In the first case, UV exposure is known to induce dimerization of adjacent pyrimidine residues in DNA, resulting in the formation of cyclobutane dimers or pyrimidine 64) pyrimidone photoproducts. The processes that control the repair of these lesions in DNA are discussed in detail elsewhere (58), but the interesting consequence of misrepair is that mutations occur most frequently at dipyrimidine sites in DNA, and on occasion double mutations are induced resulting in the conversion of TT to CC. This `signature' mutation is rarely seen except in DNA that has been exposed to UV radiation, and its detection can therefore be taken as strong evidence of exposure. Mutations characteristic of UV exposure have been detected in the p53 gene in human tumors (59), and have been seen in mouse skin tumors induced by UV exposure (60,61). Different types of mutations are seen in mouse skin tumors induced by repeated exposure to chemical mutagens (17,62), or in human tumors arising in other tissues such as the colon or lung (20). There seems little doubt, given the epidemiological and molecular evidence that has now accumulated, that the culprit for skin cancer induction is indeed UV light. Nevertheless, some important questions remain to be answered relating to the specific role of these mutations in initiation or promotion of early tumor cells (see below), and to the identity of carcinogens capable of inducing the other classes of mutations in the p53 gene in human cancers.

The debate as to which carcinogens (or endogenous processes) `cause' mutations in the p53 gene or other cellular target genes is best illustrated using colon cancer as an example. The most obvious candidate mutagen involved in colon cancer would be in the diet, since there is a large body of evidence implicating dietary factors in determination of colon cancer incidence. Some of these factors may exert their effects through non-mutational mechanisms that control the promotion stage of carcinogenesis (63), but others have been detected in cooked food, and compelling evidence points the finger at pyrolysis products of grilled meats and fish as being among the agents responsible for at least a proportion of cancers of the digestive tract. Evidence summarized by Sugimura (64) shows that cooked foods contain chemically well characterized and highly potent carcinogens, some of which induce particular `signature' mutations in the p53 gene or other target genes. The carcinogenic heterocyclic amine 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) found in cooked foods induces deletion of a G residue in the sequence 5'-GGG-3' in the lacI gene in transgenic mice. The same mutation is found in the Apc gene in rat colon cancers induced by treatment with this agent, and also in the p53 gene in some human cancers (64). The carcinogenic consequences of exposure to dietary nitrosamines are well documented (65), as are the effects of these alkylating agents on induction of G->A transition mutations in experimental cancers or in vitro model systems (51,66).

The simple elimination of these agents from our diet may, however, not be sufficient to eliminate the scourge of colon cancer in the human population, since endogenous processes can also lead to mutations in DNA. Robertson and Jones (67) discuss the importance of methylation at CpG sites in the genome as a means of controlling gene expression, and as a source of mutational events that contribute to development of cancers of the colon and other organs. They estimate that as many as 50% of all mutations in the p53 gene are at CpG sites in colon cancers, and emphasize the importance of methylation in potentiating mutation induction at other body sites through interactions with exogenous carcinogens.


    Contribution of p53 mutation spectrum analysis to molecular epidemiology
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Molecular epidemiology of human cancer risk has the challenging goal of identifying high risk individuals (68). The two major facets of molecular epidemiology are the assessment of carcinogen exposure including biomarkers of effect, and the inherited or acquired host susceptibility factors. Mutations in the p53 tumor suppressor gene frequently occur during the molecular pathogenesis of human cancer (69). The occurrence of p53 mutant cells in normal appearing tissues, preneoplastic lesions and clonally derived cancers are examples of a biomarker effect. The analysis of the mutation spectrum of the p53 gene can also generate hypotheses concerning the functional domains in the p53 protein and the etiology of the human cancer (70). The existence of a molecular link between carcinogen exposure and cancer causation can be evaluated by the criteria proposed by Hill (71). Using this `weight of the evidence' approach, there is a considerable amount of evidence now consistent with the hypotheses that sunlight exposure causes CC->TT tandem mutations in human skin cancer (Table IGo), that dietary aflatoxin B1 (AFB1) exposure can produce codon Ser249 (AGG->AGT) p53 mutations during human liver carcinogenesis (Table IIGo), and that chemical carcinogens, e.g. benzo[a]pyrene (B[a]P), in tobacco smoke cause p53 hotspot mutations in human lung carcinogenesis (Table IIIGo) (70,72). Nevertheless, alternative hypotheses should be evaluated. For example, rare, oxyradical-induced Ser249 p53 mutant hepatocytes might be more sensitive than normal hepatocytes to the genotoxicity of AFB1.


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Table I. Hypothesis: sunlight exposure can cause a characteristic CC->TT tandem double mutation in p53 in human skin cancer
 

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Table II. Hypothesis: dietary AFB1 exposure can cause Ser249 (AGG->AGT) p53 mutations during human liver carcinogenesis
 

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Table III. Hypothesis: the chemical carcinogens B[a]P in tobacco smoke can cause p53 hotspot mutations at codons 157, 248 and 273 in human lung carcinogenesis
 
The frequency and spectrum of p53 mutant cells in non-cancerous tissues may provide evidence of carcinogen exposure and cancer risk (70). This biomarker of effect also may be useful as an early indicator of the success of cancer chemotherapeutic agents. This hypothesis is currently being explored by studies of the p53 mutation load in sun-exposed skin (73,74) and oxyradical overload diseases (75,76).


    Stage-specific action of carcinogens
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Although genetic changes in a relatively large number of target genes have now been detected in human and rodent tumors, in the vast majority of cases it has not been possible to determine whether a particular mutation initiated the process, or occurred subsequent to the development of uncontrolled growth. Certain criteria have to be applied before a causal link between carcinogen exposure, genetic alteration and initiation of experimental carcinogenesis can be established. Ideally, the target tissue should be exposed only once to the initiating carcinogen. If multiple exposures occur, it cannot be concluded that any carcinogen-specific mutation found in the resulting tumor occurred at the time of initiation. Secondly, the induced mutation should be characteristic for the carcinogen used and, thirdly, the same target gene should be mutated in a different way by an alternative initiating carcinogen. Finally, the introduction of the mutant target gene into the appropriate target cell should reproduce the phenotype of initiation. Carcinogen-specific mutations in different model systems have been demonstrated for the members of the ras gene family, even after a single initiation treatment with a carcinogen (4850,77). The Apc gene is specifically mutated after exposure to the dietary carcinogen PhIP (64), and the introduction of mutations into the endogenous Apc gene leads to formation of intestinal adenomas in the mouse (78). ß-catenin, first found in an activated form in human colon tumors and melanomas that did not exhibit Apc mutations (79,80), was shown to be able to initiate tumors of the hair follicle in the mouse (81), and this observation subsequently led to the detection of point mutations in the same gene in human tumors arising from the hair follicle (82), thus establishing another important parallel between mouse and human tumor systems.

As mentioned above, carcinogen-specific mutations have also been detected in the p53 gene in both mouse and human tumors, and the suggestion has been made that at least for human skin tumors, these mutations are early, probably initiating, events (83,84). This would be in contrast to the situation seen with most solid tumors that exhibit mutistage progression, where p53 mutations are more associated with malignant progression. There is little evidence from in vivo studies that p53 mutations can act as initiating events for skin tumorigenesis. p53 null mice are not prone to spontaneous skin tumor formation unless they are initiated by treatment with a chemical mutagen. In this situation, there is strong evidence that p53 loss induces progression rather than initiation, and in fact reduces the incidence of benign tumors in chemical carcinogenesis experiments (85). In an interesting series of experiments, Roop and co-workers have shown that mice carrying an activated ras transgene, which normally develop multiple skin papillomas, fail to do so when crossed on to a p53 null background (86), again suggesting that p53 plays some essential role at a relatively early stage of tumor development. In a further test of the function of p53 in skin tumorigenesis, Wang et al. generated a transgenic mouse carrying an allele of p53 with putative gain-of-function properties (87) expressed under the control of a keratin promoter. Also in these mice there was no evidence for the ability of the mutant p53 allele to initiate carcinogenesis, since tumor development required both initiation and promotion by exogenous chemicals. The animals did, however, show increased papilloma number and carcinoma progression in comparison with wild-type mice. One caveat with these results is that the mutant p53 allele was expressed from a keratin1 promoter, which targets predominantly the more differentiated suprabasal cells. It is possible that expression of the same allele in the stem cell compartment located in the hair follicle region may have different effects, but this has not yet been investigated. Other results have clearly demonstrated that the target cell within the skin for expression of a ras oncogene is a critical determinant of the biological outcome (88), and the same may be true for expression of mutant p53. Until such studies are completed, the possible association between p53 mutation and initiation of human skin carcinogenesis will remain circumstantial.


    Individual genetic predisposition to `sporadic' cancer
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The probability that an individual will develop cancer is related both to the level of exposure to exogenous carcinogens, and the genetic background of that individual. Certain cancer-prone families carry germline mutations that facilitate the development of cancer at an early age regardless of the presence or absence of carcinogen exposure. A number of mutations in tumor suppressor genes, DNA repair genes or other genes involved in carcinogenesis have been identified that confer such `high penetrance' phenotypes. Sporadic cancers, constituting ~95% of the total human tumor burden, depend on interactions between the host genetic background and environmental carcinogens, and this area of `individualized genetic profiling of risk' will become increasingly important in the future. The only way to find the genes that may contribute to `sporadic' cancer susceptibility in humans is to make an educated guess on the basis of possible involvement in cancer, find polymorphisms in cancer patients and appropriate controls, and carry out an association study. The types of genes that have been most highly studied are those that metabolize carcinogens to an active state, or alternatively to detoxification products that are removed from the system. Different individuals have polymorphisms in any one of a panoply of genes that are involved in responses to exogenous chemicals, and extensive studies have been carried out to investigate possible associations between particular polymorphisms and cancer susceptibility. Although the indications are that some of these polymorphisms are indeed involved in determination of risk, in general the numbers of cases and controls do not allow definitive conclusions to be reached, and some of the results are still controversial (68).

Many biological events critical for tumorigenesis can occur spontaneously, particularly after early genetic changes may have decreased overall control of gene expression or genome stability, and it can safely be assumed that polymorphisms in genes that control many aspects of tumor progression, including rate of cell growth, migration, ability to induce angiogenesis, etc., contribute to susceptibility. It has been known for many years that different mouse strains show large variation in susceptibility to spontaneously arising cancers in different mouse tissues. The mapping of these `modifier' genes, many of which presumably have nothing to do with carcinogen metabolism since the tumors can often arise in the absence of carcinogen treatment, has been an arduous task. The advent of PCR, together with the development of a large panel of microsatellite-based markers (89,90) that facilitate genotyping of large numbers of mice, has revolutionized approaches to identification of susceptibility genes for multigenic traits such as cancer (9193). Novel breeding strategies have led to the development of recombinant inbred, recombinant congenic, consomic and advanced intercross lines, all of which have made important contributions to the mapping of disease loci. An important observation made using the mouse, which was presaged by studies on plant genetics (94) and predicted by earlier evolutionary theories (95) was that genetic interactions play an extremely important role in determination of susceptibility. It has been demonstrated using recombinant congenic mice that combinations of alleles at predisposition loci are critical, and even that the same allele can have either positive or negative effects depending on the genetic background of the host (9698). Such observations in well defined model systems emphasize the complexities facing us in trying to identify human tumor modifier genes. Simple association studies designed to detect an effect of a specific polymorphism on cancer susceptibility may not give a positive result if tested in isolation, but could nevertheless be very important in combination with particular alleles of genes at other locations in the genome.

The importance of high resolution mapping of these genes will become more important as the sequencing of the human and mouse genomes progresses, since at some point positional cloning will no longer be necessary. Database searching and testing of candidates will take over from gene identification strategies used at present. The possibilities presented by mouse genetics to really exploit natural genetic variation to find disease alleles, together with the unprecedented ability to manipulate the mouse genome to add or remove genes at will (99) gives the mouse community an opportunity to move from the era of testing and validation of cancer genes to discovery of novel genes and pathways that are not amenable to identification using human patients or tumors. While there is of course no guarantee that the modifier genes that may be discovered using mouse will also be polymorphic in humans, the mouse studies should nevertheless identify some of the rate-limiting pathways in cancer susceptibility, and thus help with the choice of candidates, or combinations thereof, for human association studies. This, in turn, should usher in a series of approaches to the prevention of human cancers, together with the detection of high-risk individuals who require special attention.


    Notes
 
1 To whom correspondence should be addressed Email: abalmain{at}cc.ucsf.edu Back


    Acknowledgments
 
A.B. is very grateful to the Cancer Research Campaign, UK, for funding over the past 20 years, and to numerous colleagues for their invaluable contributions and helpful discussions.


    References
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Received October 13, 1999; accepted October 29, 1999.