Manipulating the germline: its impact on the study of carcinogenesis
Alan R. Clarke
Cardiff School of Biosciences, Cardiff University, PO Box 911, Cardiff CF10 3US, UK
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Abstract
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Over the past two decades, the mouse has established itself as the primary organism in which to investigate the fundamental mechanisms of carcinogenesis and to model human neoplasia. The principal reason underlying such dominance almost certainly arises out of our ever increasing ability to manipulate the murine germline. Over the past 20 years we have moved from a position where animal models arose either spontaneously or were generated through exposure to carcinogen to a position in which it is possible to create and study precise mutations of choice. The most recent advances in inducible and conditional technologies now open the possibility for both temporal and tissue-specific gene manipulation. Each of these technological breakthroughs has facilitated significant steps forward in our understanding of the genetic basis of tumorigenesis. This review will highlight some of the major advances in the production and use of murine models of neoplasia over the last two decades.
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Modifying in the absence of transgenesis
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Prior to the ability to genetically manipulate the genome, animal models of neoplasia were principally based around the exposure of wild-type strains to carcinogen. This approach was clearly limited in its ability to analyse any genetic predisposition to disease. The first steps to resolve this problem did not strive to produce specific germline changes, but rather relied upon the use of germline mutagenesis to create strains with multiple random germline mutations. Use of N-ethyl-N-nitrosourea (ENU) had been shown to cause a variety of base changes, including transitions and transversions, with rates of forward mutations quoted as high as one in 700 for specific genes (1). This approach was used by one laboratory to generate a series of mutants affecting embryonic lethality and phenylalanine metabolism. Their phenotypic screen also identified mice characterized by anaemia, which was later shown to be a direct consequence of the development of multiple intestinal neoplasms (2).
This phenotype of this strain, now termed the Min (multiple intestinal neoplasms) mouse in view of its phenotype, closely resembled that of familial adenomatous polyposis patients, a syndrome characterized by multiple neoplasia and germline mutations of the APC gene. In due course, the mutation carried by the Min mouse was shown to be within the murine Apc gene (3), establishing the Min strain as an excellent genetic model of human intestinal neoplasia.
The use of germline mutagenesis to generate the Min mouse demonstrated the validity of such an approach; however, this route has not been widely adopted as a method to model disease for a number of reasons. Principally, these centre on the inability to control the target genes to be modified, the need for relatively large-scale breeding programmes and the difficulty in identifying subtle or recessive phenotypes. For these reasons, more directed approaches to modifying the genome have been developed.
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Addition or `conventional' transgenesis
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The ability to deliver DNA molecules into the germline of mice by pronuclear injection revolutionized our ability to study gene function. By selection of appropriate promoter and gene sequences it became possible to specifically address the role of candidate genes by adding additional wild-type or mutant copies to the germline. This approach has been extensively used to assess the heritable oncogenic potential of many different sequences. Early experiments addressed the tumour-promoting activities of the SV40 T-antigen genes. When driven by the metallothionein promoter the SV40 early region genes were demonstrated to strongly predispose to tumors within the choroid plexus (4). By pairing down the construct used in these experiments, it became possible to identify the large T antigen as the key predisposing element within this transgene (5), so establishing the T antigen as a potent oncogene. A number of similar experiments confirmed these findings for other tissues. For example, expression of the SV40 large T antigen was targeted to the pancreas both by use of rat insulin II (6) and elastase promoters (7). In both cases this resulted in tumours of the pancreas, respectively within the ß-cells of the exocrine pancreas and in the acinar cells. Similar use of the
-crystallin promoter to drive expression of the T antigens in the lens was also shown to lead to tumour development (8).
These and other experiments clearly established that transgenesis could be used to determine if a given sequence possessed true in vivo oncogenic activity. This opened the way for the rapid assessment of other candidate oncogenic sequences, and in doing so generated a series of models of neoplastic disease. In this initial tranche of experiments many of these models did not perhaps reflect the true genetic basis of human disease, rather simply establishing the oncogenic potential of sequences irrespective of evidence implicating them in human disease. This is perhaps most clearly demonstrated by the widespread use of the SV40 large T antigen to drive tumorigenesis in, apparently, almost any murine tissue type.
Although the SV40 T antigen may not be directly associated with human disease, clearly this is not true of many of the targets of this protein. This was demonstrated by experiments showing that retinal specific expression of the SV40 T antigen could mediate the development of retinoblastoma (9). These experiments achieved two important goals. First, they began to address the in vivo mechanisms of malignancy by showing that the oncogenic properties of the T antigen were at least partially dependent upon inactivation of the retinoblastoma gene product, Rb. Secondly, they demonstrated the ability of transgenesis to deliver a specific genetic model of human neoplasia.
Needless to say, this type of analysis was not confined to studies of the SV40 T antigen genes. In a parallel series of experiments several groups established a widespread role for the c-Myc gene in malignancy. Expression of c-Myc under the control of the immunoglobulin µ or
enhancers led to rapid lymphoma development (10). Use of the Thy-1 promoter delivered lymphoid and epithelial thymic tumours (11), and widespread expression of c-Myc using a mammary tumour virus LTR/c-Myc fusion transgene resulted in tumours in multiple tissue types, including testicular, mammary and lymphoid lineages (12). Whilst establishing c-Myc as a potent in vivo oncogene, these experiments also began to illustrate the complex requirement for genetic change during malignancy, as it was apparent that tissue type influenced the ability of c-Myc to predispose to neoplasia. A further general conclusion could now be made in that transgene-driven neoplasia was normally a multistage process. For example, use of the immunoglobulin heavy chain enhancer (E-µ) to drive c-Myc expression was shown to lead to aberrant B cell development, from which clonal lymphoid malignancies were ultimately assumed to result (13). This therefore delineated the effects of c-Myc overexpression upon both differentiation and ultimate tumour predisposition, and in doing so implicated aberrant B cell differentiation in the early stages of carcinogenesis.
In order to further probe gene dependencies during neoplasia, mice bearing multiple transgenic alleles were generated by intercrossing. This type of experiment rapidly identified synergy between different genes, and many such interactions have now been characterized. To take the example of c-Myc-mediated neoplasia, this has been shown to be markedly enhanced in a number of different transgenic backgrounds, including those positive for Bcl-2, Bmi-1 and cyclin D1 (1416).
The use of transgenic strains to identify co-operating events in malignancy has taken several different directions. In addition to the simple intercrosses described above, exposure to chemical carcinogen has been used. Here the concept was to use a given transgenic strain that shows a predisposition to malignancy, to accelerate neoplasia by exposure to carcinogen and subsequently to screen for co-operating events. For example, transgenic mice overexpressing the Pim-1 oncogene were characterized as predisposed to lymphoma. Additional exposure to the carcinogen ENU accelerated lymphomagenesis in this strain, and tumours that developed where characterized by increased levels of c-Myc and mutations in ras (17,18). Such results strongly argue for co-operation between these genes in neoplasia. An alternative approach has been to use viral integration to identify co-operating genes, termed `proviral tagging'. This has again been used in a Pim-1 transgenic background, where infection with murine leukaemia virus resulted in accelerated lymphomagenesis and associated proviral activation of either c-Myc or N-Myc (19). Further evidence for interaction between these genes was derived from, effectively, the inverse of this experiment, by using proviral tagging in c-Myc transgenic animals to identify Pim-1 as one of four co-operating loci (20).
Use of proviral tagging has not been constrained to analysis of Pim-1 and c-Myc. The Wnt-1 locus was identified as a key target of activation during mammary tumorigenesis in wild-type mice by proviral insertion of the mouse mammary tumour virus. This association was subsequently tested by the development of Int-1 transgenic mice (21) and proviral tagging was subsequently employed to identify Fgf3 and Fgf4 as co-operating oncogenes in mammary carcinogenesis (22).
The use of addition transgenesis revolutionized our ability to understand both the inception of neoplasia and progression of the disease. It should also be remembered that this approach has not been limited to the analysis of tumour promotion, but has also been used to assess the ability of a given gene to actively suppress neoplasia, for example by directing expression of the DNA repair gene O6-alkylguanine-DNA alkyltransferase to suppress thymic lymphomagenesis (23).
There are, however, a number of difficulties inherent in the creation and analysis of addition transgenics. First, there is little control over copy number of the transgene and there is no control over the transgene insertion site. These combine to leave the investigator with limited control over the level and pattern of transgene expression, even with the use of extremely well characterized promoters. Secondly, this approach is limited to the addition of genetic material. This does not absolutely preclude the study of loss of gene function; for example, the phenotype of p53 deficiency has been addressed through the use of dominant-negative or gain-of-function mutants (24,25). However, such models will always retain the caveat that proving total loss of function is extremely difficult. The advent of gene targeting technology, discussed below, has largely circumvented these problems.
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Inducible transgenesis
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Many of the genetic changes that predispose to neoplasia mediate the over-expression of mutant or even wild-type sequences. Conventional transgenic approaches have been used to model such genetic change with some success, ably demonstrated by the numerous experiments using c-Myc transgenes. However, using this approach temporal control over expression is usually determined by the characteristics of the promoter, and only becomes truly regulatable through the use of inducible or suppressible promoters. Although some eukaryotic promoters could theoretically be used in this way (for example the heat shock promoters) little progress has been made in their in vivo use. In the apparent absence of suitable eukaryotic promoters, several strategies have been adopted to regulate transgene expression. Perhaps the most widely used of these is the two-component tetracycline system, which has been shown to mediate both tetracycline-dependent induction and repression of target sequences in mammalian cells in vitro (26) and in transgenics (27). This approach has had widespread in vitro application in the study of carcinogenesis; however, although examples of the in vivo use of this system do exist [for example, in the conditional transformation of pancreatic ß-cells (28)], these are as yet relatively rare. One notable recent exception to this has been the use of a suppressible H-Ras transgene to demonstrate an essential role for mutant H-Ras in tumour maintenance (29), and this may well herald the more widespread use of this technology. A similar situation also pertains to use of the Ecdysone system, which exploits the Drosophila steroid-inducible ecdysone-responsive promoter (30), and for which no in vivo application has yet been reported, at least in relation to tumour development. Finally, use has been made of the ligand-binding domain of the estrogen receptor, in particular a tamoxifen-dependent mutation of this region to confer steroid-dependent inducibility to fusion proteins. Here again, this system has been used extensively in vitro, for example to render expression of the c-Myc gene steroid dependent (31), but use of this approach in vivo remains in its infancy. The potential of all these methods in the study of carcinogenesis is clearly great, as demonstrated by their use in culture and the very recent examples of in vivo use; however, as yet they have made little impact on the in vivo analysis of neoplasia.
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Gene targeting and gene knockouts
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Two significant advances were made during the 1980s that enabled the precise engineering of the genome. The first of these was the development of cultures of murine embryonic stem cells, termed ES cells, which maintained their pluripotency in culture (32), and which could be cloned and subsequently used to colonize the mouse germline (33). The second was the demonstration that endogenous sequences could be exchanged, albeit initially at low frequencies, with homology maintained in plasmid vectors. This technology, termed homologous recombination or gene targeting, permitted the exchange of subtly mutated cloned copies of a given gene with the endogenous allele (34,35). The ability of this approach to direct mutations into an endogenous gene of choice was then demonstrated for ES cells (36) and finally for the germline of mice (37).
Once gene targeting had established itself as a practical methodology for accessing the germline of mice, there has been a rapid explosion in the number of murine strains developed to study neoplasia. The first knockout of a tumour suppressor gene was of the p53 gene, created in 1992 (38). The development of this strain allowed the direct in vivo testing of a growing number of proposed roles for p53. Perhaps the first major surprise, and one to be repeated for many other genes, was that the severity of the phenotype was not as predicted. Given the multiple proposed roles for p53 it was remarkable that the mutants survived to adulthood. p53 deficiency was apparently fully compatible with normal development, although later analyses revealed a background dependent predisposition to neural tube defects (39,40). The rapid development of spontaneous tumours in these mice provided strong support for an absolute role for p53 in tumour suppression. This was further supported by observations of p53 deficiency accelerating carcinogen-induced liver neoplasia (41) and malignant progression in a chemically induced model of skin carcinogenesis (42). This strain was soon joined by other null mutations of p53 (43,44) which displayed a similar tumour predisposition and were used to probe the mechanisms underlying p53-dependent tumour suppression. For example, fibroblasts derived from mutant mice were used to confirm a role for p53 in cell-cycle arrest and in maintaining genomic stability (43). These mice were also used to establish the in vivo role of p53 in inducing apoptosis following DNA damage (4446), a role later also extended to hypoxia-mediated cell death (47).
The mechanisms underlying tumour suppression have perhaps been most extensively studied using the p53 mutant strains. Thus, we now know that p53 deficiency can co-operate with many other genetic alterations to promote neoplasia, such as with the SCID mutation (48), with mammary-specific expression of Wnt-1 (49), and with c-Myc (50). Intercrossing of p53 mutants into other transgenic lines has also helped elucidate complex interactions between p53 and other genes. For example, p53 deficiency rescues embryonic lethality in Mdm2-deficient mice, reflecting the presence of a regulatory loop between these two genes (51). However, transgenic analysis also identified a role for Mdm2 outside of this loop, as intercrossing to mice overexpressing Mdm2 identified a p53-independent role in neoplasia for Mdm2 (52). Similar approaches have characterized interactions between p53 and a range of other genes, most notably including the Atm gene (53).
As demonstrated for the p53 gene, knockout strains have proven particularly potent tools in the analysis of tumour suppressor genes. The list of genes analysed in this fashion now includes the retinoblastoma (Rb) gene (5456), the Apc gene (57), the Neurofibromatosis genes Nf1 and Nf2 (58,59), the Brca1 and Brca2 genes (6062) and the mismatch repair genes Msh2, Mlh1, Pms1 and Pms2 (63,64). Although this list now include the majority of loci associated with human tumour syndromes, it does not include a number of other genes that have become implicated in tumour suppression through their knockout phenotype, such as
-inhibin (65). This fact in itself underlines how potent this form of analysis has become.
The generation of all these strains has allowed fundamental advances in our understanding of the mechanisms by which these mutations predispose to malignancy. Often this has led to surprising results, as with the strains generated to analyse Rb gene function. These showed that functional Rb was not absolutely essential for cell-cycle progression, as although deficiency of Rb does lead to embryonic lethality, development up to day 12 of gestation is remarkably normal. Secondly, Rb mutants were found not to directly model human retinoblastoma in that heterozygotes failed to develop tumours of the retina, although they did succumb to tumours of the pituitary. This finding clearly identified a fundamental biological difference between mice and humans, and one which has been probed using intercrosses with mice mutant for other members of the retinoblastoma gene family. Thus, Rb heterozygotes crossed onto a p107-deficient background do develop multiple dysplastic lesions of the retina (66), a finding which has begun to unravel the tissue and species-dependent differences in the reliance upon different Rb family members.
As with p53, and indeed all the other models generated, intercrosses to conventional transgenic and knockout strains have been used to probe Rb-dependent pathways. This type of experiment can often yield apparently paradoxical results. Thus, inactivation of E2F-1, the transcriptional activity of which Rb normally suppresses, was shown to predispose to tumorigenesis in a range of tissue types (67). However, experiments using intercrosses with Rb heterozygotes and E2F-1 mutants confirmed the predicted requirement for E2F-1 in Rb-mediated tumorigenesis (68). These results serve to underline both the strengths and potential difficulties of transgenic analysis in the investigation of apparently simple pathways of gene dependency.
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Refining the gene knockout approach
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The advent of gene targeting has clearly had a massive impact on our ability to relate gene function and dysfunction to carcinogenesis. This technology does, however, still possess several drawbacks. First, conventional targeting strategies leave a selection cassette within the targeted locus. This presents few problems if the aim is simply to inactivate the gene of interest, but largely precludes the introduction of subtle mutations into the germline, and thereby the modelling of point mutations in human disease. One solution has been to place the selection cassette into intronic sequences; however, even this placement may influence gene expression. A number of refinements have therefore been developed to address such problems. These rely on the use of multiple targeting steps to introduce only the mutation of choice into the target locus. This route has been followed for a number of genes, including the Hox genes (69) and the cystic fibrosis gene cftr-1 (70). However, these approaches have as yet found little application in the study of neoplasia.
Perhaps the most serious drawback of conventional targeting is its inability to induce changes in the genome at specific times of development or in specific tissues. This is most limiting when constitutive loss of gene function leads to embryonic death, precluding any analysis of loss of function in adult tissues. Furthermore, studies of carcinogenesis in a given tissue may be prevented because of the severity of phenotype in another cell type. Perhaps the clearest example of this is the rapid development of lymphoma in a number of different knockout strains generated primarily to study neo- plasia of the intestine. Many of these problems may now have been overcome by the development of conditional targeting, discussed below. Another, simpler approach has been to generate animals chimeric for wild-type and mutant cells. This can lead to the complete rescue of the lethal phenotype, as occurred when Rb null ES cells were used to generate adult chimeras (71,72). Alternatively, it can allow a dominant phenotype to be studied that is otherwise incompatible with germline transmission, as occurred with a WT1 mutation modelling DenysDrash syndrome (73).
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Conditional knockout alleles
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The drive to create truly conditional alleles came from a number of different directions. Perhaps the most powerful incentive has been the high incidence of embryonic lethality observed in constitutive knockouts, which effectively precludes the analysis of gene function in adult tissues. Other reasons include the difficulty that particular tissue types cannot be properly studied in isolation, and the concern that developmental compensation may be occurring within some knockouts, thereby complicating the phenotypic analysis.
In 1988, Sauer and Henderson demonstrated that the cre protein of bacteriophage P1 could be used in mammalian cells to mediate recombination between two 34 bp sites termed loci of recombination or `lox' sites (74). The result of cre-mediated recombination is either the deletion or inversion of the sequences flanked by the lox sites, dependent on their orientation. One of the major advantages of this system, and of the essentially equivalent Flp-frt system, is that no mammalian protein is capable of recognizing the lox sites, and background recombination in the absence of the cre recombinase is undetectable. Furthermore, the recombination event is an `all or nothing' phenomenon, so partial or graded expression should not occur. The recognition that cre (or Flp)-mediated excision of lox (or frt)-flanked sequences could result in gene inactivation or upregulation (through deletion of inhibitory sequences) provided a powerful solution to many of the difficulties linked to constitutive knockouts. The first in vivo demonstration of this technology came in 1994 with the T-cell-specific knockout of the DNA polymerase ß gene (75).
In order for this technology to be applied to the study of neoplasia, two components were required. The first of these is the generation of appropriate lox/frt-flanked alleles which could be shown to be unaffected by the insertion of the lox sites. This element is now in place for a number of different genes. Lox/frt flanked alleles have been reported for an SV40 large T antigen transgene (76) and for endogenous alleles of Rb (77), Brca 1 (78) and Apc (79). To date, these have been used in a largely confirmatory manner, for example by showing that intestinal deletion of Apc leads to rapid adenoma formation. Clearly, as the use of conditional alleles grows, this role will shift to a more fundamental analysis of gene function. This is already true for the Brca1 conditional allele, where mammary specific deletion has revealed a role in normal ductal morphogenesis as well as in tumour suppression.
The second requirement is for extremely tight control over expression of the recombinase. Conventional transgenic strains have been created, wherein expression is tissue- and/or developmentally restricted, and these have been used effectively to study gene deletion, as in the Brca1 study mentioned above. This method does, however, suffer from all the drawbacks of conventional transgenesis, such that the current availability of useful strains is somewhat limited. Several different groups have developed strategies that render cre expression conditional, through use of the tetracycline system (80) or by use of the ligand-binding domain of the oestrogen receptor (8183). An alternative approach has been to directly deliver the recombinase directly. This has been most efficiently demonstrated using adenovirus engineered to express recombinase (84,85). However, this approach is again subject to difficulties, principally associated with restricted delivery and host immune responses, and although it has been used (79) to study carcinogenesis, its use is not yet widespread.
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Chromosomal rearrangements
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The development of cre/flp technology has opened another approach to altering the genome, that of engineering at the level of the chromosome. Translocations and loss of heterozygosity are key genetic events associated with neoplasia. The ability to use the cre-lox system to mediate defined deficiencies, inversions, duplications or translocations was demonstrated both in ES cells and in the germline of mice by three different groups (8688). Such macrogenetic changes can be shown to predispose to tumorigenesis, for example of the thymus in mice bearing a 1 Mb duplication of a portion of chromosome 11 (89). Perhaps the most interesting prospect for this technology is to use chemical mutagenesis in conjunction with hemizygous chromosomal deletions to drive a relatively rapid functional screen of the haploid areas so generated (90).
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Transgenic mice as reporters of carcinogenesis
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Many of the examples cited above have demonstrated how transgenic technology has enabled a better understanding of the molecular basis of neoplasia. One remaining fundamental question is how useful such transgenic models are at directly assessing the tumour preventative, mutagenic or carcinogenic properties of a given compound, and in determining the gene dependency of such predisposition. Studies of the impact of drug and genotype upon mutation rates have been facilitated by the development of transgenic strains that carry a LacZ transgene that can subsequently be rescued and scored for functional mutations. Use has been made of these strains to score spontaneous mutation rates in mutant strains, such as in p53-deficient mice (91), and also following exposure to known or potential carcinogens (92). This type of study has been subject to some criticism, principally because it uses a prokaryotic transgenic target in which mutation frequency is scored ex vivo; however, it has been shown to compare well with data collected for mutation at the Dlb-1 locus, the only widely used endogenous marker of in vivo mutation (93).
The precise relationship between mutagenesis and carcinogenesis remains unresolved, and therefore transgenic strains have principally been used to directly assess the impact upon tumour development, with a number of different models being used in this way. Mice heterozygous for the Apc gene spontaneously develop multiple intestinal adenomas, and have therefore been used as a model for human intestinal malignancy. This strain has been used to test general principles of carcinogenesis such as the role of DNA methylation in cancer genetics (94), to test the response to potential tumour suppressive agents such as aspirin (95), and to specifically test the carcinogenicity of certain compounds (96). Mice transgenic for Eµ-Pim-1 have also been proposed for use in short-term carcinogenicity testing, although this strain has been reported to lack sufficient sensitivity for such a role (97). In contrast, mice mutant for p53 and mice transgenic for an activated copy of the H-ras oncogene (termed Tg.AC mice) have both been proposed as rapid and inexpensive test systems to identify carcinogens (98), with initial results suggesting these are at least as accurate as conventional 2 year rodent assays.
These studies have therefore established the feasibility of using these models in this manner; however, some caution must be exercised in their use and interpretation. In the final analysis, carcinogenesis in these mutant strains is determined by the particular genetic alteration being used, such that mutagenic or carcinogenic properties mediated by other pathways may be underrepresented. Furthermore, it is clear that carcinogenesis is influenced by species-dependent factors. p53 deficiency in the human does not strongly predispose to lymphoma, as it does in the mouse. Similarly, mutations at the murine retinoblastoma locus predispose to pituitary tumours and not to retinal tumours. It is indisputable that analysis of this type is yielding information on gene-dependent mechanisms of neoplasia. However, where these strains are being used to directly test compounds and therapies relevant to human disease, they can only be viewed as predictors of outcome, as remains true for the use of all animal models of disease.
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Conclusions
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It is clear that the advent of transgenic technology has revolutionized the study of carcinogenesis. This has been particularly true for our understanding of the genetic basis of disease and the fundamental analysis of gene function. Transgenesis has also successfully delivered a number of specific models of human neoplasia, perhaps best exemplified by the modelling of human inherited syndromes such as LiFraumeni (mutant for p53) and familial adenomatous polyposis (mutant for APC). It would, however, be untrue to say that transgenesis is not without its technical limitations, which can sometimes confound the analysis of mutant strains. These difficulties have, however, driven a rapid evolution in technology, such that our ability to manipulate the germline is now greatly refined.
We are currently standing on a most exciting threshold for this technology, as a number of key new approaches come onstream, including the ability to regulate transgene expression in vivo and the advent of conditional gene targeting. As with the development of gene-knockout strains, these can again be expected to revolutionize our ability to understand the genetic control of neoplasia.
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Notes
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Email: clarkeAR{at}cardiff.ac.uk
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Received August 17, 1999;
accepted October 7, 1999.