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Carcinogenesis |
Department of Dermatology, University Medical Center Utrecht, 3508 GA Utrecht [R. J. W. B., H. R., W. A. V. V., F. R. d. G.]; MGC-Department of Cell Biology and Genetics, Erasmus University Rotterdam, 3000 DR Rotterdam [G. T. J. v. d. H.]; Laboratory of Health Effects Research, National Institute of Public Health and the Environment, 3720 BA Bilthoven [H. J. v. K.]; and MGC-Department of Radiation Genetics and Chemical Mutagenesis, Leiden University, 2300 RA Leiden [L. H. F. M.], the Netherlands
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1 mm) is 84 days for the XPC
-/- mice, 115 days for the CSB -/- mice, and
234–238 days for the heterozygous and wild-type control groups. These
results indicate that GGR is more important than TCR in protection
against UV-induced carcinomas of the skin but not against other UV
effects such as sunburn, epidermal thickening, scaling of the stratum
corneum, and development of papillomas. These results also indicate
that GGR capacity may serve as a better predictor for skin cancer
susceptibility than sensitivity to sunburn. The relative cancer
susceptibilities of GGR- and TCR-deficient skin could well depend on
the balance between an increased mutation rate and the presence (in
CSB -/-) or lack (in XPC -/-) of a
compensatory apoptotic response. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In humans, mutations in NER genes are the cause of the rare genetic diseases XP and CS. Complementation studies have revealed the existence of seven genes involved in XP (XPA through XPG) and two in CS (CSA and CSB; Refs. 2 and 6 ). All XP complementation groups are defective in both GGR and TCR, with the exception of XPC and XPE, which are defective in GGR only (3 , 7 , 8) . A specific defect in TCR is encountered in CSA and CSB (9, 10, 11) . Patients within the same complementation group can vary quantitatively in their skin cancer susceptibility, because different mutations in the same gene can lead to different levels of impairment. Because it is very difficult to make well-controlled, qualitative, and quantitative comparisons in cancer susceptibility among the separate XP and CS complementation groups on basis of the available patient data, mouse models for XP and CS have been developed.
XPA (12 , 13) and XPC (14, 15, 16) knockout mice show a higher susceptibility to UV-induced skin cancer than their heterozygous and wild-type littermates, and as such resemble human patients with XPA and XPC. In marked contrast to human CS patients, CSB mice are also prone to UV- and chemically induced skin cancer (11) , indicating that TCR also protects against carcinogenesis. XPC and CSB mutant mice are very well suited to compare the relative contributions of GGR and TCR to the prevention of skin cancer. However, a direct quantitative comparison of skin cancer susceptibilities between rodent XPC and CSB cannot be made on basis of the published data because: (a) animals of different genetic background were used; (b) experiments were discontinued before the repair-proficient control animals contracted tumors; and (c) different irradiation schedules and different types of lamps were used. To directly compare the effects of defective GGR versus TCR, we have crossed the CSB and the XPC defect into a strain of SKH hairless mice and compared their relative susceptibilities to UV-induced skin cancer under identical experimental conditions. Here we show that GGR deficiency results in a much higher skin cancer susceptibility than TCR deficiency, whereas other UV effects such as sunburn, parakeratosis, and the development of benign papillomas appear to be primarily related to TCR deficiency.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To make a direct comparison of the relative contribution of GGR and TCR to UV carcinogenesis XPC (129/Sv-C57Bl/6 background) and CSB animals (129/Ola-FVB background) were crossed with HRA/SKH albino hairless mice. Hairless animals do not have to be shaved before exposure and, therefore, allow a very accurate UV dosimetry. After one more backcross with HRA/SKH mice, hairless offspring with albino eyes and heterozygous for XPC and CSB were intercrossed to generate hairless albino XPC and CSB mice. Heterozygous and wild-type littermates were used as controls. Genotyping was performed by PCR analysis of genomic DNA isolated from the tail tips (11 , 14) . For XPC genotyping, the following three primers were used: (a) XPCex10s 5'-ATTGCGTGCATACCTTGCAC-3'; (b) neo 5'-CGCATCGCCTTCTATCGCCT-3'; and (c) XPCin10as 5'-TATCTCCTCAAACCC-TGCTC-3'. Primer a + c identifies the wild-type allele as a ±250-bp PCR fragment, and primer b + c identifies the targeted allele as a ±350-bp PCR fragment. For CSB genotyping, the following three primers were used: (a) CSBex5s 5'-GCTGCTTATAATAATCCTCATCTCC-3'; (b) neo 5'-ATCTGCGTGTTCGAATTCGCCAATG-3'; and (c) CSBin5as 5'-GTCTTCTG-ATGACGTTAGCTATGAG-3'. Primer a + c identifies the wild-type allele as a ±200-bp PCR fragment, and primer b + c identifies the targeted allele as a ±500-bp PCR fragment. Animal experiments were approved by an ethical committee of Utrecht University, as required by Dutch law.
Single Exposure Experiments.
The dorsal skin of hairless CSB and hairless XPC mice as well as
heterozygous and wild-type littermates was exposed to UVB radiation
using an Hanovia Kromayer lamp equipped with a Schott-WG305 filter
(exposure rate, 135 J/m2/s; 280–400 nm). This
hand-held lamp allows short exposures to limited areas of the skin by
placing its circular port (
2.5 cm2) in close
contact to the skin (17)
. For all genotypes, two male and
two female mice were exposed to 1, 2, 8, 16, and 24 s of UV
radiation from the Kromayer lamp. All exposures were given in duplicate
on separate mice. The mice were checked independently by two
experienced, but noninformed, observers for erythema and/or edema at 8,
24, 36, 48, and 72 h after the exposures.
Chronic Exposure Experiments.
During the chronic exposures (that lasted 300 days), the animals
were housed separately in macrolon type I cages. Standard mouse chow
(Hope Farms RMB-H) and tap water were available ad libitum.
The mice were kept at an ambient temperature of 25 ± 1oC. The room was illuminated with yellow
fluorescent tubes (Philips TL40W/16) in a 12-h cycle (switched on at
6:00 a.m. and off at 6:00 p.m.). These lamps do not emit any measurable
UV radiation. No daylight entered the room. In the irradiation set-up,
three fluorescent American Philips F40 sunlamps were mounted above the
animal compartments. A perforated metal sheet was positioned between
the lamps and the animals to reduce the exposure rate at the mouse
level. Fine tuning of the exposure was accomplished by electronic
dimmer circuits that controlled the radiant output of the lamps. A
schematic representation of the exposure set-up and the relative
spectral energy output of the F40 lamps have been published earlier
(18)
.
The groups of repair-deficient animals (CSB -/- and XPC -/-) consisted of 14 mice, with each 7 heterozygous (CSB +/- and XPC +/-) and 7 wild-type (CSB +/+ and XPC +/+) littermates as controls. The different genotypes were placed in random order under the lamps, and all animals were exposed daily to 80 J/m2 (250–400 nm) UV radiation from the Philips F40 lamps. Exposure time was 6 min/day, between 12:30 and 12:36 p.m. In addition, two CSB -/- mice, two XPC -/- mice, and controls were subjected to this dose regimen for 10 days. Mice were killed by cervical dislocation after ether anesthesia, and skin samples were routinely processed (H&E staining) for histopathological examination.
Animal Observations, Definitions, and Data Analysis.
Animals were checked weekly, and all deviations from normal skin
appearance (redness, scratching, scaling, tumors, and others) were
recorded. The tumor locations were mapped and numbered for each animal
separately, and lesions were counted only if the observation could be
confirmed during the next check-up. During the experiment, we
distinguished between morphologically evident papillomas (pedunculated,
protruding tumors with a "cauliflower-like" surface) and other
tumors. Previous experiments have shown that macroscopic identification
of papillomas corresponds very well with the histological findings, and
that the "other tumors" almost exclusively consist of SCCs and
their precursor lesions, actinic keratoses (18, 19, 20, 21)
.
Tumors were also subdivided according to diameter: <1 mm, 1 mm, and
2 mm. Mice were sacrificed when carrying at least 1 tumor with a
diameter 4 mm. The day of the first exposure of an experimental group
was defined as t = 0
(t50 is the median tumor induction
time). If a tumor was first seen at t = ti, and t = ti-1 was the previous checkup time,
then the induction time was defined as
(ti + ti-1)/2. Graphical representation of
the prevalence versus time is based on an actuarial method
described by Kaplan and Meier (22)
and adapted to
carcinogenesis by Peto et al. (23)
. This
procedure computes the chance of tumor-free survival. The
death-corrected tumor prevalence is then given by one minus this
chance. Individual latency times of first tumors were fitted by a
log-normal distribution using a maximum likelihood method for a concise
description of the observations in terms of
ln(t50) and the SD in
ln(time-to-first-tumor/mouse).
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RESULTS |
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We have established earlier the MED for the Kromayer lamp for hairless XPA knockout mice, which are defective in both GGR and TCR. These results parallel our present findings for the CSB mice, i.e., an MED between 1 and 2 s for XPA -/- and between 8 and 16 s for XPA +/- and +/+ (18) . Apparently, erythema and edema are triggered by persistent photoproducts in the template strand of transcriptionally active DNA, rather than by lesions in nontranscribed DNA.
Epidermal Hyperplasia Is Associated with TCR and GGR Deficiency.
Epidermal hyperplasia can be considered as a protective reaction
against carcinogenesis, because the increase in the number of epidermal
cells dilutes unrepaired DNA damage and the thickening of the
stratum corneum and stratum spinosum reduces the penetration of UV
radiation to the basal cell layer. On the other hand, it can also be
argued that the epidermal cell proliferation leading to hyperplasia
enhances the mutation rate and thus stimulates carcinogenesis
(28)
. To establish the importance of TCR and GGR for
development of epidermal hyperplasia, we sacrificed two XPC
-/- mice, two CSB -/- mice, and control animals
after 10 days of exposure to 80 J/m2/day (Philips
F40 lamps; the daily dose used in the chronic exposure experiment).
This dose corresponds to about 70% of the MED for CSB -/-
mice but is <10% of the MED for XPC -/- mice and
repair-proficient control animals. Fig. 1
shows representative samples of the epidermis of XPC -/-,
CSB -/- and control mice after 10 days of exposure. It is
evident that both TCR-deficient animals and GGR-deficient animals are
prone to epidermal hyperplasia at an exposure level that does not
induce a hyperplastic reaction in repair-proficient control animals.
Hence, unlike erythema and edema, epidermal hyperplasia appears to be
triggered by persistent photoproducts in both transcriptionally active
and inactive DNA.
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), which is in agreement with
earlier findings in shaved CSB -/- mice (11)
.
Under the same experimental conditions XPC -/- mice do not
show parakeratosis (Fig. 1A
). The parakeratosis is
macroscopically visible as scaling of the stratum corneum and is
prominently present at the irradiated dorsal skin of all CSB
-/- animals. In contrast, the skin of XPC -/-
animals and heterozygous and wild-type controls do not show any
macroscopically visible changes, besides the appearance of tumors. Fig. 2
shows representative samples of skin of CSB and of XPC mice when the
first tumors appear.
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Development of SCC Is Predominantly Associated with GGR Deficiency.
In a previous study, we have established the susceptibilities of
hairless, totally NER-deficient XPA knockout mice and their
heterozygous and wild-type littermates to UV-induced carcinogenesis
(18)
. In the present study, we have measured the relative
skin cancer susceptibility of hairless mice with a specific defect in
TCR (CSB knockouts) or GGR (XPC knockouts).
Histological analysis of an aselect sample of tumors (from
XPC knockouts, CSB knockouts, and controls) that
were macroscopically classified as "nonpapillomas" confirmed that
these tumors were SCCs and their precursors, actinic keratoses (data
not shown). If the prevalence of SCC (excluding benign papillomas from
further quantitative analysis) is plotted on a probability scale
versus time on a logarithmic scale, the points fall along a
straight line, a cumulative log-normal distribution. Fig. 3
shows these plots and the log-normal distributions for XPC
-/-, CSB -/-, and the control animals for both
strains, fitted according to a maximum likelihood method. The optimum
values for the median tumor induction time
(t50), µ = ln
(t50), and the SD (
) of the fitted
log-normal distributions are shown in Table 1
. The prevalence curves for XPC -/-, CSB -/-, and for the
repair-proficient controls run roughly parallel (i.e.,
values do not differ significantly). Most susceptible to UV
carcinogenesis is the XPC knockout strain, which has a
median tumor induction time (t50) of
1-mm tumors of 84 days (cumulative UV dose of 6.7
kJ/m2), whereas the CSB knockout
strain has a t50 of 115 days
(cumulative UV dose of 9.2 kJ/m2). The appearance
of skin carcinomas in the XPC controls (both +/-
and +/+ mice; t50 of 238
days; cumulative UV dose of 19.0 kJ/m2) does not
differ significantly from that in the CSB controls (both
+/- and +/+ mice;
t50 of 234 days; cumulative UV dose of
18.7 kJ/m2), as tested by the nonparametric trend
analysis as described by Peto et al. (23)
. A
separate data analysis of XPC +/- mice versus XPC
+/+ mice and of CSB +/- mice versus CSB +/+
mice does not show a statistically significant difference between
heterozygotes and wild-type animals (data not shown). This is in line
with our data published previously showing that XPA +/-
mice do not have a higher susceptibility to UV carcinogenesis than
XPA +/+ animals (18)
. In conclusion, our data
demonstrate that defective GGR contributes more prominently to SCC
development than defective TCR.
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DISCUSSION |
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An interesting question is whether the skin cancer susceptibilities of XPC mice (GGR-deficient) and CSB mice (TCR-deficient) "add up" to the susceptibility of XPA mice (GGR + TCR-deficient). This might be an oversimplification because the fact that both XPC/CSB double knockout mice and XPA/CSB double knockout mice die before weaning (29) suggests that there is another function for the CSB protein, besides its role in NER. To answer this question properly, we are currently determining the dose-response relationships for UV carcinogenesis in the hairless XPA, XPC, and CSB mouse strains.
Although important in protection against skin cancer, GGR appears not
to play a role in the development of UV-induced erythema/edema,
parakeratosis, and papillomatosis. We have shown that these phenomena
relate exclusively to the capacity to perform TCR. Erythema and edema
occur within 48 h after a single exposure and are therefore not
expected to originate from mutations in active genes. A plausible
explanation, put forward by Ljungman and Zhang (30)
, is
that persisting photolesions in the template strand of active genes
block the vital process of transcription by RNA polymerase II, which
triggers apoptosis. They have demonstrated that skin fibroblasts from
XPA and CSB patients are highly prone to UV-induced apoptosis,
whereas cells from XPC patients are not. Recently, these findings have
been confirmed for the XPA, XPC, and CSB hairless mouse
models.4
The increased sensitivity to UV-induced apoptosis in XPA and CSB, but
not in XPC, correlates well with the sensitivities to sunburn found in
the present experiment, suggesting that blockage of transcription is
also a key event in the development of sunburn. The same holds for the
parakeratosis observed in CSB -/- mice (Figs. 1
2
). In
TCR-deficient animals, parakeratosis can already be found after 10 days
of exposure (Fig. 1B
), whereas GGR-deficient animals do not
show parakeratosis, not even at the tumor-bearing stage (Fig. 2A
). Disturbed epidermal differentiation in TCR-deficient
animals might well be triggered by blockage of RNA polymerase II by
persisting photolesions in transcriptionally active DNA.
We have shown that under chronic UVB exposure, CSB -/-
mice get, in addition to SCCs, a fair amount of benign papillomas, the
first of which appear after about 9 weeks of exposure. This enhanced
formation of papillomas is related to the TCR defect, because XPC mice
develop these benign tumors at wild-type levels. We have reported
recently that hairless XPA mice also develop papillomas under chronic
UVB exposure, and that these tumors carry a G 
A transition at codon
12 of the H-ras gene (31)
. We hypothesized that
these mutations are caused by a UVB-induced C T transition at this
dipyrimidine site in the transcribed strand as a result of the TCR
defect rather than the GGR defect in XPA mice (31)
. The
association of papillomatosis with a TCR deficiency, as found in the
present study, strongly supports this inference.
Similar to human XPC (7
, 32)
, XPC mice are proficient in
the removal of 6-4PP and CPDs from the transcribed strand of active
genes by TCR (14
, 27)
. Also in agreement with human XPC
(32)
, the XPC mouse model is deficient in the removal of
6-4PP from inactive DNA and from the nontranscribed strand of active
genes (14
, 27) . However, in contrast to the situation in
humans, rodents are very inefficient in removing CPDs from
nontranscribed DNA (33
, 34)
. This is probably because of
the lack of expression of the p48 gene, which is required
for GGR of CPDs in human cells (8)
. As a consequence, the
effect of the lack of XPC genes is negligible in removal of
CPDs in rodent cells, whereas in human XPC removal of CPDs is strongly
affected. The high susceptibility of XPC mice to UV
carcinogenesis must, therefore, be attributable to a GGR deficiency of
DNA lesions other than CPDs, such as 6-4PP. In human XPC, in addition
to nonrepaired 6-4PP, nonrepaired CPDs are likely to contribute to the
enhanced carcinogenesis. This is in line with the observation that 85%
of skin tumors from XPC patients (35)
and only 2% of UV
tumors from XPC mice (36)
contain CPD-derived CC
TT tandem transitions in the nontranscribed strand of the
p53 tumor-suppressor gene. Thus, it is to be expected that
the observed increase in UV-induced skin cancer proneness in XPC mice
represents an underestimation of the susceptibility of human XPC.
The CSB mouse model is deficient in TCR of 6-4PP and CPD. Because mice have efficient GGR of 6-4PP but not of CPD, 6-4PP are removed from the transcribed strand of active genes by GGR. In human CSB, however, both 6-4PP and CPDs are removed from the transcribed strand of active genes by GGR. Hence, we expect that the skin cancer proneness in CSB mice represents an overestimation of the susceptibility of human CSB. This may explain the absence of skin tumors in CSB patients, whereas CSB mice are clearly skin cancer prone (11) .
An explanation for the higher carcinogenic effect of a GGR deficiency compared with that of a TCR deficiency could lie in differential mutational activation of transcriptionally inactive cancer genes. It is conceivable that GGR removes DNA photoproducts from transcriptionally inactive proto-oncogenes, thereby preventing mutations by replication of damage-containing sequences. Thus, enhanced mutagenesis attributable to GGR deficiency can lead to increased conversion of proto-oncogenes into oncogenes, which subsequently can stimulate uncontrolled cell divisions. In addition, the importance of GGR relative to TCR can be explained by the finding that TCR deficiency leads to increased apoptosis, whereas GGR deficiency does not. In summary, stimulation or inhibition of carcinogenesis depends on the balance between mutational activation of proto-oncogenes/mutational inactivation of tumor suppressor genes on the one hand and removal of precarcinogenic cells by apoptosis on the other hand. A TCR deficiency can lead to mutational inactivation of actively transcribed tumor suppressor genes but also to increased apoptosis, the net effect of which appears to be mildly procarcinogenic, at least in rodents. A GGR deficiency can also lead to mutational inactivation of actively transcribed tumor suppressor genes (via the nontranscribed strand) as well as to mutational activation of nontranscribed proto-oncogenes, but it does not influence apoptosis. Apparently, the net effect of GGR deficiency is more severely procarcinogenic.
Sensitivity to sunburn is generally considered to be associated with susceptibility to non-melanoma skin cancer (37) . The present study shows that sensitivity to sunburn is related to the capacity to perform TCR, whereas susceptibility to SCC is predominantly associated with the capacity to perform GGR. This implies that the GGR capacity may serve as a better predictor for skin cancer susceptibility than sensitivity to sunburn. Determination of MEDs and GGR capacities in non-melanoma skin cancer patients versus healthy controls will show whether this prediction, based on a study with genetically modified mice, holds true for humans.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Financed mainly by Grant UU97-1531 and also by
Grant EUR98-1774 from the Dutch Cancer Society (K. W. F.). 
2 To whom requests for reprints should be
addressed, at Department of Dermatology, University Medical Center
Utrecht, P. O. Box 85500, 3508 GA Utrecht, the Netherlands.
3 The abbreviations used are: CPD, cyclobutane
pyrimidine dimer; 6-4PP, pyrimidine [6-4] pyrimidone photoproducts;
NER, nucleotide excision repair; TCR, transcription-coupled repair;
GGR, global genome repair; XP, xeroderma pigmentosum; CS, Cockayne
syndrome; SCC, squamous cell carcinoma; MED, minimal erythema/edema
dose.
4 M. Van Oosten, H. Rebel, E. C. Friedberg, H.
van Steeg, G. T. J. van der Horst, H. J. van Kranen, A. Westerman,
A. A. van Zeeland, L. H. F. Mullenders, and F. R. de Gruijl.
Effects of UVB irradiation on cell cycle progression and apoptosis in
the epidermis of nucleotide excision repair-deficient mice, submitted
for publication.
Received 1/26/00. Accepted 4/17/00.
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REFERENCES |
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), XPC +/-, +/+ controls (
), and CSB
+/-, +/+ controls (
).