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XPC-I-p53+1- mice were more aggressive, including poorly differentiated squamous
cell carcinomas. Similarly, benzo[a]pyrene (B[a]P) induced lymphomas appeared
faster in XPA-I-p53+1- mice compared to XPA-I-p53+1+ mice but here again a
surprisingly low number of LOH of the wild-type p53 locus was observed (H. van
Steeg, personal cormn.).
These studies show that the ability to manipulate the mouse germline allows
genetic dissection of the complex, multistep process of carcinogenesis in vivo and
the contribution of the NER system in it. Extensive studies of NER-deficient mice
with alterations in different tumor suppressor genes, oncogenes and the immune
system can be anticipated.
TTD and CSB mouse models
One of the intriguing unsolved issues within the field of NER and associated
disorders is the apparent absence of skin cancer predisposition in CS and TID,
despite defective NER. Differences in catalase activity [21], natural killer cell
activity [22], UV-induced ICAM-I expression [23], and lesion-specific repair [17]
were reported between XP and TID patients. Furthermore, the physiology of CS
and TID patients will definitely influence cancer predisposition, e.g. CS and TID
patients have a poor overall condition with reduced life expectancy and frequent
hospitalization. In addition, scaling of the skin, characteristic of TTD patients,
shields underlying basal keratinocytes from UV. Finally, the partial nature of the
NER defect in both CS and TTD may permit the crippled NER system to still deal
with low, constitutive levels of DNA damage. However, the relative contribution of
each of these parameters on skin carcinogenesis in vivo is unclear. The experimental
mouse models for the NER syndromes provide a unique tool to investigate the
above parameters in a controlled and systematic fashion. Interestingly, both TID
and CSB mice displayed enhanced tumorigenesis in UV- and chemically- induced
skin carcinogenesis protocols (5, de Boer et al., submitted]. This finding is in
agreement with the dogma that a defect in NER predisposes to cancer but is in
seeming discordance with the human clinical data. Very importantly, consistent
with expectation, TTD and CSB mice appeared less cancer-prone than the totally
NER-deficient XPA mice. Quantification of cancer-predisposition in the hairlessmouse
model showed that CSB mice were approximately six times less sensitive to
UV-induced skin carcinogenesis than XPA and XPC mice in an identical
experimental setup (R. Berg, manuscript in prep.). Similarly, preliminary
comparison of oncogenesis in TID versus XPA mouse mutants suggests a lower
susceptibility to induced skin cancer in TID mice when compared with XPA
mutants (de Boer et al., submitted). Another indication for an intermediate
oncogenic response is the tumor type induced by DMBA. Under the conditions
used, skin tumors in XP A mice were exclusively papillomas whereas wild-type
mice develop only SCCs. CSB and TID mice develop a mixture of both tumor
types.
34 Chapter 2