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Thus, in an experimental setup where animals are exposed to very high genotoxic
doses, TID and CS mice unveiled a clear but intermediate cancer predisposition not
noticed with the human syndromes. Several explanations can be put forward to
account for this difference. As mentioned, the average life span of CS and TID
patients is reduced compared to XP patients. This combined with frequent
confinement to bed may prevent CS and TID individuals from acquiring the
biologically relevant UV dose necessary for completion of the multi-step
carcinogenesis process in man. Second, as deduced from the mouse experiments,
cancer predisposition caused by the CS and TID NER defects is not as dramatic as
for XP A and XPC mutations and therefore could have gone undetected in the
relatively low numbers of human patients. Both above considerations imply that CS
and TTD NER perse are associated with etihanced cancer susceptibility. Thirdly,
the persisting high genotoxic exposure used in the mouse experiments could exceed
the repair threshold mounted by the residual NER of CS and TID. In man, the
residual repair may be enough to protect against the much lower levels of UV
experienced under natural conditions. Fourth, in the case of CS the TCR defect may
mount an efficient apoptotic response after UV exposure [24], which protects
against cancer induction. To explain the cancer susceptibility in the CS (and in part
TTD) mice one has to assume that this anti-carcinogenic response is less effective in
the murine system. Finally, other interspecies physiological differences (such as
metabolic rate, immune surveillance etc.) may also influence cancer predisposition.
The inability of the mouse GGR pathway to remove CPD lesions is expected to
increase the UV-induced cancer predisposition in the wild-type mouse and
consequently diminish the relative oncogenic effect of a GGR deficiency in mice.
Another consequence of this mouse-human difference is that mice have to rely more
on TCR for CPD repair. Thus, a CS defect in the TCR pathway may have more
dramatic effects in the mouse when compared with human NER. Hence, this mouseman
variance in repair is anticipated to differentially influence the relative cancer
proneness in the two species depending on the nature of the NER defect. Future
studies in TID and CSB mice will undoubtedly focus on quantitation of cancer
susceptibility and mutagenesis and on the role ofUV-induced immune suppression
and apoptosis.
Internal tumors in NER-deficient mice
In addition to UV-induced skin cancer, a defect in NER is anticipated to predispose
patients to develop internal tumors because NER lesions are expected to be induced
by chemical compounds that enter the body via food, and environmental pollution.
Moreover, natural metabolites produced by the cellular metabolism induce NER
lesions as well, However, only limited evidence for such a predisposition in XP
patients is available [25].
In light of the above, it is of significance to note that 5 out 24 XPA mice, age 1-1.5
years, had developed internal tumors spontaneously (mostly liver adenoma) while
NER-deficient mouse models 35