Toxicology of Industrial Compounds

14
Molecular Approaches to Assess Cancer Risks
ALAN S.WRIGHT, J.PAUL ASTON, NICO J.VAN SITTERT
and WILLIAM P.WATSON
Sittingbourne Research Centre, Sittingbourne
Introduction
Carcinogenesis is a complex process which is not yet fully understood.
Nevertheless, it is generally accepted that carcinogenesis involves the
accumulation of mutations in critical genes: proto-oncogenes and/or
tumour suppressor genes. These mutations transform normal cells into
‘initiated’ cells possessing the full complement of genetic changes necessary
for malignancy (Figure 14.1). The critical mutations may result from
exposures to radiation, to genotoxic chemicals or they may arise
‘spontaneously’ as a consequence of miscoding errors during the normal
replication of DNA. Concomitantly, mutations will also accumulate in
other genes which, although not critical for cancer per se may,
nevertheless, influence cellular character thereby contributing to the
multifaceted nature of cancer.
The precise nature and number of critical genetic changes required for
initiation have not yet been established but will probably vary from case to
case. Many researchers envisage a strict temporal sequence of genetic
changes in carcinogenesis. However, it is probable that the critical
mutations can occur in any sequence and at any time. Indeed, it is clear
that one or more of the critical mutations can occur in parental cells.
Transmission (inheritance) of these mutations either through the germ line
or via somatic cell division increases the susceptibility of the progeny to
carcinogens. Furthermore, it is important to note that each of the critical
mutations necessary for malignancy may have a different cause. This
potential for multiple causation has important implications in risk
assessment (vide infra).
Fully initiated cells may not automatically proliferate to form tumours.
One possible explanation is that the surrounding normal cells restrain
the initiated or latent cancer cell by providing essential growth regulators
which are no longer produced by the initiated cell. Nevertheless, partially
and fully initiated cells have a replicative and/or survival advantage over
normal cells. Tissue injury caused by physical trauma, chemical agents or