world cancer report - iarc

PRECURSOR LESIONS IN
CHEMOPREVENTION TRIALS
Trials of agents for chemopreventive
activity which are based on assessment
of malignant disease are almost unmanageable
because of the long period of
time (perhaps decades) potentially
involved. Attention has therefore been
focused on lesions, either cellular or
molecular, demonstrated to be valid indicators
of the subsequent development of
malignancy. A trial may then evaluate the
effect of the putative chemopreventive
agent on such precursor lesions.
The best-validated precursor lesions are
benign tumours, such as colorectal adenomas.
It is established that adenoma
number, size, and severity of dysplasia are
predictive factors for colorectal cancer
incidence. It has been estimated that 2-
5% of all colorectal adenomas progress to
adenocarcinomas if not removed or treated.
The risk is greater for large and
severely dysplastic polyps. Cancer risk is
decreased by polyp removal, and a strong
correlation exists between the relative
prevalence of adenomas and cancers
across populations (Winawer SJ et al., N
Ageing
Apart from multistage development, certain
other processes are fundamental to
malignant disease. Principal amongst
these is ageing, which can be considered
both in relation to the whole individual, and
Fig. 3.4 Severe intraepithelial neoplasia (dysplasia)
in the epithelium of an intrahepatic large bile
duct, a condition caused by hepatolithiasis.
Engl J Med, 328: 901-906, 1993). Several
epidemiological studies have shown that
regular use of aspirin or related drugs is
associated with a reduced adenoma incidence
(IARC Handbooks of Cancer
Prevention. Vol. 1, Lyon, 1997). This provides
further confirmation that adenomas
are precursor lesions for colon cancer,
since aspirin is known to reduce the incidence
of malignant colon cancer.
Potential precursor lesions of carcinogenesis
include both phenotypic and genotypic
markers (Miller AB et al. Biomarkers in
Cancer Chemoprevention, IARC Scientific
Publications 154, Lyon, 2001). Thus oral
leukoplakia is a recognized precursor for
cancer of the oral cavity. Histological modulation
of a precancer (often called intraepithelial
neoplasia) has been used as a precursor
lesion in prevention trials (Kelloff GJ
et al., Cancer Epidemiol Biomarkers Prev, 9:
127-137, 2000). Additionally, genetic
lesions such as progressive genomic instability
as measured by loss of heterozygosity
or amplification at specific microsatellite
loci, have been considered (Califano J et al.
Cancer Res, 56: 2488-2492, 1996). Other
potential precursor endpoints include proliferation
and differentiation markers, spe-
also at the cellular level. In humans, as well
as in other mammals, the incidence of
cancer rises dramatically with age. An
exponential increase occurs from mid-life
[14]. Passage of time is also critical to cell
biology. Normal cells do not divide indefinitely
due to senescence (Box: Telomeres
and Telomerase, p108). Senescent cells
cannot be stimulated to divide further,
become resistant to apoptotic cell death
and acquire differentiated functions.
Senescence may be an anti-cancer mechanism
that limits accumulation of mutations.
However, when maintained in culture,
cells treated with carcinogenic chemicals
or infected with oncogenic viruses
may avoid senescence and proliferate
indefinitely. Such cell populations are
described as being “transformed” and
Fig. 3.6 Tubular adenoma of the colon is a precursor
lesion for colorectal cancer.
cific gene and general chromosomal damage,
cell growth regulatory molecules,
and biochemical activities (e.g. enzyme
inhibition). Serum proteins are of special
interest because of their availability. Thus
prostate-specific antigen (PSA) is being
used as a “surrogate” marker for prostate
cancer. It is expected that the number and
variety of biomarkers for precursor
lesions will continue to expand In parallel
with the advances in understanding of the
genetic and cellular basis of carcinogenesis.
when further maintained in culture, oncenormal
cells acquire the same characteristics
as cells cultured from malignant
tumours. These and various other alterations
in growth characteristics are recognized
as the experimental counterpart of
multistage carcinogenesis through which
tumours develop in intact animals or
humans. The genetic basis for senescence,
and its relationship to malignancy, is a subject
of intense investigation [15].
Preventing cancer
The significance of multistage carcinogenesis
extends beyond facilitating
understanding of how a transition from
normal to malignant cell growth occurs.
The fundamental cellular studies outlined
earlier provide a basis for preventing can-
Multistage carcinogenesis 87