Page 206 - 20dynamics of cancer

CARCINOGENS 191

Traditional explanations suggest that carcinogens affect only a subset
of stages in progression. Such specificity in carcinogenic effects would
often lead to incidence patterns that fit the observations.
I discussed in the previous section how an alternative model in which
carcinogens affect all stages also fits the observations. The fact that the
observations can be fit by a model in which all stages are affected does
not argue against the traditional explanation in which only a few stages
are affected. Rather, the proper inference is that we need to be cautious
about drawing firm conclusions about mechanism solely from models
fit to age-incidence curves.
Further progress requires testing alternative hypotheses about the
link between, on the one hand, how carcinogens affect the mechanisms
of progression dynamics and, on the other hand, how perturbations of
progression dynamics cause shifts in the age-onset curves. I focus on
shifts in age-onset curves because carcinogenic perturbations are impor-
tant only to the extent that they cause changes in incidence patterns.
In this section, I present alternative mechanistic hypotheses about
how carcinogenic perturbation affects progression dynamics. I also con-
sider the sorts of comparative tests that could distinguish between al-
ternative mechanistic hypotheses.

BACKGROUND
Tumors arise when cell lineages evolve ways around the normal limits
on tissue growth. Because tumors develop through evolutionary pro-
cesses, we can classify the mechanisms of carcinogen action by the par-
ticular evolutionary processes that they affect.
Variation and selection comprise the most important evolutionary
processes. For variation, I consider carcinogenic effects that act directly
by mutagenesis, defined broadly to include karyotypic and epigenetic
change. The different types of heritable change cause different spectra
of variation and act at different rates. For selection, I divide mecha-
nisms into three classes: mitogens directly increase cellular birth rate,
anti-apoptotic agents directly reduce cellular death rate, and selective
environment agents favor cell lineages predisposed to develop tumors.
Those selective mechanisms may indirectly increase variation. For ex-
ample, mitogens often increase mutation by raising the rates of DNA
replication.