Page 213 - 20dynamics of cancer

198 CHAPTER 9

cells may happen slowly as a predisposed clone expands, causing a slow
rise in the transition rate to the following stage.
In the theory chapters, I demonstrated a clear difference in how age-
incidence curves shift in response to a change in transition rate. A quick
rise in a particular transition abrogates a rate-limiting step and reduces
the slope of the age-incidence curve. In an idealized model, each abro-
gation of a rate-limiting step reduces the slope by one unit. By contrast,
a slow rise in a transition rate causes a slow rise in the slope of the age-
incidence curve. Multiple rounds of slow clonal expansion can lead to
high age-incidence slopes. (See Section 6.5, which describes the theory
of clonal expansion.)
Increasing the dosage of a mitogen may cause more rapid clonal ex-
pansion. The theory predicts that the increase in the rate of clonal ex-
pansion causes a steeper rise in the slope of the incidence curve over a
shorter period of time. If the rate of clonal expansion is not too fast,
then longer duration of exposure to a mitogen may cause a sequence of
clonal expansions as one transition follows another, leading to a steep
rise in the slope of the incidence curve. At high doses and rapid rates of
clonal expansion, transitions may occur so rapidly that the rate-limiting
effects of a stage may be abrogated, causing a drop in the slope of the
incidence curve.

ANTI-APOPTOTIC AGENTS: DECREASE CELLULAR DEATH RATE

Anti-apoptosis may act in at least two different ways. First, blocking
cell death may allow mutations to accumulate at a faster rate, because
apoptosis is an important mechanism for purging damaged cells. Sec-
ond, absence of cell death may cause clonal expansion, with an increase
in the number of target cells for the next transition.
I discussed in the previous sections some of the ways in which to
study increased mutation rate per cell versus increased target size in
an expanding clone of cells. It may be possible to complement those
approaches by study of genotypes with loss of apoptotic function.

SELECTIVE ENVIRONMENT: FAVORS PREDISPOSED CELL LINEAGES
The previous sections discussed carcinogens that directly cause mu-
tations or directly affect cellular birth or death. This section focuses on