Page 207 - 20dynamics of cancer

192 CHAPTER 9

I do not use the common classification that divides the effects of car-
cinogens into initiation, promotion, and progression. That classification
primarily arises from the tendency of certain agents, at certain doses,
to have stronger effects when applied before or after other agents. Such
patterns certainly exist and must, to some extent, be correlated with
mechanism of action. Indeed, initiators do sometimes act as direct mu-
tagens that cause particular mutations early in tumor formation, and
promoters do often act as mitogens. But there are many exceptions with
regard to the consistency of the patterns, and the connections to mech-
anism often remain vague and somewhat speculative (Iversen 1995).
My focus on variation and selection does not set a mutually exclu-
sive alternative against the classical initiation-promotion-progression
scheme. Instead, my emphasis on variation and selection simply puts
the processes of tumor evolution ahead of the sometimes debatable pat-
terns for the ordering of consequences under certain experimental con-
ditions.
I place carcinogenic mechanism in the context of multistage progres-
sion, measured by shifts in age-onset curves. I therefore emphasize how
certain mechanisms affect rate processes and the time course of tumor
formation. For example: How does a carcinogenic agent affect the rate
of transition between particular stages? How many stages does an agent
affect? Does a particular agent have an effect only on tissues that have
already progressed to a certain stage? Put concisely, the issues concern
changes in rate, number of stages affected, and order of effects.

MUTAGENS: INCREASE HERITABLE VARIATION

I begin with background observations from the mouse skin model
of chemical carcinogenesis (Slaga et al. 1996). I then interpret those
observations in terms of hypotheses about rate, number, and order.

BACKGROUND
The first step in skin tumor development often appears to be a muta-
tion to H-ras that causes an amino acid substitution at codon positions
12, 13, or 61 in the phosphate binding domain of the protein (Brown
et al. 1990). Those substitutions can abrogate negative regulation of the
Ras signal that stimulates cell division (Barbacid 1987).
Different carcinogens induce different spectra of mutation to H-ras
isolated from papillomas or carcinomas of mouse skin. Table 9.1 shows