Page 211 - 20dynamics of cancer

196 CHAPTER 9

Summary.—These tests emphasize treatments that apply chemical car-
cinogens to altered animal genotypes, with age-incidence curves mea-
sured as the outcome and interpreted in the light of quantitative predic-
tions of multistage theory.

MITOGENS: INCREASE CELLULAR BIRTH RATE
Increased cell division raises the rate of tumor formation (reviewed
by Peto 1977; Cairns 1998). Higher rates of tumorigenesis occur in re-
sponse to irritation, wound healing, and chemical mitogens.
I first describe three hypotheses to explain the association between
mitogenesis and carcinogenesis. Ideally, I would follow with tests that
clearly distinguish between alternative hypotheses. However, given the
current level of technology, it is not easy to define practical experiments
that connect biochemical changes caused by mitogens to consequences
for rates of tumorigenesis. With that difficulty in mind, I finish by laying
a foundation for how to formulate tests as understanding and technol-
ogy continue to improve.

HYPOTHESES
Faster cell division balanced by increased cell death.—In this case, the
number of cells does not increase because tissue regulation balances
cell birth and death, but the mitogen increases cell division and turnover.
The faster rate of DNA replication increases the rate at which mutations
occur (Cunningham and Matthews 1995).

Normally asymmetrically dividing cell lineages divide symmetrically.—
Epithelial stem cells sometimes divide asymmetrically. One daughter
remains as a stem cell to provide for future renewal; the other daughter
often initiates a rapidly dividing and short-lived lineage. Cairns (1975)
suggested that in each asymmetric stem cell division, the stem lineage
may retain the older DNA templates, with the younger copies segregat-
ing to the other daughter cell (supporting evidence in Merok et al. 2002;
Potten et al. 2002; Armakolas and Klar 2006). If most mutations occur
in the production of new DNA strands, then most mutations would seg-
regate to the nonstem daughter lineage, and the stem lineage would ac-
cumulate fewer mutations per cell division. In addition, stem cells may
be particularly prone to apoptosis in response to DNA damage, killing