Page 307 - 20dynamics of cancer

292 CHAPTER 14

Methylation diversity in APC-mutated crypts may be higher because
each stem lineage may survive longer, slowing down the rate of clonal
succession. In Figure 14.1a, long-lived stem lineages retain methylation
differences that arise in the separate lines, creating relatively high di-
versity over time. By contrast, in Figure 14.1b, each clonal succession
drives out the diversity carried by the extinct lineages, keeping diversity
low within the crypt.
Alternatively, APC mutations may increase methylation diversity by
raising the number of stem lineages within a crypt. More stem lineages
provide greater opportunity for the origin and maintenance of variation.
In either case, the greater methylation diversity in crypts with APC
mutations signals that those crypts accumulate more genetic variation
than normal crypts. Initially, that genetic variation may be neutral in
the sense that it does not directly affect the survival or expansion of cell
lineages. However, some of that variation may predispose to subsequent
progression.
For example, a mutation to one allele of a tumor suppressor gene may
have no consequences because the other, normal allele masks the effect
of the mutation. But the hidden mutation poses a risk, because the next
mutation to the normal allele knocks out function and may be a key step
in progression (Nowak et al. 2002; Kim et al. 2004). So greater genetic
diversity in crypts may itself be a predisposing risk.

STEM CELL HIERARCHY IN HAIR RENEWAL
Mammalian hair follicles renew throughout adult life. I described the
hair renewal cycle in Section 12.2. Figure 14.2 reviews the main steps.
The cell lineage history within the hair follicle remains a puzzle (Pot-
ten and Booth 2002). One hypothesis suggests that, as a new hair cy-
cle begins, stem cells in the bulge region divide, and their daughters
move down to the follicular base to form the progenitors for the next
round of growth. Those follicular progenitor cells act as the stem lin-
eage during the growth phase, dividing to produce a transit lineage that
moves up and forms the growing hair. As the growth cycle ends for that
follicle, the follicular germ regresses to form the resting morphology
(Figure 14.2).
If the follicular germ cells die off during regression, then the next
round of growth must be seeded by new daughter cells from the stem