Page 67 - 20dynamics of cancer

52 CHAPTER 3

Rapid genetic change can increase the rate of progression. Some peo-
ple have argued that cancer development requires such acceleration of
progression (Loeb 1991). Others argue that normal rates of somatic
mutation are sufficient to explain progression, and widespread genetic
changes arise late in progression as a consequence of excessive cell di-
vision or other processes (Tomlinson et al. 1996).

CELL-CYCLE CHECKPOINTS AND ACCELERATORS
Cell-cycle checkpoints block progress through the cell cycle in the ab-
sence of appropriate external growth signals or in response to internal
damage (Kastan and Bartek 2004; Lowe et al. 2004). These brakes on
cell division often fall in the class of tumor suppressors—genes with
products that can suppress uncontrolled cell division. Mutation of the
tumor suppressor genes may set key rate-limiting steps in progression.
Usually, both alleles of a tumor suppressor locus must be knocked out
to release the brake, because the protein product from one functional
copy is sufficient to keep the cell cycle in check. For example, the reti-
noblastoma protein blocks transition into the S phase of the cell cycle,
during which the cell copies its DNA in preparation for splitting into two
daughter cells (Fearon 2002). Only a proper combination of other cell-
cycle controls can release the retinoblastoma block, providing a check
that the cell is ready for the complex process of DNA replication.
Tumor suppressors brake cellular proliferation. By contrast, onco-
genes stimulate cell division (Park 2002). For example, nondividing cells
express little of the myc gene (Pelengaris et al. 2002). When such cells
receive external growth signals, they quickly ramp up expression of myc,
which in turn stimulates expression of many growth-related factors. Tu-
mors often express high levels of the myc gene or similar oncogenes,
causing rapid growth even in the absence of normally required external
growth signals.

AVOIDING CELLULAR SENESCENCE
Most cells can divide only a limited number of times (Mathon and
Lloyd 2001). With each cell division, the chromosome ends (telomeres)
shorten because they are not copied by the normal DNA replication en-
zymes. After forty or so divisions, the special telomeric caps have worn
down. Normal cells will not continue to divide. If cell division continues,