Page 319 - 20dynamics of cancer

304 CHAPTER 14

2005). Such reconstructions will open a new window onto the dynamics
of progression.

CLONAL EXPANSIONS AND CANCER STEM CELLS
Clonal expansion gives rise to a population of cells. Those cells may
be in a precancerous state, ready to make the next transition along the
pathway of progression. Or those cells may form a malignant tumor
that will continue to grow and evolve.
In a clonal population, what fraction of the cells retain the potential
to be the progenitors of future cell lineages? Put another way, what
fraction can act as the stem cells that renew the population?
Some studies suggest that only a small fraction of cells in a tumor
retain the potential to renew the population—the cancer stem cells (Reya
et al. 2001; Pardal et al. 2003; Huntly and Gilliland 2005; Bapat 2006).
Little information exists about earlier stages in progression.
Suppose, in an early precancerous clonal expansion, only a small frac-
tion of the cells can act as long-term progenitors. Then, in spite of the
large population of cells in the clone, only a small number of cells may
drive progression to the next stage along the pathway to cancer. So
clonal expansions do not necessarily raise the target size for future tran-
sitions and the rate of progression. What matters is the number of cells
that retain the potential to be long-term progenitors.

14.3 Somatic Mosaicism
In each cell division, new heritable changes may arise in DNA se-
quence, in DNA methylation, and in modifications to histone proteins. A
change in the first few post-zygotic divisions alters many descendants;
a change in an epithelial stem cell modifies the descendants within the
local tissue compartment. In either case, the organism develops into a
mosaic of different genotypes.
Most observations of mosaicism derive from some spectacularly no-
ticeable change. Pigmented skin patches mark the bounds of mosaic
regions. A tumor emerges from several heritable changes in a region.
Sometimes, multiple tumors develop within a broader field of altered
cells.
Pigmented skin patches and tumors are rare, but mosaicism may be
common. As individuals age, different tissue regions progress through