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MULTISTAGE PROGRESSION 55

changes, which may help them to adapt to the new conditions required
for growth.

3.8 How Do Changes Accumulate in Cell Lineages?

My goal is not to describe all changes. Rather, I seek alternative hy-
potheses about how the major, rate-limiting steps accumulate. Three
possibilities seem most promising as points of departure for further
study.

SINGLE DOMINANT CELL LINEAGE

Suppose a single original cell suffers the primary change. That cell
may, for example, obtain a mutation that weakens its apoptotic response.
Subsequent rate-limiting changes accumulate in the descendant lineages
of that original cell. The progressing lineage creates changes in nearby
tissues by signaling. At several stages, the dominant lineage expands
into a precancerous population of cells; a new change then hits one of
those cells, which subsequently expands and becomes the dominant lin-
eage.
A single, continuous line of descent can be described most easily by
the shape of cellular lineages in the historical pattern of cellular ances-
try. In evolutionary biology, the historical pattern of ancestry is called
the phylogeny or phylogenetic tree. Figure 3.5 shows an example of how
phylogenetic shape corresponds to the history of accumulated changes
in progression. The description ultimately reduces to the time to the
most recent common ancestor among extant tumor cells. This coales-
cence time describes the degree to which one or a few lineages have
dominated. In Figure 3.5d, with a single dominant lineage, the time to
the most recent common ancestor of all extant cells is short. By con-
trast, in Figure 3.5a, with no dominant lineage, the coalescence time to
a common ancestor is relatively long.
In precancerous colon crypts, the cells in the whole crypt often derive
from a recent common ancestor: a single stem cell lineage and its de-
scendants dominate the crypt (Kim and Shibata 2002). At any time, a few
stem cells may be present. Over time, one of the stem lineages survives
and the others drop out. The different stem lineages may compete, or
differential success may just be a random process in which one lineage,
by chance, takes over. With each replacement, the primary stem lineage