Page 93 - 20dynamics of cancer

78 CHAPTER 4

crypts. A mutation in one compartment remains confined to that loca-
tion, unless the mutation provides an invasive phenotype that causes
cells to break into neighboring compartments. Put another way, the
compartmental structure reduces competition between cellular lineages
by providing a barrier to clonal expansion, thus limiting the number of
descendant cells that carry a noninvasive mutation.
To summarize Cairns’ view, asymmetric mitoses of stem cells reduce
mutation accumulation within lineages, and compartmentalization re-
duces competition and selection between lineages. Symmetric mitoses
and exponential cell lineage expansion increase the risk of cancer pro-
gression. I follow up on these issues in a later chapter on cell lineages.

4.7 Hypermutation, Chromosomal
Instability, and Selection
Two process may accelerate the accumulation of genomic change.
First, changes early in progression may accelerate the production of
subsequent changes. Second, competition and selection between cell
lineages that harbor various genomic changes would favor clonal ex-
pansion of more aggressive lines.

ACCELERATION OF VARIATION BY MUTATORS
Burdette (1955, p. 218) nicely summarized the potential role of mu-
tators in early stages of progression: “A logical corollary to the so-
matic mutation hypothesis is that [inherited] mutants act as mutators.”
Those mutators would accelerate the accumulation of subsequent so-
matic changes in cells. Loeb developed the mutator hypothesis through
a series of papers (Loeb et al. 1974; Loeb 1991, 1998; Beckman and Loeb
2005).
Nowell (1976, p. 26) emphasized chromosomal instabilities: “It is pos-
sible that one of the earliest changes in tumor cells involves activation of
a gene locus which increases the likelihood of subsequent nondisjunc-
tion or other mitotic errors.” Recent reviews of chromosomal instability
can be found in Rajagopalan et al. (2003) and Michor et al. (2004).