Page 56 - 20dynamics of cancer

MULTISTAGE PROGRESSION 41

play a role in cell adhesion processes, effectively increasing the sticki-
ness of surface epithelial cells. In either case, repression of β-catenin
reduces the tendency for abnormal tissue expansion.
APC expression rises and represses β-catenin as cells migrate from
the base of crypts toward the epithelial surface. Rise in APC expres-
sion and repression of β-catenin associate with increased apoptosis as
cells approach the surface. Loss of surface cells is necessary to balance
production from the base of crypt.
In tumors, mutations in APC usually include domains involved in
binding β-catenin; abrogation of APC binding releases β-catenin from
the suppressive effects of APC (Kinzler and Vogelstein 2002). Both APC
alleles are probably mutated in most tumors, consistent with the hy-
pothesis that lack of functional APC releases suppression of β-catenin
and leads to adenomatous growth.
The occasional tumors that lack APC mutations frequently have β-
catenin mutations that resist repression by APC (Jass et al. 2002b; Kin-
zler and Vogelstein 2002). β-catenin resistance requires that only one
allele mutate to escape suppression by APC.
Disruption of the APC pathway may be sufficient to start a small ade-
nomatous growth. Two lines of evidence point to disruption of the APC
pathway as an early, perhaps initiating event in carcinogenesis (Kinzler
and Vogelstein 1996, 2002). First, APC mutations occur as frequently
in small, benign tumors as they do in cancers. By contrast, mutations
in other genes commonly altered in colorectal cancers, such as p53 and
K-RAS, appear only later in tumor progression (Figure 3.2). Second, APC
mutations occur in the earliest stages of aberrant crypts, consistent with
the hypothesis that the first steps of stickiness and lack of cell death at
the epithelial surface arise from disruption of the APC pathway.

GROWTH BEYOND SMALL ADENOMAS

Mutation of a RAS gene often occurs among the next genetic events
of progression (Kinzler and Vogelstein 2002). Among early adenomas
less than 1cm, fewer than 10 percent had mutations to either K-RAS
or N-RAS, whereas more than 50 percent of adenomas greater than 1cm
and carcinomas had a mutation to one of these genes. Mutations usually
occur in K-RAS but occasionally in H-RAS. The RAS family acts oncogeni-
cally, with a mutation to a single allele sufficient to cause progression.