Page 55 - 20dynamics of cancer

40 CHAPTER 3

DCC
SMAD4 Other
APC/ -catenin K-RAS SMAD2 p53 Changes
Dysplastic
Normal Crypt and Intermediate Late Carcinoma Metastasis
Epithelium Early Adenoma Adenoma
Adenoma

Figure 3.2 Morphology of colorectal cancer progression. This classical path-
way is characterized by traditional adenoma morphology, slow progression,
high adenoma:carcinoma ratio, frequent chromosomal instability and aneuploi-
dy, and rare microsatellite instability. Particular genetic changes often associate
with morphological stage, suggesting that the genetic changes play an impor-
tant role in driving progression. Approximately 50–85 percent of colorectal
cancers follow this pathway. Redrawn from Figure 3 of Fearon and Vogelstein
(1990).

the base of the crypt. Migrating cells move from the base to the sur-
face in about 3–6 days. Normal cells die at the surface, replaced by the
continuous stream of new cells from below.
Most colorectal cancers progress through a series of morphological
stages (Figure 3.2). In the first histological signs, one or more crypts
show accumulation of excess cells at the surface. The cells in these
aberrant crypt foci may appear normal, forming hyperplastic tissue, or
the cells may have abnormal intracellular and intercellular organization,
forming dysplastic tissue. As excess cells accumulate, visible polyps
grow and protrude from the epithelial surface.
If the polyp is dysplastic, the tumor is called an adenoma. Adenomas
tend to become more dysplastic as they grow. If the polyp is hyper-
plastic, it usually does not follow the classical pathway to cancer in Fig-
ure 3.2, but may occasionally follow an alternative route, as discussed
later.

EARLY STAGES
What change causes cells to accumulate at the epithelial surface and
initiate adenomatous growth? Mutation of the APC regulatory path-
way appears to be the first step (Kinzler and Vogelstein 2002). APC
represses β-catenin, which may have two different consequences for
cellular growth. First, β-catenin may enhance expression of c-Myc and
other proteins that promote cellular division. Second, β-catenin may