Biomedical Engineering Reference
In-Depth Information
and the mechanisms that temporarily allow such expansion during epithelial
repair remain poorly studied and understood. Some understanding of the mole-
cular machinery can, however, be extrapolated from the deregulation of the
control of crypt fissioning that causes adenoma formation during the first steps
of colorectal carcinogenesis (see next section).
3 Colorectal Carcinogenesis and Origin of the Colon-Cancer
Stem Cell
As illustrated in the section above, a complex and only partially resolved
interplay between different morphogenetic signal transduction routes regu-
lates homeostasis of the colonic epithelial layer. The transition from this
normal homeostatic system to the formation of an invasive carcinoma is a
very slow, stepwise process that is estimated to take at least 10 years in
humans. Colon cancers develop in the so-called adenoma to carcinoma
sequence, a histopathologically recognizable series of events. Adenoma for-
mation starts at the level of a single crypt that accumulates a larger-than-
normal number of precursor cells that no longer occupy only the base of the
crypt but lead to an expanded precursor cell zone more toward the top of the
crypt and generate dysplastic, i.e., poorly polarized, and crowded epithelial
cells (Leedham and Wright, 2008). The presence of abnormal proliferation
and that of dysplasia are the hallmarks of an adenoma. The single crypt
adenoma will subsequently expand laterally through the colonic epithelium
through a process of crypt fission to form a very small or minute adenoma that
now encompasses several crypts. Adenomas can continue to grow through
crypt fission and possibly by mutant precursor cells leaving their own crypt
and occupying neighboring crypts and the superficial epithelium. Adenomas
classically appear macroscopically as exophytic polypoid growths within the
colonic lumen that can reach several centimeters in size; however; they can
also grow as flat lesions, the so-called flat and depressed adenomas, that can
be hard to recognize during colonoscopy. It is important to realize that
adenomas are in principle benign (non-invasive) lesions that are highly pre-
valent in the general population. The risk of malignant transformation of an
adenoma correlates with adenoma size, the degree of dysplasia, and its mor-
phology. Adenomas
>
1 cm, with 'high-grade' dysplasia or villous histology,
are believed to carry the highest risk of malignant transformation and are
termed advanced adenomas. The prevalence of adenomas is difficult to esti-
mate in the general population as only larger adenomas are reliably detected
during colonoscopy. Even the prevalence of advanced adenomas is already
around 6% in the population between 50 and 66 years of age at average risk
for colorectal cancer (Regula et al., 2006). Given the fact that the prevalence of
colorectal cancer is around 0.9% in the same population (Regula et al., 2006)
most adenomas do not progress to cancer.
