Biomedical Engineering Reference
In-Depth Information
(neoplasms) are initially adenomas and only rarely undergo malignant conver-
sion, a process that is typically estimated to take at least 10 years. In this chapter
we therefore propose to distinguish adenoma stem cells from carcinoma stem
cells and consider the term adenoma to carcinoma stem cell transition. We will
give an outline of an adenoma to cancer stem cell model for colorectal cancer. We
will discuss the methods and markers that are used to identify them and the
relation between normal colon stem cells and colon-cancer stem cells.
2 Normal Colon Stem Cells
The colonic epithelial layer is characterized by its high turnover rate and is orga-
nized in functional units called crypts of Lieberku¨ hn. Stem cells at the base of the
crypt generate a population of transit-amplifying cells that fill the lower part of the
crypt and divide several times before giving rise to the differentiated goblet cells,
endocrine cells, and enterocytes. Crypts in both mice and humans are populated in a
clonal manner (Winton et al., 1988; Novelli et al., 1996). The differentiated cells
migrate upward and fill the upper part of the crypt and the intercrypt tables before
being shed into the lumen of the gut. Colonic epithelial cells show a very high rate of
renewal: the entire epithelial layer is replaced every 5-14 days depending on the
species. To maintain homeostasis in such a rapidly renewing system, the control of
cell fate in colon epitheliummust be very tightly regulated. It is therefore no surprise
that signal transduction pathways important for the development of the intestine
such as the Wnt, Notch, TGFb family and Hedgehog pathways regulate home-
ostasis of this highly dynamic system (van den Brink and Offerhaus, 2007).
2.1 Identification of Colonic Stem Cells
Until recently no simple reliable markers were available for the identification of
colonic epithelial stem cells. Some researchers have used long-term DNA label
retention to identify the stem cell compartment (Potten et al., 1997; Table 1).
The idea behind those studies is that stem cells divide relatively infrequently
while the more rapidly dividing progenitor cells dilute out the DNA label after
the labeling pulse is given. Alternatively BrdU could be retained because stem
cells would segregate their chromosomes asymmetrically to protect one strand
against replication-induced somatic mutations (the so-called immortal strand
hypothesis; Cairns, 2006). It has been difficult to prove that BrdU-retaining
cells are really stem cells due to a lack of universally accepted stem cell markers
in most organs. Recently, however, no evidence was found for label retention in
hematopoietic stem cells (HSCs) that can be purified using well-characterized
markers (Kiel et al., 2007). The authors demonstrated that HSCs are not slow-
cycling cells but enter the cell cycle at a rate of 6% per day in mice. If we infer
from this study that BrdU label retention may not be a reliable method to
identify colonic stem cells, then the identification of colonic stem cells was
