Biomedical Engineering Reference
In-Depth Information
3.1 Clonal Stem or Precursor Cell Expansion Initiates Adenoma
Formation
The possibility of lateral clonal expansion of stem cells through crypt fission
during intestinal epithelial growth and repair needs to be tightly controlled to
prevent the formation of clonal growths (neoplasms). It is therefore no surprise
that mutations that initiate adenoma formation compromise pathways
involved in the regulation of precursor crypt fissioning. The best example is
probably the mutations in APC that result in adenoma formation in patients
with familial adenomatous polyposis (FAP) and sporadic adenomas. Patients
with FAP have a single functional APC allele; the reduced dosage of wild-type
APC in normal crypts of the colon of these patients is sufficient to result in a
substantially (19-fold) increased rate of crypt fissioning compared to normal
(Wasan et al., 1998). Upon loss of the second APC allele in an epithelial cell, this
mutant cell fills a crypt with its dysplastic progeny. Loss of APC not only causes
dysplasia but also results in accumulation of mutated cells in the crypt. It is
believed that when these precursor cells exceed a certain threshold the crypt
starts to fission to form a second crypt. This is exactly what can be observed in
minute adenomas. These small adenomas form by fissioning from the mutant
'mother-crypt' (see, e.g., Fig. 3B; van den Brink and Offerhaus, 2007). It is not
known if the cell that gives rise to an adenoma is in fact a stem cell, a precursor
cell, or even a differentiated cell that regains stem cell properties. Cells that drive
adenoma growth are capable of formation of all cell lineages, self-renewal,
and even clonal expansion but possess no malignant properties, i.e., are non-
invasive. In this respect the term colon-cancer stem cell does not cover the long
adenoma stage that precedes colorectal cancer and the term adenoma stem cell
may be more apt to describe the cells that drive adenoma growth.
3.2 Identification of Initiators of Clonal Growth
Impressive insight has been obtained into the genes that are genetically or
epigenetically modified during the formation of a colorectal cancer, especially
with the sequencing of the entire genome of several different colorectal cancers
(Wood et al., 2007; Sjoblom et al., 2006). Although we now have a long list of
genes that are (epi)genetically modified during colorectal carcinogenesis, it is
still difficult to say if these changes play a causal role and even more difficult to
tell at what stage during the 10-year-long adenoma to carcinoma progression
modification is required. As we have argued previously (van den Brink and
Offerhaus, 2007) it is only in patients with inherited syndromes that predispose
to colorectal cancer formation that the genetic lesion capable of initiating clonal
growth is known with certainty. Mutations in the most frequently occurring
genetic syndrome, the hereditary non-polyposis colorectal cancer (HNPCC)
syndrome, are in mismatch repair genes. These mutations are not informative
