Biomedical Engineering Reference
In-Depth Information
for our understanding of the initiation of clonal growth as they are not initiators
of clonal growth per se but cause genomic instability that subsequently results
in other mutations that induce clonal growth.
3.2.1 APC Mutations and Adenoma Initiation
One of the major advances in our understanding of the initiation of clonal
growth was made with the identification of APC as the gene mutated in patients
with FAP and the subsequent demonstration that APC is required for the
proper restriction of the activity of b-catenin-TCF/LEF signaling in what is
called the canonical Wnt signaling pathway. It is now clear that Wnt signaling
activity specifies colonic epithelial precursor cell phenotype and turnover. The
mutation in APC is believed to result in unrestricted clonal expansion of the
mutated cell due to the unrestricted Wnt pathway activity which maintains the
cells in a precursor cell state, impedes their differentiation, and probably also
their migration out of the crypt. The main remaining problem in the under-
standing of the effects of the APC mutation remains the fact that APC not only
regulates the stability of b-catenin but is also involved in the regulation of
chromosomal stability (Fodde et al., 2001). The APC mutation remains the
only mutation of which certainty exists regarding its capacity to initiate clonal
growth that results in adenoma formation in humans.
3.2.2 BMP and Receptor Tyrosine Kinase Signaling and Hamartoma Initiation
Mutations that initiate polyp growth have been identified in patients with
genetic polyposis syndromes that do not result in adenoma formation but in
hamartoma formation. Although hamartomas also show polypoid growth,
they are distinct from adenomas in the sense that the epithelium on a hamar-
toma is non-dysplastic. In the general adult population hamartomas are very
rare benign lesions that are not believed to progress to cancer. In patients with
hamartoma syndromes areas of dysplasia can develop in some of the hamarto-
mas, a process sometimes called adenomatous transformation. In contrast to
sporadically occurring hamartomas, hamartomas of patients with hamartoma
syndromes can progress to cancer (Giardiello et al., 1987; Brosens et al., 2007).
Mutations that initiate hamartomas may tell us little of the genetic lesions
that initiate sporadic colorectal cancer but still give us a valuable insight into the
mechanisms that regulate precursor cell homeostasis in the colon. As hamarto-
mas are clonal growths, the mutations that cause hamartoma syndromes are
very interesting from the perspective of our understanding of the molecular
mechanisms that prevent clonal stem cell expansion. The genes mutated in these
syndromes affect two morphogenetic pathways. Patients with juvenile polypo-
sis have mutations in the BMP receptor 1a and its signaling mediator SMAD4
(Howe et al., 1998, 2001). Patients with Cowden syndrome and Peutz-Jeghers
syndrome have mutations in negative regulators of the PI3 kinase-Akt-mTOR
signaling pathway, a critical pathway in receptor tyrosine kinase signaling.
