Biomedical Engineering Reference
In-Depth Information
Activity of PI3 kinase results in phosphorylation of the membrane lipid phos-
phatidylinositol 4,5-diphosphate (PIP2) to generate phosphatidylinositol 3,4,5-
trisphosphate (PIP3). PIP3 plays a critical role as a cell membrane anchor of
AKT kinase, a central kinase in the suppression of apoptosis and induction of
cellular growth and proliferation. AKT activation subsequently results in the
activation of mammalian target of rapamycin (mTOR), a kinase involved in the
regulation of protein synthesis and cell cycle progression. Cowden syndrome is
caused by mutations that inactivate the phosphatase PTEN (Liaw et al., 1997).
PTEN is the major antagonist of PI3 kinase as it is the phosphatase required for
dephosphorylation of PIP3 to PIP2 and therefore the inactivation of PI3
kinase-mediated signaling. Patients with Peutz-Jeghers syndrome have muta-
tions in the LKB1 gene (Hemminki et al., 1998). LKB1 is a kinase that phos-
phorylates and activates cAMP-dependent kinase (AMPK), a critical negative
regulator of mTOR.
In conclusion, three pathways have been identified that are critical regulators
of clonal growth in colonic epithelium. The Wnt pathway stimulates clonal
growth and is involved in adenoma stem cell formation that is relevant to our
understanding of colorectal carcinogenesis. Formation of hamartoma stem
cells is stimulated by the PI3 kinase signaling pathway and restricted by BMP
signaling. Hamartoma stem cells behave differently from adenoma stem cells
and their relevance to colorectal carcinogenesis is much less straightforward.
3.3 Adenoma to Carcinoma Transition
As described above adenomas are formed by accumulation of mutated ade-
noma stem cells and lateral expansion through crypt fissioning. Subsequent
accumulation of (epi)genetic changes in the adenoma stem cells is probably
responsible for the generation of a clone within the adenoma stem cell pool that
has invasive (malignant) characteristics and causes the transition from ade-
noma to carcinoma. This mutant adenoma stem cell will be referred to as colon-
cancer stem cell here. The generation of new mutations within the initial
adenoma stem cell pool may explain why different degrees of dysplasia can be
observed within an adenoma and small areas of invasiveness can be observed
within early colorectal cancers that consist mostly of non-invasive adenoma-
tous epithelium. Causality is much less clear in genetic lesions involved in
adenoma to carcinoma transition than the APC mutations that are involved
in adenoma initiation. One of the changes associated with adenoma to carci-
noma progression is allelic loss of chromosome 17p, the minimal region being
17p13.1 which includes p53 (Baker et al., 1989). When Baker et al. (1989)
examined the remaining p53 allele in colon cancers with allelic loss of p53
they found that it was affected by point mutations in the remaining allele,
suggesting that p53 was inactivated by two independent genomic 'hits.' While
there have been several screens using different techniques to identify changes
