Biomedical Engineering Reference
In-Depth Information
pathways functioning in embryonic cells (Nusslein-Volhard and Wieschaus,
1980). One pathway, controlled by the Hedgehog (HH) and WNT signaling
molecules, contains several genes functioning as either tumor suppressor
genes or oncogenes (Dean, 1997). For example Patched (PTCH) is the recep-
tor for HH molecules and PTCH is mutated in patients with nevoid basal cell
carcinoma syndrome (Chidambaram et al., 1996; Hahn et al., 1996a; Johnson
et al., 1996). The PTCH gene is also mutated in virtually all sporadic basal cell
carcinomas and in some medulloblastomas, rhabdomyomas, and rhabdo-
myosarcomas (Bale and Yu, 2001; Gailani et al., 1996; Tostar, et al., 2006).
The mammalian HH genes (IHH, SHH, DHH) are overexpressed in a large
number of cancers including small cell lung, pancreas, gastric, breast, and
prostate (Berman et al., 2003; Karhadkar et al., 2004; Thayer et al., 2003;
Watkins et al., 2003). HH ligand overexpression and PTCH mutation both
have the effect of constitutive expression of smoothened (SMO), a G-protein-
coupled receptor family protein, a key signaling protein in the pathway.
Constitutive HH expression could be an important component to the stem
cell activation in many cancers and therefore represents an attractive target
for cancer therapy.
Cyclopamine is a compound discovered in the Corn Lily (Veratrum califor-
nicum), a plant teratogenic to sheep (James et al., 2004). Cyclopamine binds to
and inhibits the SMO protein and suppresses the growth of cells and tumors
with activated HH signaling (Chen et al., 2002). Human prostate tumor cell
lines grown as xenografts in mice were eliminated following 21 days of treat-
ment with cyclopamine (Karhadkar et al., 2004), and UV-induced basal cell
carcinomas were suppressed in mice given low levels of cyclopamine in their
drinking water (Athar et al., 2004). Recently it has been demonstrated that
vitamin D3 is a critical signaling molecule between PTCH and SMO. PTCH
normally secretes vitamin D3 and this molecule inhibits SMO on that cell as
well as adjacent cells (Bijlsma et al., 2006). HHs inhibit this secretion and cause
a release from repression. Cyclopamine competes for the binding of vitamin D3
on SMO and so appears to act in a similar manner. It is likely that vitamin D3
and/or other steroidal analogues could have a similar effect and be candidate
anticancer compound.
Other pathways critical to embryonic development and potentially impor-
tant in cancer have also been described and include the WNT and NOTCH
pathways. A number of experimental inhibitors of these pathways have been
developed. These pathways are also the subject of drug development for a
number of conditions and one example is the drug MK0752, which is in clinical
trials for the treatment of acute T-cell lymphoblastic leukemia, myelogenous
leukemia, chronic lymphocytic leukemia, and myelodysplastic syndrome.
Gamma-secretase is required for the maturation of the NOTCH protein, and
g-secretase inhibitors have been developed for a number of pathological condi-
tions. In a recent study, one such gamma secretase inhibitor was effective in the
inhibition of stem-like cells in embryonal brain tumors (Fan et al., 2006).
