Biomedical Engineering Reference
In-Depth Information
therefore a better understanding of exactly which transporters are highly expressed
in prostate CSCs will also aid in the selection of therapeutic agents.
5.2 Targeting the Sonic Hedgehog Pathway
Cyclopamine targets Smoothened, a G-protein receptor that is kept inactive by
Patched. Treatment of mice with xenograft PC3 tumors with cyclopamine
resulted in apoptosis and tumor regression and inhibited recurrence of the
tumor for 5 months after removal of treatment (Karhadkar et al. 2004).
Furthermore, it was shown that treatment of PC3 CD44
+
CSCs with cyclopa-
mine results in a decreased expression of MDR1 and ABCG2 suggesting that
hedgehog signaling may also lead to a decrease in multi-drug resistance (Sims-
Mourtada et al. 2007). Therefore, targeting hedgehog for the treatment of
prostate cancer may indeed kill the CSC population and result in a greater
toxicity to the cells in general by reducing multi-drug resistance.
5.3 Targeting the Notch Pathway
Gamma-secretase inhibitors prevent the formation of an active Notch by
inhibiting its cleavage. In the case of AML, the use of a g-secretase inhibitor
(DAPT) inhibited the growth of the AML stem cell (CD34
+
CD38
) (Gal et al.
2006). The search for other g-secretase inhibitors continue, especially for the
treatment for Alzheimer's where this protein is also important in the etiology of
the disease. A new inhibitor, LY15039, is currently being investigated for safety,
tolerance, and efficacy in the Alzheimer's setting (Siemers et al. 2007). It
remains to be determined if the use of g-secretase inhibitors will have an effect
on prostatic CSC, however, the intricacies of Notch signaling, such as an
increase in TA cells with the inhibition of Notch (discussed in more detail
above), may make this a less desirable target in prostate cancer.
5.4 Targeting the Niche of Stem Cells
Several lines of evidence show the importance of the niche in tumorigenesis.
There is often critical interaction between the tumor cells and cells found within
the niche, and this has also been demonstrated for CSCs. In brain tumors, the
CSCs are located in close proximity of vessels that provide an environment
enriched in factors that shelter them from apoptosis and maintain the balance
between self-renewal and differentiation (Shen et al. 2004; Ramirez-Castillejo
et al. 2006). In this system, it is thought that the endothelial cells that line the
blood vessels promote survival and self-renewal. Indeed, Calabrese et al. (2007)
demonstrate co-culture of CSCs and endothelial cells results in proliferation of
