Biomedical Engineering Reference
In-Depth Information
3.1 Normal and Cancer Stem Cell Signals
A number of signaling pathways have been identified in normal (Ivanova
et al., 2006) and cancer (Sell, 2007b; Dreesen and Brivanlou, 2007; Farnie
and Clarke, 2007) stem cells. Signals that maintain normal stem cells are
Wnt/b-catenin, Oct-4, Notch, BMP (bone morphogenic protein), JAK (Janus
family kinase), and sHH (sonic hedgehog). Inhibition of these signals by
RNA interference allows the stem cells to begin differentiation (Ivanova
et al., 2006), establishing the principle that the stem cell properties of normal
stem cells are maintained by stemness signals. A large number of signaling
pathways have been identified in cancer cells (Sell, 2007b; Dreesen and
Brivanlou, 2007; Farnie and Clarke, 2007). Most of them are shared by
normal and cancer stem cells, including JAK-Stat, Notch, PI3K/AKT, NF-
kB, Wnt, and TGF-b (Dreesen and Brivanlou, 2007). Although some of the
signal proteins, such as Notch and NF-kB, may eventually be targeted
(Farnie and Clarke, 2007; Zhou et al., 2007), it would appear more effective
to target signals that at least are more prominent in cancer cells than in
normal stem cells. Signals that have been specifically identified as being
associated with cancer stem cells and poor prognosis are Bmi1, Oct-4
(Pou5F1), EED, and Lmo4 (Glinsky, 2006). Specific inhibitors need to be
identified and ways found to deliver the inhibitor effectively in vivo.
3.2 Cancer Stem Cell Inhibition
Possible inhibitors of cancer stem cell signaling pathways include inhibitory
RNA (iRNA) and specific molecular inhibitors of the signaling pathway (Sell
2006a, 2007b).
3.3 Inhibitory RNA
Potential targets for inhibition via iRNA are listed in Table 1. Whereas inhibi-
tion by iRNA has been shown in some instances in vitro, major problems exist
in adapting iRNA inhibition for use in vivo (Pirollo and Chang, 2008; Pirollo
Table 1 Some potential targets for iRNA inhibition in cancer therapy
Cancer type
Targets
Breast
HER-2/neu, EGFR, epithelial specific antigen (ESA),
CD44, Notch, TGF-b
Leukemia/non-Hodgkin's
lymphoma Cancer stem cells
CD33, CD45, etc. Bmi1, c-kit, Notch 1, CD133,
chemokine receptor CXCR4, CD34, SCA-1, Thy-1,
EED, Oct-4, Lmo4
Solid tumors
SLAM family members CD48, CD150, and CD244
