Biomedical Engineering Reference
In-Depth Information
the promoter sequence context (Pesce and Scholer 2001) and is a key regulator
of pluripotency in mouse and human ES cells. These important ES cell tran-
scription factors form an interdependent regulatory network where they can
enhance or restrict expression of each other in order to maintain pluripotency
and self-renewal (Boyer et al. 2005). This complex regulatory network is likely
necessary to ensure proper embryonic development, and which differentiation
pathway is activated, and at what stage, may depend on as yet uncharacterized
Nanog, Oct3/4, and Sox2 interactions with co-activators or repressors (Babaie
et al. 2007). A recent study of telomerase-immortalized primary human prostate
cancer progenitor-like cells found Oct4, Nanog, and Sox2 genes were expressed
(Gu et al. 2007). Moreover, these cells were also AR negative and CD44 positive
and were tumorigenic in mice. In addition both Patrawala et al.(2006) and Hurt
et al. (2008) reported that CD44
+
prostate cancer cells are enriched for Oct3/4
gene expression while Tcf3 expression was decreased (EMH unpublished obser-
vations). These studies strongly suggest that Nanog/Oct3/4/Sox2 network is
important in maintaining prostate CSCs. However, the mechanisms controlling
these transcription factors and the downstream effects have yet to be fully
elucidated in both normal and CSCs.
5 Targeting of CSCs
With the understanding of the molecular events governing CSCs it will be possible
to develop therapeutics aimed at them. This is of paramount importance since the
CSCs may mediate resistance and relapse of the most aggressive tumors to current
treatments. This resistance may in part be the reactivation of several signaling
cascades, such as sonic hedgehog, Wnt, Notch, epidermal growth factor (EGF/
EGFR) in the CSCs combined with increases in DNA repair mechanisms and
ABC transporter-mediated multi-drug resistance (Mimeault et al. 2007a,b; Dean
et al. 2005; Galmozzi et al. 2006; Barker and Clevers 2006; Rubin and De Sauvage
2006; Fodde and Brabletz 2007; de Jonge-Peeters et al. 2007; Bao et al. 2006).
5.1 Targeting ABC Transporters
Chemotherapeutic agents are effluxed using mechanisms similar to those for
Hoechst 33342 dye. The SP are enriched in prostatic CSCs. Therefore, blocking
drug transporters in combination with administration of a chemotherapeutic agent
may be effective at inducing cell death of CSCs simply by keeping the chemother-
apeutic agent within the cell. The development of ABC transporter inhibitors has
been plagued by many problems, including toxicity and adverse pharmacokinetics
(Shukla et al. 2008). It was shown that ABCG2 does not identify the tumor-
initiating cells in the prostate cancer cell line DU145 (Patrawala et al. 2005),
