Biomedical Engineering Reference
In-Depth Information
Several lines of evidence suggest that Hh signaling is also important in
prostate CSCs. One study found that SMO mRNA is more highly expressed
in xenograft tumors initiated from CD44
+
stem cell-like subpopulation in
DU145, LAPC4, and LAPC9 human prostate cancer cell lines relative to
CD44
cells (Patrawala et al. 2006). A more recent study using microarrays
found that SHHandSMOH genes are expressed at higher levels in
CD44
+
CD24
LNCaP tumor-initiating cells compared with the non-
tumorigenic CD44
+
CD24
depleted population, while the SMOH inhibitor
PTCH is downregulated (Hurt et al. 2008). In addition, enforced overexpres-
sion of GLI in normal primary prostate progenitor-like cells confers unlimited
growth, while daily injection of the Hh pathway inhibitor cyclopamine com-
pletely represses xenograft tumors (Karhadkar et al. 2004). Even 5 months after
halting cyclopamine treatment, tumors failed to regrow, suggesting that tumor-
initiating cells require Hh signaling and that these cells were killed by cyclopa-
mine. These reports support the notion that the Hh pathway is a key component
in CSC maintenance and also suggest the exciting possibility some prostate
CSCs may originate from a normal prostate SC that acquires an upregulated
Hh pathway (Karhadkar et al. 2004).
The polycomb group transcription factor protein Bmi-1 is a key regulator in
self-renewal in hematopoietic, leukemic, and neural SCs (reviewed in Grinstein
and Wernet 2007; Liu et al. 2005). Bmi-1 is a transcriptional repressor of p16
and INK-4A/ADP ribosylation factor (ARF), important cell cycle regulatory
genes linked to cancer (Molofsky et al. 2003). Recently it was shown that the Hh
pathway in human breast CSCs upregulates Bmi-1 and that Bmi-1 promotes
mammosphere growth and thus CSC self-renewal and proliferation (Liu et al.
2006). This report suggests that the effects of Hh signals in stem cells may in fact
be mediated by Bmi-1 (Liu et al. 2006). Consistent with its role in other CSCs,
Bmi-1 is also preferentially expressed in LNCaP and other prostate tumor-
initiating cells (Hurt et al. 2008; Patrawala et al. 2006) compared with the non-
stem cell population.
4.3 Notch Signaling
Notch signaling is important in regulating cell fate determination in developing
tissue, for cell proliferation and for maintaining SC self-renewal (reviewed in Weng
and Aster 2004; Liu et al. 2005) (Fig. 2C). Mammals have four Notch proteins,
Notch 1-4, that are transmembrane receptors existing as a heterodimer pro-form.
These interact with surface ligands such as Delta, Delta-like, and Jagged (DSL
ligands) from another cell. This interaction triggers a series of proteolytic events by
ADAM (a disintegrin and metalloproteinase) and g-secretase/presenilin that ulti-
mately release the intracellular Notch domain, which translocates to the nucleus
and binds to the transcription factor CSL and transcriptional activators of the
mastermind-like family. This ternary complex binds to genes containing CSL-
binding sites and activates their transcription.
