Targeted Inhibition of Hh, Wnt, TGF-B Signalling Complex - Therapeutic Strategies in Cancer Biology and Pathology - page 39

ability to activate Gli transcription factors (Douglas et al., 2011). This information
is highly valuable since SMO inhibitors can function in synergy with Gli inhibi-
tion. Furthermore, PTCH, SMO and Gli transcription factors may be differentially
expressed; this can affect the response of the target cells to inhibitors (Decker et al.,
2012). Also Hh signalling can adopt the non-canonical systems and inter alia func-
tion via the Smad, Notch and PI3K/Akt and MAPK/ERK pathways. Thus besides the
considerable focus on SMO, Gli has been recognised and targeted to inhibit aberrant
Hh signal transduction.
As noted earlier, Hh signalling activates the embryonic developmental pro-
gramme EMT and induces the formation and maintenance of CSCs. Hh expres-
sion has correlated with aggressive cancers with enhanced tumour vascularisation,
marked extension of the tumour to regional lymph nodes and poor disease prognosis.
Therefore it is noteworthy that Gli transcription factors could be directly related to
the process of angiogenesis. Overexpression of Gli3 seems to induce endothelial cell
migration in vitro and this was dependent upon activation of Akt and ERK1/2 path-
way (Renault et al., 2009). These findings provide additional support to the deploy-
ment of Gli inhibitors in a therapeutic mode. Growth factors such as EGF and VEGF
activate PI3/Akt and ERK signalling systems. EGFR mediated MEK/ERK activation
appears to co-operate with Gli1 and Gli2 to induce cellular transformation. Blocking
EGFR and Gli1 inhibits the proliferation of murine BCC cells with activated Gli
signalling (Schnidar et al., 2009). Since MAPK signalling promotes Gli1 activity,
inhibition of MAPK/MEK pathway is a target worthy of pursuit. So it seems that
not only is Gli a valuable target, but it can be inhibited directly or by inhibiting the
upstream signalling links. Of the other signalling pathways integrating with Hh/Gli1
is Notch signalling. Notch possibly directly targets Gli. Schreck et al. (2010) have
found that the downstream effector of Notch, namely Hes1 binds to the first intron of
Gli1 and might be inhibiting its expression.