Hedgehog Signalling in EMT - Therapeutic Strategies in Cancer Biology and Pathology - page 29

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Hedgehog Signalling in EMT

Hedgehog (Hh) signalling represents a well-established developmental pathway of
embryogenesis. With the widespread recognition of EMT also as a developmental
programme, it is little wonder that Hh signalling can markedly influence EMT in
embryonic development, in the formation and maintenance of CSCs and acquisi-
tion of EMT characteristics. Hh expression has correlated with aggressive cancers
with enhanced tumour vascularisation, marked extension of the tumour to regional
lymph nodes and poor prognosis. Kelleher et al. (2011) have recently highlighted the
fact that as many as a dozen signalling pathways are deregulated and that in a large
majority of cases Hh signalling is affected.
It would be appropriate to open this analysis with a discussion of stem cells and
how their expansion and perpetuation might be shaped and affected by Hh signal-
ling. Albeit subject to much debate and discussion, CD44+/CD24+/ESA+ (epi-
thelial cell specific antigen) are regarded as putative stem cell markers and a clone
of cells carrying these markers might be expanded and tumour enriched in respect
of this subpopulation. This subpopulation is seen as representing a stem cell clone
capable of initiating tumour development. The CD44+/CD24+/ESA+ cells form a
tiny proportion of the total tumour cell population in pancreatic cancer. Pancreatic
cancer cell lines do not show a consistent pattern of expression of these different
antigens and also the diversity of expression depends upon the microenvironment,
namely whether grown as cell cultures or cell spheres (Wei et al., 2011). In xeno-
graft experiments, the percentage successful takes using a small number of stem
cells is virtually the same as xenografting a total cancer cell population. CD44+/
CD24+/ESA+ clone is found in breast cancers (Fillmore and Kuperwasser, 2008).
But CD133 positivity seems to be associated with glioma initiation and resistance to
therapy (Woodward and Sulman, 2008).
Here of considerable interest is that not only does this clone of cells showed
expansion in pancreatic cancer but also this stem cell subpopulation showed 46-fold
enhancement of Sonic hedgehog (SHh) expression as compared with normal epi-
thelial cells. Furthermore, the stem cell subclone of pancreatic cancer is believed
to be resistant to ionising radiation and to conventional chemotherapy. It has been
suggested that this chemoresistant subpopulation is accountable for the high recur-
rence rate of breast cancer (Fillmore and Kuperwasser, 2008). The development of
chemoresistance by stem cells may be defined by the microenvironment, but a tem-
poral acquisition of stem cell characteristics has also been advocated. However, the
distinction between CSCs and other stem cells founded on plausible influences of
the microenvironment and temporal acquisition of drug resistance would be too arti-
ficial to contemplate. An extended definition of microenvironment would include