Biomedical Engineering Reference
In-Depth Information
Furthermore, more recently ABCB5 was demonstrated to mediate doxorubicin
transport and chemoresistance in a subset of human malignant melanoma
(Frank et al., 2005). Furthermore, in melanoma a subpopulation of CD133/
ABCG2+ cells were demonstrated (Monzani et al., 2007) according to other
tumours (Zhou et al., 2001; Doyle and Ross, 2003). More recently, systemic
administration of a monoclonal antibody directed against ABCB5 was demon-
strated to induce antibody-dependent cell-mediated cytotoxicity in ABCB5+
cells exerting tumour-inhibitory effects (Schatton et al., 2008).
Thereby, it is clear that if the tumour is driven by CSCs, a radical change in the
treatment of tumour should arise. In particular, new diagnostic and therapeutic
targets expressed by stem cells should be identified. Clearing the CSCs should
cure the disease since the remaining cells have limited proliferative capabilities.
However, targeting CSCs is problematic since CSCs share many molecular
factors with normal stem cells (Galmozzi et al., 2006) such as PTEN, Bmi-1.
Thus targeting such a modulator of CSCs is likely to increase side effects resulting
from stem cell loss. Therefore, the similarities between CSCs to the adult tissue
stem cell seriously hinder systemic cytotoxic therapies.
To bypass all these problems it seems important to deeply investigate the
biology of CSCs. Much research is focused on targeting essential genes or path-
ways crucial for cancer development with any therapies against targets expressed
by tumour-initiating cells. For example, a comparison of the pathways that
regulate stem cell homing with those responsible for metastasis may prove useful
too. Treatment of mice with the Hedgehog pathway inhibitor such as cyclopa-
mine inhibits the growth of medulloblastomas in mouse models, without any
apparent toxicity (Berman et al., 2002). Thus, the Hg pathway may be inactive in
most normal adult tissue, hence minimizing the toxicity effects of these inhibitors
(Beachy et al., 2004). Interference with the hedgehog-GLI signalling using a viral
vector has been demonstrated to remove resistance to temozolomide in glioblas-
toma multiforme (Clement et al., 2007). Therefore, GLI regulates stemness and
tumour progression and metastatic growth (Altaba et al., 2007). In melanoma,
GLI1 function was demonstrated to be striking (Stecca et al., 2007), suggesting
that manipulation of GLI1 code could provide a wide-spectrum anticancer target
for therapeutic intervention. The finding that oncogenic RAS-AKT pathways
regulate GLI1 and that there is a mutual proliferative dependence between
oncogenic RAS and HH-GLI function further supports the idea and raises the
interesting prospect of using combinatorial therapies targeting oncogenic RAS,
AKT and HH-GLI (Stecca et al., 2007). An interesting drug is cyclopamine
which is a natural plant alkaloid that is available and effective orally in form
and range as well as in laboratory animals withminimal side effects. Cyclopamine
treatment has proven good at inhibiting tumour growth and survival of TYr-
RASQ61K INK4a-/- melanoma (Stecca et al., 2007). Interestingly, temozolo-
mide has additive and synergistic effects with cyclopamine in glioblastoma stem
cell cultures (Clement et al., 2007).
Acknowledgment I thank Riccardo Bazzotti for the relevant contribution to the ABC picture.
