Biomedical Engineering Reference
In-Depth Information
The stemness is conceivably maintained through deregulation of pathways
such as Bmi-1, Notch, Wnt and Sonic Hedgehog (Shh). Recent evidence sug-
gests an additional existence of distinct self-renewal mechanisms between nor-
mal stem cells and CSC involving the tumour suppressor protein Pten (Yilmaz
et al., 2006). Both Wnt signalling and Shh signalling are inappropriately acti-
vated in epidermal tumours (Niemann and Watt, 2002; Owens and Watt, 2003;
Fuchs et al., 2004; Hutchin et al., 2005). Uncontrolled activation of these
pathways may result in specific cancers, possibly as an attempt to recapitulate
normal embryonic organogenesis (Molofsky et al., 2004; Ruiz et al., 2004).
Aberrant Notch signalling has been detected in several cancers and has recently
strongly connected to T-cell acute lymphoblastic leukaemia (Grabber et al.,
2006). Aberrant activation of the Wnt pathway has been found in a variety of
human tumours and is strongly associated with colorectal cancer (Taipale and
Beachy, 2001). Increased Hedgehog signalling has been linked not only to small
subset of tumours in the brain, skin and muscle but recently also to cancers in
the lungs, gastrointestinal tract and pancreas (Pasca di Magliano and Hebrok,
2003). Bmi-1, a transcription repressor of Ink4a/Arf locus (Jacobs et al., 1999)
which encodes two separate tumour suppressor genes p16 and p14, is an
oncogene that is found overexpressed in several human cancers (Valk-Ling-
breek et al., 2004) like, for instance, in the majority of medulloblastomas (Leung
et al., 2004; Marino, 2005). More recently, Bmi-1 expression was demonstrated
to be associated with an increased risk of melanoma metastasis (Mihic-Probst
et al., 2007). Finally, activation of Myc, a classical proto-oncogene, was demon-
strated not only to promote growth and proliferation but also to induce highly
invasive tumours in a transgenic model of pancreatic tumorigenesis using the
insulin promoter (Pelengaris et al., 2002). In addition, c-myc is closely corre-
lated with the progression from the in situ to the invasive stage in human breast
carcinomas (Robanus-Mandag et al., 2003). Therefore, the disruption of c-Myc
through Miz1 could contribute to the genesis of skin tumours affecting or
contributing to the development of cancer stem cells. More recently, CD133-
positive cells were demonstrated to occur in melanoma biopsy (Monzani et al.,
2007). Furthermore, a recent paper showed an increased expression of CD166,
CD133 and nestin during melanoma progression (Klein et al., 2007).
3 Pharmacological Perspectives
Cancer chemotherapeutic efficacy is frequently impaired by either intrinsic or
acquired tumour resistance to multiple, structurally unrelated therapeutic drugs
with different mechanisms of action, a phenomenon termed multidrug resistance
(MDR). MDR can result from several distinct mechanisms, including alterations
of tumour cell cycle checkpoints, impairment of tumour apoptotic pathways,
repair of damaged cellular targets and reduced drug accumulation in tumour cells
(Gottesman et al., 2002).
