Biomedical Engineering Reference
In-Depth Information
Therefore, the most primitive prostatic CSCs appear to be CD44
+
CD133
+
integrin-a2b1
hi
CD24
. However, more extensive experiments need to be con-
ducted using primary samples to confirm that this is an accurate phenotype in
prostate cancer patients.
4 Signaling Pathways Important in Prostate CSCs
By definition, both normal and CSCs must maintain self-renewal capacity in
addition to giving rise to differentiated progeny cells, and thus there is likely to
be similarity in the pathways governing these processes between normal and
CSCs. Understanding the signaling pathways and the molecular mechanisms
that are responsible for regulating these events in CSCs is extremely important,
as it is likely that tumor growth is determined in part by disregulation of the
Wnt, hedgehog, Bmi-1, and/or Notch signaling pathways (Lobo et al. 2007). An
overview of the pathways discussed below can be found in Fig. 3.
4.1 Wnt/b-Catenin Pathway
The Wnt/b-catenin pathway is important for cell proliferation, differentiation,
and self-renewal in hematopoietic stem cells (reviewed in Mohinta et al. 2007).
In addition, defects in Wnt signaling are associated with several tumor types
including colon, skin, breast, prostate, and bone marrow (Taipale and Beachy
2001; Mohinta et al. 2007; Bastian et al. 2005; Bruxvoort et al. 2007; Reya et al.
2003). Wnts are a 19-member family of secreted glycoproteins that bind to
several different cell surface receptors and determine signal transduction by the
canonical or non-canonical pathway (Cadigan and Nusse 1997). Wnt binding
to LRP5/6 and Frizzled receptors on a Dishevelled (Dvl) platform inhibits
GSK-3b, which, in the absence of Wnt binding, is found in complex with axin
and APC and phosphorylates b-catenin, marking it for proteolytic degradation.
Accumulation of free b-catenin in the cytoplasm and nucleus is followed by
direct association with the transcription factors TCF/LEF, resulting in subse-
quent activation of Wnt target genes that involve epithelial-to-mesenchymal
(EMT) transition and cell proliferation (e.g., c-myc, cyclin D1, and CD44). In
addition, b-catenin is a coactivator of AR-mediated transcription activity,
which suggests a crosstalk between Wnt and androgen signaling in prostate
cancer (Yang et al. 2002; Terry et al. 2006). Several secreted antagonists help
regulate Wnt signaling to prevent overactivation. WIF1 and SFRPs blockWnt/
Frizzled binding, and DKK proteins interfere with LRP5/6 (Kawano and
Kypta 2003). In many cancers including prostate, these Wnt inhibitors are
downregulated through both genetic and epigenetic changes (Wissmann et al.
2003; Kawano et al. 2006), resulting in upregulation of the Wnt pathway.
