Biomedical Engineering Reference
In-Depth Information
coordinates. There is increasing evidence suggesting that there are subtler
interactions between components of the signaling transduction pathways con-
trolling cell fate during development and we will now move on to explore these
entities in the context of the lung, firstly by describing their most important
interactions, both during development and tissue maintenance and during
carcinogenesis. We will also consider the microenvironment, a crucial factor
to stem cells, providing the necessary signs for their correct regulation and
function, and we will investigate how anomalies in this may contribute to the
process of malignant conversion.
2.1 The Wnt Signaling Pathway in Lung Cancer
The Wnt pathway was named after the wingless gene, the Drosophila homo-
logous gene of the first mammalian Wnt gene characterized, int-1 (Rijsewijk
et al., 1987). Wnt signaling occurs upon the binding of secreted Wnt ligands,
triggering changes in gene expression, cell behavior, adhesion, and polarity. In
mammals, Wnt proteins comprise a family of 19 highly conserved cysteine-rich
signaling glycoproteins. In the human adult lung Wnt2, Wnt5a, and Wnt11 are
expressed in the mesenchyme and Wnt7 is expressed in lung epithelium (Wang
et al., 2005; Lako et al., 1998; Li et al., 2002; Shu et al., 2002). So far, Wnt
transduction has been described in at least three pathways (Widelitz, 2005). The
most characterized Wnt pathway is the canonical signaling cascade, in which
Wnt ligands bind to two distinct families of cell surface receptors, the Frizzled
(Fz) receptor family and the LDL receptor-related protein (LRP) family, and
activate target genes through the stabilization of beta-catenin in the nucleus
(Akiyama, 2000) (Fig. 1). In the non-canonical Wnt/Ca2
þ
pathway, Wnt
proteins signal through the activation of calmodulin kinase II and protein
kinase C, leading to an increase in intracellular Ca2
þ
. Wnt can also signal
non-canonically through Jun N-terminal kinase (JNK); this is known as the
planar cell polarity pathway, controlling cytoskeletal rearrangements (Veeman
et al., 2003).
2.1.1 The Canonical Wnt Pathway
The canonical Wnt pathway becomes active whenWnt ligands bind to respective
Frizzled (Fz) receptors and low-density lipoprotein receptor-related proteins-5/6
(LRP5/6) co-receptors. Subsequently activation of the cytoplasmic phospho-
protein, Disheveled (Dvl), causes inhibition of a cytoplasmic complex made of
glycogen synthase kinase 3 (GSK-3), Axin, and adenomatous polyposis coli
(APC), to then repress the phosphorylation of beta-catenin by GSK-3 (Nusse,
2005). Stabilization and release of hypophosphorylated beta-catenin leads to
cytoplasmic accumulation and translocation with the help of BCL9, to the
nucleus (Kramps et al., 2002; Krieghoff et al., 2006; Sampietro et al., 2006). In
