Biomedical Engineering Reference
In-Depth Information
been identified, many of which have multiple isoforms. The inhibitory transcrip-
tional function of Ci in mammals seems to occur through Gli-3, while Gli-1 and
Gli-2 behave as activators of the pathway. However, a lot remains unknown in
the mammalian Hh pathway and its complexities.
Epithelial-mesenchymal tissue interactions control the branching of embry-
ological murine pulmonary buds, when expression of Shh is at its highest level.
These levels decrease becoming very low around birth, though remaining
detectable throughout the epithelium postnatally (van Tuyl and Post, 2000;
Bellusci et al., 1997). Shh-null mice exhibit hypoblastic lung buds without
airway branching with serious consequences to viability. In contrast, transgenic
overexpression of Shh leads to the absence of functional alveoli and hyperpro-
liferation of epithelial and mesenchymal pulmonary cells (Bellusci et al., 1997;
Litingtung et al., 1998). In adult lungs, only a small number of basal bronchial
epithelial cells show constitutive hedgehog signaling. Mice exposed to naphtha-
lene airway damage demonstrate an expansion of the intraepithelial cell popu-
lation with active Hh during airway regeneration. Interestingly, the expansion
of these regenerative cells precedes the increase of a rare pulmonary neuroendo-
crine population of cells, which is considered to be a potential stem epithelial
progenitor (Litingtung et al., 1998; Reynolds et al., 2000a). The growth of
SCLC cell lines, which maintains components of the Hedgehog pathway and
with features of primitive neuroendocrine differentiation, was inhibited by
cyclopamine, a naturally occurring steroidal alkaloid inhibitor of Smoothened
and therefore the Hedgehog pathway. These results, however, were not
observed in NSCLC cell lines (Cooper et al., 1998; Watkins et al., 2003)
indicating that progenitor respiratory epithelial cells may follow a neuroendo-
crine route in response to Hedgehog signaling elicited by neighboring cells. In
contrast, SCLC could be the result of unchanged and unregulated Hedgehog
signaling. Similar to the case of Wnt and Notch, the robust identification of
putative CSCs in the lung and how this pathway may influence them is
essential.
2.3 The Notch Signaling Pathway in Lung Cancer
The Notch protein belongs to a family of single-transmembrane-domain recep-
tors that have an extracellular domain consisting of EGF-like repeats and an
intracellular domain with seven Ankyrin (ANK) repeats (Ehebauer et al., 2005;
Nam et al., 2003, 2006; Zweifel et al., 2003). The Notch intracellular domain
(NICD) acts as a membrane-bound transcription factor. Binding of Notch to its
ligands Serrate and Delta releases NICD (Kopan, 2002). Free NICD translo-
cates into the nucleus, to interact with CSL (CBF in vertebrates, Suppressor of
Hairless [Su(H)] in Drosophila, and LAG-1 in C. elegans), to initiate the tran-
scription of target genes. Endocytic trafficking and/or the localization of Notch
to a specific endocytic compartment is necessary for the cleavage of NICD
