Biomedical Engineering Reference
In-Depth Information
grow in a more distal fashion. The tumor regionality observed in the mouse may
suggest that there are a defined number of distinct pulmonary niches and cells
capable of initiating, promoting, and sustaining the carcinogenic cascade. There
is evidence that humans also display pulmonary tumor regionality (Fig. 3),
although thus far, the exact location of potential lung cancer stem cells is still
unknown. A classical lung cancer mouse model is the mutant pan-pulmonary
K-ras model. In these animals only non-cancerous adenomatous hyperplastic
lesions exclusively localized to the bronchoalveolar region despite the fact that
identical mutations had been universally induced through the tracheobroncho-
pulmonary apparatus (Fisher et al., 2001; Meuwissen et al., 2001; Johnson et al.,
2001; Jackson et al., 2001; Guerra et al., 2003). Other mouse models have
demonstrated that bronchiolar stem cells, within neuroepithelial body microen-
vironments (NEB), have been linked to SCLC (Watkins et al., 2003; Collins et al.,
2004; Ball et al., 1993; Giangreco et al., 2004; Williams et al., 1994; Wikenheiser-
Brokamp, 2004; Meuwissen et al., 2003; Minna et al., 2003; Reynolds et al.,
2000b; Linnoila et al., 2000, 2005; Van Lommel et al., 1999; Miller et al., 2001;
Giangreco et al., 2007) and central bronchiolar adenocarcinoma and bronchoal-
veolar cell carcinomas have been shown to arise within distal pulmonary niches,
from the bronchoalveolar duct junction (BADJ) harvesting bronchioalveolar
stem cells (BASCs). These BASCs have been identified, expanded, and char-
acterized in mice (Kim et al., 2005). Although, in general, human lung cancers
either exhibit airway or alveolar differentiation some types of cancers exhibit
both airway and alveolar differentiation, which is similar to what is found in
most mouse models (Kim et al., 2005). The working hypothesis for potential
human BASCs is that either Clara or alveolar type 2 (AT2) cells give origin to
the cellular precursors of adenocarcinomas (Fisher et al., 2001; Kim et al.,
2005). There is increasing evidence from the murine adenocarcinoma models
that in humans, precursor cells for adeno and bronchoalveolar carcinoma also
localize to the BADJ zone (Meuwissen and Berns, 2005; Meuwissen et al.,
2001; Jackson et al., 2001; Politi et al., 2006; Ji et al., 2006; Bottinger et al.,
1997; Wikenheiser et al., 1992; DeMayo et al., 1991). These examples show
how different histological types of lung cancer are linked to specific pulmon-
ary microenvironments with unique stem cells and will hopefully lead to the
identification of such entities in the human lung, with obvious potentially
beneficial new therapeutic targets (Fig. 3).
3.3.2 Identification of Pulmonary Cancer Stem Cells
The presence of a clonogenic population of cells in human lung cancer was
described almost three decades ago. Clinical specimens from SCLC and ade-
nocarcinoma patients were found to contain a small subpopulation of cells
(
<
1.5%) that possessed the ability to form colonies when grown on agar. Upon
their intracranial injection into athymic nude mice, they yielded cancers with
features identical to those of the original specimens. This supports the notion of
cancer stem cell (CSC) populations within some lung cancers (Carney et al.,
