Biomedical Engineering Reference
In-Depth Information
2 Embryological Signaling Pathways in Lung Cancer
Liu et al. compared the molecular signatures of different human lung cancers
against the changing expression profiles of mouse orthologs at different stages
of mouse lung development: normal human lung samples were histologically
most resembling of late mouse lung embryological stages; human small cell lung
cancer (SCLC), which is the most aggressive malignant subtype of lung cancer,
appeared first. Squamous carcinoma followed and then adenocarcinomas,
which have the best 5-year survival rates. The observation that the earlier
stage of mouse lung development to which a human lung tumor resembled
was linked with worse survival rates suggested that abnormally activated
embryological cell signaling pathways are important in lung carcinogenesis
(Liu et al., 2006). It is fascinating that these experiments justly support Rudolf
Virchow's old hypothesis of 'Omnis cellula e cellula' ('Every cell is originated
from another mother-like cell'), which proposes that embryonic cells are the
originators of cancer (Virchow, 1858). As we continue to understand in detail
the repercussions of deregulation in key embryonic signaling pathways, we
begin to dissect their intricate relationships with stem cells and malignancy
(Reya et al., 2001; Pardal et al., 2003; Wicha et al., 2006). In order for an
organism to develop, its cells need to be able to proliferate and to follow specific
fates of cellular differentiation in a tightly controlled temporospatial manner, to
ultimately ensemble and organize into functioning tissues and organs. Cell fate
specification and complex gene regulatory networks (GRN) control develop-
ment (Davidson and Erwin, 2006). Cellular phenotypes are the result of pat-
terns of gene expression. Intrinsic transcription factors released by cells in a
timely manner provide the coordinates that delineate their individual fate.
Extrinsic factors influence cells as groups through the process of differentiation.
The integration of intrinsic and extrinsic cues is the decisive denominator
providing the coordinates of cell fate and differentiation. By understanding
the interplay between these factors we will hopefully dissect the processes
leading to cell fate assignment. Research data from the last two decades suggest
that there are six main signaling transduction pathways in the cell (Martinez
Arias and Stewart, 2002): Wnt (Wingless/Int-1), Hedgehog (Hh), Notch, recep-
tor tyrosine kinase (RTK), steroid hormone receptor, and bone morphogenic
proteins (BMP). They are thought to act in parallel, to ultimately enhance
specific genes that result in cell type-specific combinations of transcription
factors responsible for cellular behavior (Martinez Arias and Stewart, 2002;
Barolo and Posakony, 2002), representing the basic machinery for the determi-
nation of embryonic cell fate determination. Examples include the photorecep-
tor cellular fate determination in the Drosophila model (Silver and Rebay, 2005;
Voas and Rebay, 2004) and in the eight-cell embryo of Caenorhabditis elegans
during the formation of blastomeres (Rose and Kemphues, 1998; Newman-
Smith and Rothman, 1998; Platzer and Meinzer, 2004). The combined activity
of transcription factors in these examples is defined via specific temporospatial
