Biomedical Engineering Reference
In-Depth Information
2.
Glioma biology
Genomic DNA aberrations are key genetic events in gliomagenesis.
Recurrent genomic regions of alteration, including net gains and losses,
have been found in gliomas. Whereas some of these regions contain
known oncogenes and tumor suppressor genes, the biologically relevant
genes within other regions remain to be identified. The phenotypic and
genotypic heterogeneity indicate that no isolated genetic event accounts
for gliomagenesis, but rather the cumulative effects of a number of alter-
ations that operate in a concerted manner. In this pathological process
are included various biological events, such as activation of growth factor
receptor signaling pathways, down-regulation of many apoptotic mecha-
nisms, and imbalance of pro- and anti-angiogenic factors. Several growth
factor receptors, such epidermal growth factor receptor (EGFR), platelet-
derived growth factor receptor (PDRGF), C-Kit, vascular endothelial
growth factor receptor (VEGFR) are over-expressed, amplified and/or
mutated in gliomas (Figure 2-1). In Table 2-1 are summarized the most
common glioma genetic alterations frequently found. In the light of this
novel information, the modulation of gene expression at more levels, such
as DNA, mRNA, proteins and transduction signal pathways, may repre-
sent the most effective modality to down-regulate or silence some specific
genic functions or introduce genes, down-regulated or deleted selectively,
into neoplastic cells.
2.1 Invasion and angiogenesis
Glioma cell invasion consists of an active translocation of glioma cells
through host cellular and extracellular matrix barriers [6-7]. Cerebral
gliomas show a unique pattern of invasion and with rare exceptions do not
metastasize outside of the brain. How invasive glioma cells survive in the
setting of invasion, evading immune detection, and deferring commitment
to proliferation, remains unknown. Invading glioma cells normally migrate
to distinct anatomical structures. These structures include the basement
membrane (BM) of blood vessels, the subependymal space, the glial limi-
tans externa, and parallel and intersecting nerve fibre tracts in the white
matter. Glioma cells adhesion to proteins of the surrounding extracellular
matrix (ECM), degradation of ECM components by proteases secretion
by neoplastic cells and migration of glioma cells are fundamental phases in
this process. ECM is composed of proteoglycans, glycoproteins, and colla-
gens and also contains fibronectin, laminin, tenascin, hyaluronic acid, and
vitronectin. Critical factors in glioma invasion include the synthesis and
deposition of ECM components by glioma and mesenchymal cells, the re-
lease of ECM-degrading activities for remodeling interstitial spaces, the
presence of adhesion molecules and the effects of cell-matrix interactions
on the behavior of glioma cells. ECM modification aids the loss of contact
