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growth factor receptor, platelet-derived growth factor cell migration into the brain. [12] Another study utilizing
receptor (PDGFR), vascular endothelial growth factor neutralizing antibodies directed toward the α or the
v
receptor (VEGFR), and hepatocyte growth factor/scatter β integrin subunits reported complete inhibition of
1
factor receptor. Several hormones and cytokines are GBM cell migration by most substrates, suggesting the
also involved in the regulation of molecular pathways α and β integrins play a crucial role in GBM tumor
v 1
[5]
related to GBM development. Recent data implicate cell infiltration into the normal brain. [12]
the inflammatory interleukins (IL)-1β, -6 and -8 in
GBM pathophysiology. It has been found that these Integrins modulate several functions of GBM
cytokines are upregulated in GBM cell lines as well cells-including survival, adhesion, and migration-
as in patients’ samples while some of them have high through interaction between growth factors and their
prognostic potential. [7] receptors with subsequent formation of complexes.
There is robust evidence suggesting the formation of
Angiogenesis is considered to be the key regulating analogous complexes in different types of cells, such as
factor of vascular development in tumors and especially complexes of various types of integrins with VEGFR-2,
for GBMs. The development and growth of MGs seem PDGFR-β, and EGFR. [14,15]
to be dependent on angiogenesis since microvascular
proliferation can only be observed in high-grade FOCAL ADHESION KINASE
gliomas. [2,8-10] Apart from growth factors and their
receptors, other molecules that significantly contribute Focal adhesion kinase has been recently established
to angiogenesis in gliomas and growth of GBMs are the as a key component of the signal transduction
integrins and focal adhesion kinase (FAK). pathways triggered by integrins. FAK not only acts
directly on the plasticity of cytoskeletal structures
INTEGRINS at focal adhesions, but also mediates effects on
gene expression that indirectly alter the ability of
Integrins are cell surface receptor glycoproteins, cells to migrate and invade. [13] The interaction of
mediating various intracellular signals through urokinase-type plasminogen activator receptor (uPAR)
interaction with the extracellular matrix (ECM). Integrins with integrins during cell adhesion and migration has
also significantly contribute to the attachment of cells also been proposed. uPAR binds the urokinase-type
to the ECM through the formation of cell adhesion plasminogen activator (uPA) and facilitates a
complexes consisting of integrins and cytoplasmic proteolytic cascade focused on the cell surface. uPAR
proteins. There are many types of integrins, which are has recently been recognized as a multifunctional
obligate heterodimers containing two distinct chains protein that, through its interactions with integrins,
called α and β subunits. The combination of α and β initiates signaling events that alter cell adhesion,
subunits determines the ligand specificity. [11-13] migration, and proliferation of various cancer cells,
including GBM cells. [11,12,16]
Integrins are crucial molecules in glioma because of
their contribution to enhanced invasion capacity in All these molecular and genetic alterations contribute
glioma cells. This phenotype can be defined by three to the well-established biological features of GBMs
attributes. The cells at the invasive edge of the tumor and may provide a target to enhance therapeutic
are able to: (i) detach and migrate forward; (ii) adhere responsiveness of these lethal brain malignancies.
via local and self-produced ECM; and (iii) degrade Recent advances in thorough understanding of the
the local/surrounding ECM in order to clear a path complex molecular pathogenesis of GBMs have led
for further invasion. Since integrins are integral to to the rational development of new treatment options
the process of cell adhesion and migration, these targeting intracellular signaling. [1,2] Despite these
receptors have been assessed as potential contributors advances, most single-agent therapies targeted to growth
to glioma invasion, as have been the cooperating ECM and survival pathways have failed to demonstrate a
components. [11] Multiple integrins have been reported significant survival benefit, mainly because of the
to be expressed on GBM in tissue biopsies, including complexity of the implicated signaling pathways
α β , α β , α β , α β , α β , α β , and α β . and their interactions. Thus, targeting multiple
ν 3 ν 5 5 1 2 1 3 1 6 1 ν 1
signaling pathways by multi-target kinase inhibitors
Functional studies with blocking antibodies directed or combinations of single-target kinase inhibitors may
toward the β integrin subunit have shown an inhibition increase treatment efficacy. Multi-targeted agents are
1
of adhesion, motility, and invasion of cultured glioma needed to simultaneously target multiple signaling
cells plated on multiple ECM substrates (laminin, pathways that occur either at the same time or
collagen type IV, fibronectin, and vitronectin), suggesting sequentially, as a compensatory mechanism to tumor
a role for one or more β integrins in neoplastic glial growth and resistance to treatment. Currently, several
[1]
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Neuroimmunol Neuroinflammation | Volume 2 | Issue 1 | January 15, 2015 5