Drug Targeting Organ-Specific Strategies

236 9 Tumour Vasculature Targeting
9.1.2.2 Role of Integrins
Integrins are transmembrane proteins composed of an α and β subunit in over 20 different
αβ heterodimeric combinations. They bind to ECM proteins or cell surface ligands through
short peptide sequences and are implicated in angiogenesis control. Combinations of different
integrins on (endothelial) cell surfaces allow cells to recognize and respond to a variety
of different ECM proteins [22].They are able to transduce signals from within the cells to the
outside as well as from the outside into the cell [23]. Integrin-mediated cell adhesion has impact
on two key aspects of growth regulation. First, it can influence the activity of the basal
cell cycle machinery consisting of cyclin-dependent kinase complexes. Second, integrins play
a vital role in anchorage-dependent cell death or anoikis [24,25]. For example, integrin α Vβ 3
mediates endothelial cell adhesion to vitronectin, fibrinogen, laminin, collagen, von Willebrand
Factor or osteopontin through their exposed tripeptide Arg-Gly-Asp (RGD) moiety
[26]. Since α Vβ 3 is minimally expressed on normal resting endothelium, but significantly upregulated
on tumour and other activated endothelium, it is believed to play a critical role in
the process of angiogenesis. Both peptide and antibody inhibitors of α Vβ 3 induced endothelial
cell apoptosis, suggesting a role for this integrin in endothelial cell survival during angiogenesis
[27]. Another α V integrin associated with angiogenesis is α Vβ 5. Whereas in vivo
FGF-2 or tumour necrosis factor α (TNFα) induced α Vβ 3-dependent angiogenesis,VEGF or
transforming growth factor β (TGF-β) initiated an angiogenesis pathway dependent only on
α Vβ 5 [28].
9.1.2.3 Role of the Extracellular Matrix
Components of the ECM play an important role in the regulation of endothelial cell morphology
and function. Thrombospondin (TSP), for example, can affect endothelial cell proliferation
negatively as well as positively, depending on the endothelial microenvironment.
Furthermore, through binding to and activation of TGF-β and affecting protease activity,TSP
may be able to influence cell growth, migration and differentiation [29]. Laminin also plays a
role in cell attachment, growth promotion, protease secretion and interactions with other
ECM components. It can bind to cell surface binding proteins including integrins which leads
to integrin signalling [30]. SPARC (Secreted Protein Acidic and Rich in Cysteine), also
known as BM40 or osteonectin, is a protein whose expression is elevated under stress conditions.Transient
expression of SPARC during endothelial cell injury and cellular activation indicate
a role in tissue repair, remodelling and angiogenesis [31]. Exogenously added SPARC
or SPARC-derived peptides were able to modify endothelial cell behaviour via the induction
of proteases and inhibitors of plasmin generation [32,33].
9.1.2.4 Role of Subendothelial Support Cells
Endothelial cell interaction with ECM and mesenchymal cells is a prerequisite to form a stable
vasculature. Therefore, after endothelial cell proliferation and maturation, and the formation
of endothelial tube structures, surrounding vessel layers composed of mural cells