(Dominique, 2013)
Because
Glioblastoma multiforme is rapidly growing; it needs more oxygen and nutrients
than what is supplied by the current blood that nourishes normal tissue (Black
et al, 2005). Glioblastoma gets this
additional supply of oxygen and nutrients via angiogenesis (Genentech
BioOncology, 2013). Not only does Angiogenesis supply additional nutrients, but
it also plays an important role in the metastases of tumors and the enlargement
of the tumor (Black et al, 2005).
Angiogenesis
can be simply defined as “the formation of blood vessels from pre-existing
blood vessels” (Choudhury et al, 2010). These blood vessels play a vital part
in reproduction, development, and repair of cancer cells (Black et al, 2005).
Angiogenesis
originates from angioblasts of extraembryonic mesoderm (Polin et al, 2011).
Once the embryo has formed a primary vascular plexus called vasculogenesis,
more blood vessels are modeled via sprouting and non-sprouting angiogenesis
(Choudhury et al, 2010). Adults can form new blood vessels under pathologic
conditions such as wound healing, ophthalmologic disorders, and tumors (Black
et al, 2005).
Even
though, angiogenesis has been known for over a 100 years now, the mechanism at
which it functions is unclear. (Italiano et al, 2008) In 1971, Judah Folkman
proposed the interesting hypothesis that, “tumor growth is angiogenesis
dependent and that endothelial cells may be switched from a resting state to a
rapid growth phase by diffusible chemical signal from tumor cells” (Pollack et
al, 2008). Today evidence supports angiogenesis to being essential for tumor
growth and propagation in glioblastoma multiforme (Black et al, 2005).
Tumor
angiogenesis parallels developmental angiogenesis, except for that fact that
tumor angiogenesis continues uncontrollably ceasing to stop (Hillen et al,
2007). The tumor vasculature consists of vessels from a preexisting network, as
well as vessels resulting as an angiogenic response to cancer cells (Murat et
al, 2009).
In
order for Angiogenesis to occur, there is a complex interplay between tumor
cells, endothelial cells, and several angiogenic factors that promote
endothelial cell migration, (Lamalice et al, 2013) proliferation, vascularization,
and capillary formation (Black et al, 2005). Angiogenesis is facilitated by
growth factors, adhesion molecules, and matrix-degrading enzymes (Ingber et al,
1989).
Figure 2 Factors Influencing Angiogenesis
(Koontongkaew, 2013)
Facilitation
via cytokines (regulatory proteins) (Lee et al, 2013) occurs if there is an
overexpression of angiogenic factors through hypoxia or mutations (Choudhury et
al, 2010).
Angiogenesis begins with the breaking down of the basement membrane of the vessel,
(Rundhaug, 2003) and continues with the migration of the endothelial cells
towards a stimulus. Endothelial cells start proliferating and trail behind leading
cells invading the stroma (Choudhury et al, 2010). Lumen begins to form in the
endothelial sprout, and branches and loops develop to allow blood flow. Pericytes
will than provide support around immature vessels (Black et al, 2005).
Once
the endothelial cells are activated, they release proteolytic enzymes such as
matrix metalloproteinase (MMPs), (Page-McCaw et al, 2007) which degrade the
extracellular matrix and the basement membrane, allowing activated cells to
migrate towards the tumor (Birkedal-Hansen et al, 1993). Integrin molecules
play a role in pulling the sprouting new blood vessels forward (Mizejewsk et
al, 1999). The endothelial cells deposit a new basement membrane and secrete
growth factors such as the platelet derived growth factor (PDGF), attracting
supporting cells to stabilize the new vessel (Sato et al, 1993).
Another mechanism of formation can be by the insertion of interstitial tissue
column into to the lumen of existing vessels (Davis et al, 2012). Despite the
mechanism of formation, the vessels lose the normal anatomic structural
arrangements and can be leaky and fragile leading to hemorrhaging (Xia et al,
2004).
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