Recent Advances in Angiogenesis and ... - Bentham Science

86 Recent Advances in Angiogenesis and Antiangiogenesis, 2009 Pastorino and Mirco Ponzoni
sentation and are not amenable to curative surgical
excision.
Among pediatric solid tumors, neuroblastoma (NB),
most commonly occurring in the adrenal gland, is
predominantly a tumor of infancy with 16% of
children diagnosed within the first month of life and
41% diagnosed within the first 3 months of life.
Several recent studies implicate angiogenesis in the
regulation of NB growth and inhibition of
angiogenesis is a promising approach in the treatment
of NB because of the high degree of vascularity of
these tumors. In 1994 Kleinman and co-workers
published a paper in which they showed that human
NB cells induce angiogenesis in nude mouse during
tumorigenesis [4]. Meitar et al. (1996) evaluated the
vascularity of primary untreated NB from 50 patients.
They found that the vascularity of NB from patients
with widely metastatic disease is significantly higher
than in tumors from patients with local or regional
disease [5]. Ribatti et al. (1998) investigated the
angiogenic potential of two human NB cell lines
demonstrating their capacity to induce in vitro human
microvascular endothelial cells to proliferate and in
vivo angiogenesis in the chick embryo chorioallantoic
membrane assay [6].
Canete et al. (2000) in a retrospective study showed
that tumor vascularity was not predictive of survival of
NB patients and that neither disseminated nor local
relapses were influenced by the angiogenic
characteristics of the tumors [7]. Eggert et al. (2000)
performed a systematic analysis of expression of
angiogenic factors in 22 NB cell lines and in 37 tumor
samples. They found that high expression levels of
seven angiogenic factors correlated strongly with the
advanced stage of NB and this suggests that several
angiogenic peptides set in concert in the regulation of
neovascularization [8].
Ara et al. (1998) found that increased expression of
MMP-2, but not of MMP-9, in stromal tissues of NB
had significant association with advanced clinical
stages [9]. Sarakibara et al. (1999) have demonstrated
that the higher gelatinases activation ratio resulting
from high espression of a novel membrane-type matrix
metalloproteinase-1 (MT-MMP-1) on NB specimens
is associated significantly with advanced stage and
unfavorable outcome [10]. Ribatti et al. (2001) showed
that the extent of angiogenesis and the expression of
the MMP-2 and MMP-9 were upregulated in advanced
stages of NB [11].
MYC-N may regulate the growth of NB vessels,
because its amplification or overexpression is
associated with angiogenesis in experimental [12] and
clinical settings [5]. Amplification of MYC-N is a
frequent event in advanced stages of human NB.
MYC-N amplification correlates with poor prognosis
and enhanced vascularization of human NB, sugges-
ting that the MYC-N oncogene could stimulate tumor
angiogenesis and thereby allow NB progression [13].
Erdreich-Epstein et al. (2000) demostrated by
immunohistochemical analysis that ανβ3 integrin was
expressed by 61% of microvessels in high-risk NB, but
only by 18 % of microvessels in low-risk tumors [14].
It has been reported a very low tumor vascularity in
Schwannian stroma-rich/stroma-dominant NB tumors
and that Schwann cells produce angiogenesis
inhibitors, such as tissue inhibitor of
metalloproteinase-2 (TIMP-2) and pigment
epithelium-derived factor (PEDF), that are capable of
inducing endothelial cell apoptosis [15, 16]. Chlenski
et al. (2002) isolated an angiogenic inhibitor in
Schwann cell conditioned medium, identified as
SPARC, which expression is inversely correlated with
the degree of malignant progression in NB tumors.
Furthermore, SPARC inhibited angiogenesis in vivo
and impaired NB tumor growth [17].
Leali et al. (2003) demonstrated that FGF-2 causes
osteopontin (OPN)-upregulation in endothelial cells, in
vitro and in vivo, resulting in the recruitment of
proangiogenic monocytes [18]. Takahashi et al. (2002)
demonstrated that OPN-transfected murine NB cells
significantly increased neovascularization in mice
[19]. Enforced expression of OPN in NB cells
significantly stimulated endothelial cells migration and
induced angiogenesis in mice, as evaluated by dorsal
air sac assay.
2. ANGIOGENESIS AS THERAPEUTIC
TARGET
It is exhaustively reported in the literature that a
functional blood supply is essential to meet the oxygen
and nutrient demands of growing solid tumors [20].
Moreover, since the neovasculature that arises from
the normal host vessels by the process of angiogenesis
also is the principal vehicle for metastatic spread [21],
we can conclude that tumor neo-vasculature is a
potential therapeutic target [22] for all solid tumors,
including neuroblastoma.
There are two major approaches in controlling tumor
vasculature. One strategy is to prevent the
development of tumor blood vessels by inhibiting the
angiogenesis process (AIAs, angiogenesis inhibiting
agents); the other strategy acts by compromising the
function of established tumor blood vessels
(VTAs/VDAs, vascular targeting/vascular disrupting
agents). The latter strategy has been shown to disrupt
established tumor vasculature causing rapid and
sustained inhibition of tumor blood flow. By depriving
tumors of the nutrients necessary to growth and
survive, VTAs/VDAs induce necrosis, particularly
within the core of the tumor.