Recent Advances in Angiogenesis and ... - Bentham Science

68 Recent Advances in Angiogenesis and Antiangiogenesis, 2009 Sandra Liekens
neurons [10]. Although the 3 names refer to the same
protein, “PD-ECGF” and “TP” are used throughout
the literature, whereas the use of “gliostatin” is
mainly confined to arthritis and neurological
research.
2. ANGIOGENIC ACTIVITY OF TP (Fig. 2)
TP has been shown to stimulate (i) chemotaxis of
endothelial cells (ECs), (ii) tube formation of ECs in
a collagen gel, (iii) outgrowth of vessels from rings of
rat aorta and (iv) angiogenesis in several in vivo
models, including the CAM assay, gelatin sponges
and matrigel plugs implanted in mice and a freezeinjured
skin graft model [11-16].
Overexpression of TP in various tumor cell lines did
not confer a growth advantage to the cells in vitro
[11,13,16,17]. However, transfection of RT112
bladder carcinoma cells with a retroviral vector
containing TP cDNA resulted in enhanced
regeneration of a wounded monolayer and increased
invasion in vitro. [16,18]. Also MKN-45 and YCC-3
gastric cancer cell lines overexpressing TP showed
increased adhesion, migration and invasion in vitro
[19]. The in vivo effects of TP transfection were
found to vary depending on the cell type used. Upon
subcutaneous inoculation of Ha-ras-transformed 3T3
cells transfected with TP cDNA, tumors were formed
that contained significantly more blood vessels than
tumors from mock-transfected cells, but tumor
growth itself was not affected by TP [11]. Also, TP
overexpression in a rat carcinoma cell line (PROb) had
a relatively minor effect on tumor growth and this
effect concerned only the initial stages of tumour
expansion. However, the number of endothelial cells
was consistently higher in TP-expressing tumors than in
controls [20]. In contrast, overexpression of TP in
MCF-7 breast carcinoma cells markedly increased both
the vascular density and the tumor growth rate in vivo
[14]. Also TP-overexpressing RT112 cells were
characterized by a significantly greater xenograft
growth rate than mock-transfected RT112 cells [18].
Nude mice inoculated with TP-overexpressing KB
(human epidermoid carcinoma) cells had shorter
survival times than those injected with control KB cells,
and KB/TP tumors were more invasive than control
tumors. [21]. TP also induced invasiveness and
metastasis in lung adenocarcinoma [17]. Finally, lung
colonization and spontaneous metastasis of A-07
melanoma cells were inhibited by treatment with a
neutralizing antibody against TP, indicating that TP
might promote lung metastasis of melanomas [22].
Thus, although the effect of TP on tumor growth rate in
vivo is cell-type dependent, these studies clearly
demonstrate the malignant potential of TP and its
capacity to increase tumor vascularization and invasion.
The angiogenic activity of TP was inhibited by the TP
inhibitor 6-amino-5-chlorouracil and by neutralizing
antibodies to TP [11-13]. Moreover, lysates of COS-7
Fig. (2). Various conditions of cellular stress, such as low pH, hypoxia, inflammatory cytokines, radio- and chemotherapy
may induce the expression of TP. Degradation of thymidine by TP results in the formation of 2dR-1P, which causes oxidative
stress, resulting in the increased expression and secretion of several oxidative stress-response angiogenic factors. 2dR can
also leave the cell and induce integrin expression and activation in endothelial cells.