Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 663

Galectin-1 synthesized in endothelial cells of various tumors for vessel guidance
and growth is a receptor for anginex, an angiogenesis inhibitor [ 1352 ]. Galectins
localize to the nucleus, cytoplasm, or extracellular matrix according to the cell type.
Promyelocytic leukemia (PML) tumor suppressor 85

inhibits angiogenesis in

ischemic and neoplastic tissues. 86

Agent PML prevents the synthesis of hypoxia-

inducible factor-1 , interacting with target of rapamycin (TOR), thereby hampering

TOR association with cytoplasmic RHEB GTPase [ 1353 ].
Vascular endothelial growth factor inhibitors destroy most of the tumor vascula-
ture, but the remaining structural components of the local vasculature, the basement
membrane and pericytes, 87 allow the rapid growth of new vessels once VEGF
inhibitor administration is stopped [ 1354 ].
Growth factor signaling (e.g., EGF, IGF1, FGF2, PDGF, and VEGF) increases
reactive oxygen species, such as hydrogen peroxide (H 2 O 2 ), which oxidizes (inac-
tivates) protein Tyr phosphatases, hence enhancing phosphorylation of ERK1/2 in
endothelial cells. Superoxide dismutase SOD1 is an abundant copper/zinc enzyme
in the cytoplasm (cytosol, nucleus, and intermembrane space of mitochondria) 88
that converts superoxide into hydrogen peroxide and molecular oxygen. Enzyme
SOD1 thereby favors growth factor-mediated ERK1/2 phosphorylation. It can thus
be targeted by anti-angiogenic and antitumor agent to repress signaling pathways in
endothelial and tumor cells that promote growth [ 1355 ].
Gene silencing through RNA interference can serve as a treatment (specific
action). In addition, therapies can be based on a non-specific process mediated by
activation of cell surface receptors. In the case of choroidal neovascularization in
age-related macular degeneration or cancers, specific small interfering RNAs that
target VEGFa or VEGFR1 may be used. Furthermore, non-specific siRNAs can
act without entering into cells via Toll-like receptor TLR3 [ 1356 ]. Any double-
stranded siRNA of at least 21 nucleotides that binds to TLR3 impede angiogenesis
in the mouse model of choroidal neovascularization. Efficient siRNAs triggers the
TRIF-NF

α

κ B cascade to activate genes encoding interleukin-12 and interferon- γ that

inhibit angiogenesis.
On the other hand, reducing the blood supply to cancer cells causes hypoxia and
may favor metastasization. Repression of tumor cell oncogenes (Ras, PI3K, PKB,
and HER2) diminishes production by tumor cells of several pro-angiogenic factors,
thereby stabilizing vessel architecture and improving perfusion, oxygenation, and
drug delivery [ 1357 ]. In tumors characterized by a BRAF oncogenic mutation

85 A.k.a. RING finger protein RNF71 and tripartite motif-containing protein TRIM19.
86 Promyelocytic leukemia, which regulates tumor suppressor transcription factors, is lost in various
types of human cancers.
87 Many pericytes survive after VEGF inhibitor administration. However, the pericyte phenotype
reversibly changes during treatment, with a downregulation of the expression of α -smooth muscle

actin. This change reverses when the treatment is stopped.
88 Manganese-containing enzyme SOD2 ( Mn SOD) resides in the mitochondrial matrix. Secreted,
copper-containing SOD3 ( Cu SOD) lodges in the extracellular matrix.