Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 662

Numerous anti-angiogenic compounds exist, such as inhibitors of: (1) matrix
remodeling, such as MMP inhibitors 83 (TIMP1-TIMP4) [ 1348 ]; (2) adhesion

molecules, in particular antagonist of α v β 3 [ 1349 ]; (3) activated endothelial cells;

(4) angiogenic mediators or receptors; and (5) signaling in endothelial cells.
Therapies aimed at struggling against tumor angiogenesis must target a set of growth
factors and mediators to be successful. Depletion in VEGF, in IL8, the expression of
which is regulated by nuclear factor-

κ B, and in hypoxia-inducible factor-1 reduces

tumor angiogenesis [ 1350 ].
Angiogenesis inhibitors can be used as single agents or in combination with cy-
totoxic drugs. Treatments that target multiple angiogenic mechanisms can increase
the effectiveness of anti-angiogenic therapy. Direct angiogenesis inhibitors hinder
the ability of endothelial cells to form new vessels. Indirect angiogenesis inhibitors
block either the production of angiogenic factors or signaling pathways. Mixed
angiogenesis inhibitors include kinase inhibitors, epidermal growth factor receptor
inhibitors, inhibitors of cyclooxygenase, inhibitors of Ang2, etc.
Certain microtubule-disrupting agents used in cancer therapy, such as combre-
tastatin A4 phosphate 84 (CA4P), have additional antitumor effects, inducing tumor
vasculature regression, acting on the Cdh5-Ctnn -PKB pathway, thus hampering

between-cell junctions, cell migration, and anchorage [ 1351 ]. CA4P not only blocks
the formation of a capillary network, but also induces the regression of unstable
tumor neovessels.
Angiogenic factors released by tumor cells promote activation, proliferation,
and migration of endothelial cells to the tumor tissue for neovessel formation.
Tumor cells produce angiogenic factors, such as VEGFa, VEGFc, FGF2, PlGF,
angiopoietins, and interleukin-8 (CXCL8).
Tumors

β

recruit not only neighboring vascular endothelial cells, but also

VEGFR2 + , bone marrow-derived, circulating endothelial precursors as well as

VEGFR1 , pro-angiogenic, hematopoietic cells.

Tumor cells secrete stromal cell-recruitment factors, such as PDGFa, PDGFc,
or transforming growth factor-

+

. Tumor-associated endothelial cells synthesize
PDGFb, which promotes recruitment of pericytes after activation of PDGFR

β

.
Angiogenic factors such as CXCL12 chemokine, which can recruit bone marrow-
derived angiogenic cells, are also released by stromal cells (fibroblasts and inflam-
matory and immune cells).
Tumor-associated fibroblasts produce hepatocyte growth factor and heregulin.
Because PDGFa is involved in the recruitment of angiogenic stromal cells that
produce angiogenic factors, PDGF and VEGF inhibitors can be combined for tumor
treatment.

β

83 Activation of matrix metallopeptidase-9 leads to the release of soluble SCF, which promotes the
proliferation and motility of circulating endothelial precursors.
84 Molecule CA4P binds to tubulin. It selectively targets endothelial cells, but not smooth myocytes.