Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 661

Limitation in angiogenesis is provided by protein fragments, such as angiostatin
(fragment of plasminogen), released by tumor-infiltrating macrophages, and en-
dostatin, which specifically inhibits EC proliferation. The angiogenesis inhibitor
angiostatin, which acts via its receptor angiomotin, is specific for endothelial cells.
Angioinhibins and other factors prevent angiogenesis, either by inhibiting EC
proliferation (CXCL4, Ifn , and thrombospondin-1) [ 1343 ], hampering

EC migration (serpin-F1 and IL4), or EC proliferation induced by other mediators
(FGF2 and ILs). Uncontrolled growth is prevented by growth factors, intercellular
and cell-matrix contacts, and mechanical forces.

α and Ifn γ

10.7.2.2 Tumoral Angiogenesis

Inhibition of angiogenesis is useful to treat cancers. Angiogenesis is a regulated
process necessary for tumor growth beyond 1 to 2 mm 3 (tissue oxygen diffusion

limit is 100-200 m, i.e., from 3 to 5 cell layers around a blood vessel), locoregional

invasion, and metastasis.
Tumor endothelial cells divide up to about 40 times more frequently than normal
cells. They overexpress

α V β 3 -integrin, E-selectin, endoglin, endosialin, and VEGF

receptors.
Tumor vasculature is less organized and more fragile than that of normal tissues.
Altered tumoral blood vessels are mainly due to abnormal pericytes and endothelial
cells. Vascular wall abnormalities are caused by regulator of G-protein signaling
RGS5 [ 1344 ]. 82
Inhibition of RGS5 induces a more mature tumor vasculature and an elevation in
the number of CD4 T lymphocytes in the tumor parenchyme that leads to

a strong antitumor immune response. Loss in RGS5 function thereby increases the
effectiveness of T-cell immunotherapy in cancer.
The turnover of tumor endothelial cells is much greater than in normal endothe-
lium. Activated endothelial cells express specific markers, like certain adhesion
molecules and growth factors. Drugs can target activated endothelial cells. Plas-
malemmal coreceptor CD276 is specifically overexpressed in endothelial cells
of tumors. Costimulatory molecule CD276 can be targeted by anti-angiogenic
therapies [ 1345 ].
Matrix metallopeptidase MMP9 produced by cancer cells and tumor-infiltrating
neutrophils favor tumor angiogenesis. Angiogenesis induced by neutrophil zymogen
proMMP9 released from neutrophil granules required activation of tissue inhibitor
of metallopeptidases-free zymogen [ 1346 ]. The proMMP9-TIMP1 complex cannot
cause angiogenesis.
MicroRNA-378 promotes tumor growth and angiogenesis. It reduces expression
of 2 tumor suppressors, Suppressor of Fused and Fus1 [ 1347 ]. Cancer treatment can
thus target oncogenic microRNAs.

+ ,CD8 +

82 Regulator of G-protein signaling RGS5 is a marker for pericyte progenitor cells.