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Table 2 Endogenous angiogenesis inhibitors

From: Targeting TNF-α for cancer therapy

Inhibitor Molecular and physiologic properties
Proteolytic fragments
Angiostatin 38-kD internal fragment of plasminogen (kringles 1-4); kringles 1-3 and kringle 5 also active.
Arrestin 26-kD carboxy-terminal noncollagenous domain of a1 chain of Type IV collagen; inhibits endothelial cell (EC) proliferation.
Antithrombin (cleaved) 53-55-kD cleaved conformation inhibits EC proliferation and tumor growth in mice.
Canstatin 24-kD carboxy-terminal noncollagenous domain of a2 chain of Type IV collagen; inhibits EC proliferation and apoptosis.
Endostatin 20-kD fragment of carboxy-terminal noncollagenous domain of Type XVIII collagen; mechanism of action unknown.
Fibronectin fragments 29-kD amino-terminal and 40-kD carboxy-terminal heparin-binding fragments inhibit EC proliferation.
PEX Carboxy-terminal hemopexin-like domain of matrix metalloproteinase-2 inhibits EC proliferation and tumor growth in mice.
Prolactin (16-kD) Naturally occurring 16-kD cleaved amino-terminal fragment of prolactin; retains activity as partial prolactin agonist.
Prothrombin kringle-2 22-kD prothrombin fragment initially isolated from lipopolysaccharide-treated serum.
Restin 22-kD fragment of carboxy-terminal noncollagenous domain of Type XV collagen; 60% homology to murine endostatin.
Vasostatin Amino-terminal fragment of calreticulin; inhibits EC proliferation and tumor growth in mice.
IL-1 17-kD β-isoform inhibits FGF-stimulated angiogenesis by an autocrine pathway.
IL-4 13-kD lymphokine; inhibits basic FGF-induced angiogenesis.
IL-10 Inhibits tumor vascularity and growth, possibly by decreasing macrophage-derived angiogenic factors.
IL-12 75-kD glycoprotein; inhibits in vivo angiogenesis via IFN-γ - and IP-10-related mechanism.
IL-18 IFN-γ-inducing cytokine; inhibits FGF-stimulated EC proliferation and in vivo angiogenesis.
IFN-α 8 to 20-kD glycoproteins secreted by lymphocytes and phagocytes; inhibits EC proliferation and migration.
IFN-β 23-kD glycoprotein derived from fibroblasts and epithelial cells.
IFN-γ 20 to 25-kD glycoprotein secreted by T cells and natural killer cells; cytotoxic to proliferating ECs.
TIMP metallopeptidase inhibitors
TIMP-1 (TIMP metallo-peptidase inhibitor 1) Soluble 8.5-kD collagenase inhibitor.
TIMP-2 Soluble 21-kD collagenase inhibitor.
TIMP-3 Extracellular matrix-associated collagenase inhibitor.
Other molecules
1,25-(OH)2-vitamin D3 Antiangiogenic effect similar to that of retinoic acid; nonhydroxylated vitamin D3 not active.
2-methoxyestradiol 0.3-kD estrogen metabolite; inhibits EC migration and urokinase plasminogen activator.
Angiopoietin-2 Inhibits angiopoietin-1-mediated activation of EC tyrosine kinase receptor, Tie2; role in vascular remodeling.
EMAP-II Tumor-derived 20-kD (34 kD proform) inflammatory cytokine.
Gro-β 8-kD CXC chemokine; inhibits tumor growth in mice.
IP-10 8.6-kD CXC chemokine induced by IFNγ -.
Maspin 42-kD serine protease inhibitor (serpin); inhibits EC migration and tumor growth and vascularity in mice.
METH-1, METH-2 110- and 98-kD proteins with metalloprotease and disintegrin-like domains, and carboxy-terminal type 1 TSP-1 repeats.
MIG 11.7-kD CXC chemokine induced by IFN-γ.
p16 Tumor supressor gene; wild type downregulates VEGF expression and inhibits angiogenesis in gliomas.
p53 Tumor suppressor gene; wild type increases TSP-1 expression, decreases VEGF expression.
PEDF 50-kD inhibitor expressed by retinal pigment epithelial cells.
Platelet factor-4 28-kD heparin-binding platelet-derived inhibitory factor.
Proliferin-related protein Inhibitor of placental angiogenesis in late gestation.
Prostate-specific antigen Serine protease associated with prostate carcinoma and other tumors.
Protamine 43-kD heparin-binding protein produced by sperm; role in vessel remodeling.
Retinoic acid 0.3-kD inhibitor of EC migration; appears to act as transcriptional regulator.
Soluble FGF receptor 60 to 85-kD circulating binding proteins that may regulate pro-angiogenic activity of FGF.
Transforming growth factor β1 25-kD inhibitor of EC growth and proteolytic activity.
Troponin I Subunit of troponin complex recently found to be present in cartilage and to inhibit angiogenesis.
TSP-1, TSP-2 450-kD platelet- and fibroblast-derived trimeric glycoproteins.