Table 2 Endogenous angiogenesis inhibitors
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. |
Interleukins | |
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. |
Interferons | |
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. |