Table 2 Endogenous Inhibitors of Angiogenesis

Thrombospondin-1

Platelet-derived 450 kD protein, binds CD 36 on ECs

[37]

Cleavage products of ECM

   Endostatin

20 kD C-terminal fragment of collagen XVIII, multiple pathways, incl. alpha5beta1 integrin

[171, 172]

   Tumstatin

Cleavage fragment of alpha3 chain of type IV collagen, activity mediated by alphavbeta3 integrin

[41]

   Arresten

26-kDa NC1 domain of the alpha1 chain of type IV collagen, activity mediated by alpha1beta1 integrin

[53]

   Canstatin

24 kD fragment of alpha2 chain of type IV collagen, activity via proapoptotic pathways in ECs

[54, 173]

   Vastatin

NC1 domain of type VIII collagen (alpha 1), induces cell cycle arrest and apoptosis

[55]

   Restin

22 kD collagen XV fragment, inhibits EC migration, induces apoptosis

[56, 174]

Plasma proteins

   Angiostatin

38 kD internal fragment of plasminogen, binds ATP synthase, angiomotin, and alphavbeta3 integrin, multiple mechanisms of action

[60]

   16-kd prolactin fragment

16 kD N-terminal fragment of prolactin, inhibits EC proliferation, induces apoptosis

[64, 65, 175]

Chemokines

   Platelet factor-4

Chemokine with antiproliferative and antimigratory properties on ECs

[176]

   Interferon-inducible protein-10 (IP-10)

Member of CXC chemokine family, potent immunomodulatory and antiangiogenic activity

[74]

Angiopoietins

Bind EC-specific receptor Tie2, complex roles in angiogenesis

[76]

Interleukins

   IL-12

Heterodimeric pro-inflammatory cytokine, antiangiogenic effects via induction of IFN-gamma and IP-10

[78, 79]

   IL-18

Cytokine with antiangiogenic activity via induction of IFN-gamma

[86]

Interferons

Multifunctional cytokines that regulate antiviral, antitumor, and cellular immune responses, potent antiangiogenic properties via inhibition of bFGF

[92]

Endothelial-monocyte activating polypeptide II (EMAP II)

Tumor-derived cytokine, induces tissue factor, upregulates TNF receptor 1, E-selectin and P-selectin on ECs, induces EC apoptosis

[94]

Tissue inhibitors of metalloproteinases (TIMPs)

Block the activity of MMPs, complex role in tumor angiogenesis and tumor growth

[97]

Tumor necrosis factor alpha (TNF-alpha)

52 kD homotrimeric complex, potent vasculotoxic effects on tumors, activity mediated by TNF receptor

[99, 177]

p53

Tumor suppressor gene, wild-type antiangiogenic activity via increased thrombospondin-1 expression, decreased VEGF

[101, 102]

Serine protease inhibitors

   Cleaved antithrombin III, maspin, pigment epithelium-derived factor (PEDF)

Potent antiangiogenic activities

[178-180]

Vascular endothelial growth inhibitor (VEGI)

Cytokine in the TNF superfamily expressed by ECs, promotes EC cell cycle arrest and apoptosis

[181, 182]

2-methoxyestradiol

Endogenous metabolite of estrogen, exerts antiangiogenic effects by inhibiting HIF-1alpha

[183]

Tetrahydrocortisol

Most potent naturally occurring angiostatic steroid

[184]

Secreted protein acidic and rich in cysteine (SPARC)/BM-40/osteonectin

34 kD matricellular protein, inhibits EC spread, abrogates binding of PDGF and VEGF to their receptors

[185, 186]

Domain 5 of high molecular weight kininogen (HMWK)/kininostatin

Cleaved component of HMWK inhibits EC proliferation and induces apoptosis by binding EC tropomyosin

[187-189]