Endostatin

Endostatin is a naturally occurring, 20-kDa C-terminal fragment derived from type XVIII collagen. It is reported to serve as an anti-angiogenic agent, similar to angiostatin and thrombospondin.

Endostatin is a broad-spectrum angiogenesis inhibitor and may interfere with the pro-angiogenic action of growth factors such as basic fibroblast growth factor (bFGF/FGF-2) and vascular endothelial growth factor (VEGF).

Endostatin is an endogenous inhibitor of angiogenesis. It was first found secreted in the media of non-metastasizing mouse cells from a hemangioendothelioma cell line in 1997 and was subsequently found in humans. It is produced by proteolytic cleavage of collagen XVIII, a member of the multiplexin family that is characterized by interruptions in the triple helix creating multiple domains, by proteases such as cathepsins. Collagen is a component of epithelial and endothelial basement membranes. Endostatin, as a fragment of collagen 18, demonstrates a role of the ECM in suppression of neoangiogenesis. Pro-angiogenic and anti-angiogenic factors can also be created by proteolysis during coagulation cascades. Endogenous inhibitors of angiogenesis are present in both normal tissue and cancerous tissue. Overall, endostatin down regulates many signaling cascades like ephrin, TNF-α, and NFκB signaling as well as coagulation and adhesion cascades. Other collagen derived antiangiogenic factors include arresten, canstatin, tumstatin, α 6 collagen type IV antiangiogenic fragment, and restin.

Human monomeric endostatin is a globular protein containing two disulfide bonds: Cys162−302 and Cys264−294. It folds tightly, has a zinc binding domain at the N-terminus of the protein, and has a high affinity for heparin through an 11 arginine basic patch. Endostatin also binds all heparan sulfate proteoglycans with low affinity. Oligomeric endostatin (trimer or dimer) binds mainly with laminin of the basal lamina.

In-vitro studies have shown endostatin blocks the proliferation and organization of endothelial cells into new blood vessels. In animal studies endostatin inhibited angiogenesis and growth of both primary tumors and secondary metastasis.

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