Endostatin's emerging roles in angiogenesis, lymphangiogenesis, disease, and clinical applications

Abstract

Background: Angiogenesis is the process of neovascularization from pre-existing vasculature and is involved in various physiological and pathological processes. Inhibitors of angiogenesis, administered either as individual drugs or in combination with other chemotherapy, have been shown to benefit patients with various cancers. Endostatin, a 20-kDa C-terminal fragment of type XVIII collagen, is one of the most potent inhibitors of angiogenesis.

Scope of review: We discuss the biology behind endostatin in the context of its endogenous production, the various receptors to which it binds, and the mechanisms by which it acts. We focus on its inhibitory role in angiogenesis, lymphangiogenesis, and cancer metastasis. We also present emerging clinical applications for endostatin and its potential as a therapeutic agent in the form a short peptide.

Major conclusions: The delicate balance between pro- and anti-angiogenic factors can be modulated to result in physiological wound healing or pathological tumor metastasis. Research in the last decade has emphasized an emerging clinical potential for endostatin as a biomarker and as a therapeutic short peptide. Moreover, elevated or depressed endostatin levels in diseased states may help explain the pathophysiological mechanisms of the particular disease.

General significance: Endostatin was once sought after as the 'be all and end all' for cancer treatment; however, research throughout the last decade has made it apparent that endostatin's effects are complex and involve multiple mechanisms. A better understanding of newly discovered mechanisms and clinical applications still has the potential to lead to future advances in the use of endostatin in the clinic.

Keywords: Anti-angiogenic factor; MMP; Matricryptin; Short endostatin peptide; Tumor angiogenesis; Type XVIII collagen.

FIGURE 1

Schematic model of the α1 chain of human collagen XVIII. The human collagen XV α1 chain is structurally homologous. They belong to a collagen subfamily, the multiplexins, on the basis of their central triple-helical domain (green boxes) interrupted by non-collagenous sequences. They contain an extended non-collagenous N-terminal domain, which, in collagen XVIII, can undergo alternative splicing (pale orange boxes), and a non-collagenous C-terminal domain (NC1; blue). The homotrimers (dark blue circles); a hinge domain (blue lines), which is highly susceptible to proteolytic processing; and a C-terminal endostatin domain (blue ovals), which has angiostatic properties. [Adapted from Iozzo [37] with permission from Nature Publishing Group.]

FIGURE 2

The NC1 domain of type XVIII collagen can be cleaved into endostatin by cathepsin L, into neostatin-14 by MMP-14, and into neostatin-7 by MMP-7. [Adapted from Schenk et al. [99] with permission from Elsevier].

FIGURE 3

Schematic illustration of distinct signaling pathways induced by rhTum and rhEndo. rhTum binds to α_vβ₃ integrin, whereas rhEndo binds to α₅β₁. Both rhEndo and rhTum inhibit phosphorylation of FAK (yellow). Downstream of FAK, rhTum inhibits PI3-K/Akt/mTor/4EBP1 pathway, resulting in inhibition of endothelial protein synthesis and proliferation. MAP kinase pathways are not affected by rhTum. In contrast, inhibition of FAK activation by rhEndo binding to α₅β₁ integrin leads to inhibition of ERK1/p38 MAP kinase pathways with no effect on PI3-K/Akt/mTOR/4EBP1 pathways, resulting in inhibition of endothelial cell migration. [Adapted from Sudhaker et al. [107]]

FIGURE 4

Complete amino acid sequence of recombinant human endostatin. The sequences with improved activity compared to wild type, unmodified endostatin are highlighted and labeled according to the original study, as listed in Table 4.