Characterization of the anti-angiogenic properties of arresten, an alpha1beta1 integrin-dependent collagen-derived tumor suppressor

Exp Cell Res. 2008 Nov 1;314(18):3292-305. doi: 10.1016/j.yexcr.2008.08.011. Epub 2008 Aug 26.


Physiological and pathological turnover of basement membranes liberates biologically active cryptic molecules. Several collagen-derived fragments possess anti-angiogenic activity. Arresten is the 26-kDa non-collagenous domain of type IV collagen alpha1 chain. It functions as an efficient inhibitor of angiogenesis and tumor growth in mouse models, but its anti-angiogenic mechanism is not completely known. Here we show that arresten significantly increases apoptosis of endothelial cells in vitro by decreasing the amount of anti-apoptotic molecules of the Bcl-family; Bcl-2 and Bcl-xL. Although the pro-apoptotic effect of arresten is endothelial cell specific in vitro, in mouse tumors arresten induced apoptosis both in endothelial and tumor cells. The tumor cell apoptosis is likely an indirect effect due to the inhibition of blood vessel growth into the tumor. The active site of arresten was localized by deletion mutagenesis within the C-terminal half of the molecule. We have previously shown that arresten binds to alpha1beta1 integrin on human umbilical vein endothelial cells. However, the microvascular endothelial cells (MLECs) are more important in the context of tumor vasculature. We show here that arresten binds also to the microvascular endothelial cells via alpha1beta1 integrin. Furthermore, it has no effect on Matrigel neovascularization or the viability of integrin alpha1 null MLECs. Tumors implanted on integrin alpha1 deficient mice show no integrin alpha1 expression in the host-derived vascular endothelium, and thus arresten does not inhibit the tumor growth. Collectively, this data sheds more light into the anti-angiogenic mechanism of arresten.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / genetics
  • Angiogenesis Inhibitors / metabolism
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Aorta / cytology
  • Apoptosis / drug effects
  • Blotting, Western
  • Cattle
  • Cell Line, Tumor
  • Cell Proliferation
  • Cells, Cultured
  • Collagen Type IV / chemistry*
  • Collagen Type IV / genetics
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects*
  • Humans
  • Integrin alpha1beta1 / genetics
  • Integrin alpha1beta1 / metabolism*
  • Mice
  • Mice, Knockout
  • Mutagenesis, Site-Directed
  • Protein Structure, Tertiary / physiology
  • Proto-Oncogene Proteins c-bcl-2 / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pulmonary Artery / cytology
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Tumor Suppressor Proteins / pharmacology*
  • bcl-X Protein / drug effects
  • bcl-X Protein / metabolism


  • Angiogenesis Inhibitors
  • Collagen Type IV
  • Integrin alpha1beta1
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Proteins
  • Tumor Suppressor Proteins
  • bcl-X Protein