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An Endogenous Inhibitor of Angiogenesis derived from a Transitional Cell Carcinoma: Clipped β2-Glycoprotein-I

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Abstract

Background

Invasive cell carcinoma of the bladder often develops after complete transurethral excision of superficial transitional cell carcinoma. It has been postulated that primary tumors release angiogenesis-blocking proteins which suppress distant metastases. We have identified an endogenous protein which might be responsible for tumor dormancy.

Methods

A transitional cell carcinoma cell line was developed (UMUC-3i) which inhibits the growth of a tumor implant at a distant site in SCID mice. Conditioned media of UMUC-3i cultured cells was first pooled and then fractioned, and the capacity of individual components to block endothelial cell growth was tested. The protein fraction responsible for blocking endothelial cell growth was identified by N-terminal amino acid sequencing as well as by mass-spectrometry. The effects of the purified protein in preventing endothelial cell proliferation and tube formation in an in vitro angiogenesis assay was investigated.

Results

The plasma protein β2-glycoprotein-I (β2gpI) was isolated and identified from conditioned medium of UMUC-3i cultured cells. Based on the in vitro angiogenesis assay, β2gpI strongly inhibited endothelial cell growth and tube formation, whereby the inhibitory activity corresponded to the clipped version of β2gpI (cβ2gpI). Clipping was induced by adding plasmin at a molar ratio 1:15 (plasmin:substrate). Further analysis indicated that cβ2gpI effects were mediated by annexin II surface receptors expressed on endothelial cells.

Conclusions

cβ2gpI may be involved in blocking angiogenic processes and bladder cancer progression. In this case, cβ2gpI may be a promising tool in bladder cancer therapy.

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Abbreviations

β2gpI::

β2glycoprotein-I

cβ2gpI::

clipped version of β2gpI

TCC::

Transitional cell carcinoma

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Acknowledgements

We would like to thank Karen Nelson for critically reading the manuscript.

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Authors and Affiliations

  1. Department of Urology, J.W. Goethe University, Frankfurt am Main, Germany

    Wolf-Dietrich C. Beecken, Tobias Engl, Eva M. Ringel, Dietger Jonas & Roman A. Blaheta

  2. Radiation Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA

    Kevin Camphausen

  3. Institute for Hygiene, J. W. Goethe University, Frankfurt am Main, Germany

    Martin Michaelis

  4. Vascular Biology Program, Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Judah Folkman & Yuen Shing

  5. J. W. Goethe-Universitätsklinik, Zentrum der Chirurgie, Klinik für Urologie und Kinderurologie, Interdisziplinäres Forschungs- und Laborgebäude, Haus 25, Raum 204, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany

    Roman A. Blaheta

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  1. Wolf-Dietrich C. Beecken
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Correspondence to Roman A. Blaheta.

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Beecken, WD.C., Engl, T., Ringel, E.M. et al. An Endogenous Inhibitor of Angiogenesis derived from a Transitional Cell Carcinoma: Clipped β2-Glycoprotein-I. Ann Surg Oncol 13, 1241–1251 (2006). https://doi.org/10.1245/s10434-006-9009-9

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