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An Endogenous Inhibitor of Angiogenesis derived from a Transitional Cell Carcinoma: Clipped ß2-Glycoprotein-I

¹ Department of Urology, J.W. Goethe University, Frankfurt am Main, Germany
² Radiation Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
³ Institute for Hygiene, J. W. Goethe University, Frankfurt am Main, Germany
⁴ Vascular Biology Program, Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

Correspondence: Address correspondence and reprint requests to: Roman A. Blaheta; J. W. Goethe-Universitä tsklinik, Zentrum der Chirurgie, Klinik fü r Urologie und Kinderurologie, Interdisziplinä res Forschungs- und Laborgebä ude, Haus 25, Raum 204, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany. E-mail: blaheta{at}em.uni-frankfurt.de

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 ß₂-glycoprotein-I (ß₂gpI) was isolated and identified from conditioned medium of UMUC-3i cultured cells. Based on the in vitro angiogenesis assay, ß₂gpI strongly inhibited endothelial cell growth and tube formation, whereby the inhibitory activity corresponded to the clipped version of ß₂gpI (cß₂gpI). Clipping was induced by adding plasmin at a molar ratio 1:15 (plasmin:substrate). Further analysis indicated that cß₂gpI effects were mediated by annexin II surface receptors expressed on endothelial cells.

Conclusions: cß2gpI may be involved in blocking angiogenic processes and bladder cancer progression. In this case, cß2gpI may be a promising tool in bladder cancer therapy.

Key Words: ß₂-glycoprotein-I • Transitional cell carcinoma • Angiogenesis • Tumor dormancy

Abbreviations: ß₂gpI: ß₂glycoprotein-I • cß₂gpI: clipped version of ß₂gpI • TCC: Transitional cell carcinoma

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