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Int J Clin Exp Pathol 2012;5(7):674-683

Original Article
Angiogenesis in upper tract urothelial carcinoma associated with Balkan endemic

Ljubinka Jankovic Velickovic, Ana Ristic Petrovic, Slavica Stojnev, Zana Dolicanin, Takanori Hattori, Hiroyuki Sugihara, Ken-ichi Mukaisho,
Mariola Stojanovic, Vladisav Stefanovic

Institute of Pathology, Faculty of Medicine,University of Nis, Nis, Serbia; Department of Pathology, Shiga University of Medical Science, Ohtsu,
Japan; Public Health Institute, Nis, Serbia; Department of Clinical Research, Faculty of Medicine, University of Nis, Nis, Serbia

Received July 17, 2012; Accepted August 3, 2012; Epub September 5, 2012; Published September 15, 2012

Abstract: Upper tract urothelial carcinoma (UTUC) associated with Balkan endemic nephropathy (BEN) is characterized by a number of
aberrations in cell-cycle regulation and apoptosis. The aim of this study was to detect angiogenesis-related marker(s) specific for BEN UTUC,
and to examine the influence of HIF 1α upon angiogenesis and apoptosis in UTUC. Present investigation included 110 patients with UTUC, 50
from BEN region and 60 control tumors. Altered expression of VEGFR1 was more often present in control UTUC than in BEN tumors (p<0.005).
It was associated with high grade, low and high stage, solid growth, and metaplastic change of control UTUC. Microvessel density assessed
by CD31 (MVD CD31) was significantly higher in UTUC with lymphovascular invasion (p<0.05), and in BEN tumors with papillary growth (p<0.
05). Discriminant analysis indicated that BEN and control tumors do not differ significantly in expression of angiogenesis related markers. The
most important discriminant variable that determined control UTUC was expression of VEGFR1 (p=0.002). HIF 1α in UTUC significantly
correlated with the low stage, papillary growth and expression of Bcl-2, Caspase-3 index, and MVD CD34 (p<0.001; 0.0005; 0.01; 0.005; 0.01,
respectively). HIF-1α may be helpful marker in evaluation of UTUC, especially when combined with angiogenesis and apoptosis.

Keywords: Balkan endemic nephropathy, upper tract urothelial carcinoma, angiogenesis, VEGF, VEGFR1, VEGFR2, CD31, CD34, HIF 1α,

Address all correspondence to:
Professor Vladisav Stefanovic, MD, PhD
Faculty of Medicine, Bul. Zorana Djindjica 81, 18000 Nis, Serbia.
Tel: +-381-18-4570029 Fax: +381-18-4238770
E-mail: stefan@ni.ac.rs Or: dravel@open.telekom.rs