Evaluation of hypoxia-mediated growth factors in a novel bladder cancer animal model.
OBJECTIVE
The outcome of advanced transitional cell carcinoma (TCC) is poor. Changes taking place in the tumor microenvironment are receiving increased scrutiny. Hypoxia is the key to increased expression of HIF-1alpha (hypoxia-inducible factor 1alpha) resulting in increased expression of growth factors (e.g. vascular endothelial growth factor (VEGF), epidermal growth factor (EGF)). The aim of our study was to establish an animal model with modulatable tumor hypoxia. Resulting tumor growth and growth factors were assessed.


METHODS
Low Hb levels were induced in rats by total body irradiation (5 Gy). Twenty animals received EPO erythropoietin (EPO), 1000 IE/kg/week subcutaneously). After subcutaneous injection of NBT-II cells a weekly determination of Hb concentration, leukocyte counts and tumor volume were performed. Serum VEGF levels were quantified and oxygen Hb saturation in healthy tissue and tumors were measured by percutaneous laser spectroscopy. HIF-1alpha and VEGF were examined immunohistochemically.


RESULTS
Reduced O2 supply promoted expression of HIF-1alpha and VEGF. Low oxygen availability was essential for tumor growth. EPO improved the O2 supply and decreased expression of growth factors but did not reduce tumor volumes.


CONCLUSIONS
Based on these studies, treatment of low Hb levels appears reasonable in TCC. O2 supply is improved and expression of tumor growth factors is decreased. Tumor volumes did not differ between the groups, causatively adverse effects of EPO overtreatment might negatively affect microcirculation. Restoring low Hb levels and improvement in the O2 supply resulted in tumor shrinkage.
Fechner
Guido
G
Department of Urology, University of Bonn, D-53105 Bonn, Germany. guido.fechner@ukb.uni-bonn.de
Müller
Georg
G
Schmidt
Doris
D
Garbe
Stefan
S
Hauser
Stefan
S
Vaupel
Peter
P
Müller
Stefan C
SC
D000818:Animals; D002295:Carcinoma, Transitional Cell / Q000097:blood / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000494:pharmacology; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000378:metabolism*; D008297:Male; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D001749:Urinary Bladder Neoplasms / Q000097:blood / Q000098:blood supply / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D006454:Hemoglobins; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D010100:Oxygen