Evaluation of Hypoxia-mediated Growth Factors in a Novel Bladder Cancer Animal Model

Abstract

Background and Aim: 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-1α (hypoxia-inducible factor 1α) 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. Materials and 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-1α and VEGF were examined immunohistochemically. Results: Reduced O₂ supply promoted expression of HIF-1α 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. Conclusion: 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.