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Coexpression of hypoxia-inducible factor 1-alpha and vascular endothelial growth factor in Wilms' tumor
J Karth1, F A Ferrer, E Perlman
1Division of Pediatric Urology and the Brady Research Laboratories, The James Buchanan Brady Urological Institute, the Department of Pathology, The Johns Hopkins Hospital and The Johns Hopkins School of Medicine, Baltimore, MD 21287-2101, USA.
Background/Purpose:
Hypoxia-inducible factor 1 alpha (HIF-1alpha) is an important transcriptional factor responsible for regulating expression of the angiogenic cytokine, vascular endothelial growth factor (VEGF). Little information is available regarding factors involved in the hypoxic cascade, such as HIF or VEGF in Wilms' tumor. We concomitantly evaluate the expression of HIF-1alpha and VEGF in ex vivo human Wilms' tumor specimens.
Methods:
Immunohistochemical analysis (IHC) utilizing a monoclonal human anti-HIF-1alpha or a polyclonal anti-VEGF antibody was performed on ex vivo specimens of Wilms' tumor (n = 18). Predominant tumor histologic subtype was divided equally between epithelial (n = 6), blastemal (n = 6), and mixed (n = 6). Specimens were scored on a predetermined scale for distribution (percent positive cells) and intensity of HIF-1alpha/VEGF expression within areas of tumor.
Results:
IHC analysis found that HIF-1alpha and VEGF were expressed in all Wilms' tumor specimens. Strong nuclear staining for HIF-1alpha was seen in all samples evaluated, (n = 18), mean score 2.7 (>50% cells exhibiting nuclear HIF-1alpha expression). Cytoplasmic staining for HIF-1alpha also was seen in 15 of 18 samples (83%). Distribution of VEGF was equivalent between blastemal and epthelial components, mean score 2.23 versus 2.35.
Conclusions:
HIF-1alpha and one of its regulatory end-products, the angiogenic cytokine VEGF, are simultaneously expressed in human Wilms' tumor. In Wilms' tumor, intratumoral hypoxia may stimulate tumor conversion to the angiogenic phenotype and incite production of VEGF. Strategies targeting the hypoxic cascade ultimately may prove efficacious against Wilms' tumor.