Phosphorylated KDR is expressed in the neoplastic and stromal elements of human renal tumours and shuttles from cell membrane to nucleus.
Vascular endothelial growth factor (VEGF)-A is an important angiogenic factor in establishing the vasculature in renal cell carcinomas (RCCs). Since little is known about VEGF signalling in RCCs, the profile of phosphorylated KDR (pKDR) has been investigated and the intracellular location of the receptor has been examined in the present study. Using two monoclonal antibodies raised against the phosphorylated KDR epitopes (Y1059 and Y1214) known to mediate different VEGF functions, together with a commercial anti-KDR antibody and immunohistochemistry, the expression of pKDR was investigated in a series of normal (n = 25) and neoplastic kidneys (n = 54; clear cell n = 35; papillary n = 10; oncocytomas n = 8). pKDR was present in many tissue elements of both normal and neoplastic renal tissues, with strong expression in the cell membrane, cytoplasm, and nuclei of normal kidney and tumour cells, as well as endothelial cells in tumours of all histological types. Patterns and intensity were similar using both anti-pKDR antibodies. There was no significant correlation in clear cell carcinomas between pKDR expression and age (p = 0.57), tumour size (p = 0.2), gender (p = 0.59), grade (p = 0.2) or histological type (p = 0.36). To delineate further the intracellular processing that might account for the cellular distribution, confocal microscopy was also performed. Antibodies to the different phosphorylated epitopes demonstrated different intracellular staining patterns. This study shows that pKDR is present in a wide variety of renal tumours, suggesting that anti-VEGF therapy might have direct effects on tumour cells. It further suggests that cells traffic pKDR depending on the precise KDR tyrosines that are autophosphorylated in a manner that enables receptor activation to result in different functions.
CRUK Tumour Pathology Group, Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. stephen.fox@ndcls.ox.ac.uk
Stephen B
SB
Fox
Helen
H
Turley
Michelle
M
Cheale
Cristina
C
Blázquez
Helen
H
Roberts
Neil
N
James
Nathan
N
Cook
Adrian
A
Harris
Kevin
K
Gatter
D018249:Adenoma, Oxyphilic / Q000737:chemistry; D002291:Carcinoma, Papillary / Q000737:chemistry; D002292:Carcinoma, Renal Cell / Q000737:chemistry*; D016022:Case-Control Studies; D002462:Cell Membrane / Q000737:chemistry; D002467:Cell Nucleus / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007668:Kidney / Q000737:chemistry; D007680:Kidney Neoplasms / Q000737:chemistry*; D018613:Microscopy, Confocal; D011233:Precipitin Tests; D018709:Statistics, Nonparametric; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis*
D040301:Vascular Endothelial Growth Factor Receptor-2