Comparative analysis of COX-2, vascular endothelial growth factor and microvessel density in human renal cell carcinomas.
OBJECTIVE
Cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) are frequently up-regulated in malignant tumours and play a role in proliferation, apoptosis, angiogenesis and tumour invasion. In the present study, the expression of COX-2 and VEGF in renal cell carcinoma (RCC) was analysed and correlated with the microvessel density (MVD).


RESULTS
COX-2 and VEGF were analysed by realtime reverse transcriptase-polymerase chain reaction and immunohistochemistry. The MVD was assessed by CD31 immunohistochemistry. The expression of COX-2 and VEGF was determined in the RCC cell lines A498 and Caki-1 under short-term hypoxia and in multicellular tumour cell aggregates. COX-2 was expressed in RCC by tumour epithelia, endothelia and macrophages in areas of cystic tumour regression and tumour necrosis. COX-2 protein in RCC was not altered in comparison with normal renal tissue. VEGF mRNA was up-regulated in RCC and positively correlated with MVD. RCC with high up-regulation of VEGF mRNA showed weak intracytoplasmic expression of VEGF in tumour cells. Intracytoplasmic VEGF protein expression was negatively correlated with MVD. In RCC with necrosis the MVD was reduced in comparison with RCC without necrosis. A498 RCC cells down-regulated COX-2 and up-regulated VEGF under conditions of hypoxia. In Caki-1 cells COX-2 expression remained stable, whereas VEGF was significantly up-regulated. In multicellular A498 cell aggregates COX-2 and VEGF were up-regulated centrally, whereas no gradient was found in Caki-1 cells.


CONCLUSIONS
COX-2 and VEGF are potential therapeutic targets because COX-2 and VEGF are expressed in RCC and associated cell populations such as endothelia and monocytes/macrophages.
Hemmerlein
B
B
Institute of Pathology, Georg-August University Hospital, Göttingen, Germany. hemmer@med.uni-goettingen.de
Galuschka
L
L
Putzer
N
N
Zischkau
S
S
Heuser
M
M
D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D008565:Membrane Proteins; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D051546:Cyclooxygenase 2; D008565:Membrane Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011451:Prostaglandin-Endoperoxide Synthases; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C496540:PTGS2 protein, human