CD31 angiogenesis and combined expression of HIF-1α and HIF-2α are prognostic in primary clear-cell renal cell carcinoma (CC-RCC), but HIFα transcriptional products are not: implications for antiangiogenic trials and HIFα biomarker studies in primary CC-RCC.
Hypoxia-inducible factors, HIF-1α and HIF-2α, are expressed in the majority of clear-cell renal cell carcinoma (CC-RCC). In vitro, HIFα isoforms regulate a differential set of genes, and their effects in vivo within CC-RCC tumours may affect outcome. The role of angiogenesis and HIFα transcriptional products, including those involved in cell metabolism and morphological dedifferentiation have not been extensively investigated and might have relevance to the development of antiangiogenic or anti-HIFα trials in primary CC-RCC, either before or after radical nephrectomy. We analysed 168 consecutive clear-cell renal tumours from 1983 to 1999 within tissue microarrays and assessed expression of HIF-1α and HIF-2α together with the protein expression of seven of their target genes (BNIP3, CA9, Cyclin D1, GLUT-1, LDH5, Oct-4 and VEGF). The expression of these factors was compared with patient overall survival and CD31 angiogenesis. We found that HIFα antigenicity deteriorated with the age of the paraffin block (P < 0.0001) and in tumours from 1983 to 1992 was deemed not to be reliable. Similar findings were found in aged archival osteosarcoma samples. This might have important implications for retrospective biomarker studies that rely on archival tissue material. HIF-1α(HIGH)/HIF-2α(LOW) tumours had a worse overall survival compared with HIF-1α(LOW)/HIF-2α(LOW) tumours (P = 0.04). Surprisingly, on multivariate analysis, high levels of CD31(+) angiogenesis was shown to be an independent prognostic marker of increased overall survival (P = 0.003). We propose that better differentiation of vascular endothelium may be a reflection of a greater production of vessel stabilization factors versus pro-angiogenic factors, and therefore a less aggressive phenotype.
Northern Institute for Cancer Research, Paul O'Gorman Building, Newcastle University, Framlington Place, Newcastle-Upon-Tyne, NE2 4HH, UK. swethajit.biswas@ncl.ac.uk
Swethajit
S
Biswas
Philip J S
PJ
Charlesworth
Gareth D H
GD
Turner
Russell
R
Leek
Paul T
PT
Thamboo
Leticia
L
Campo
Helen
H
Turley
Petra
P
Dildey
Andrew
A
Protheroe
David
D
Cranston
Kevin C
KC
Gatter
Francesco
F
Pezzella
Adrian L
AL
Harris
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000032:analysis; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D019938:Cyclin D1 / Q000032:analysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000502:physiology*; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis / Q000502:physiology*; D011379:Prognosis; D000099162:Endothelial PAS Domain-Containing Protein 1
D020533:Angiogenesis Inhibitors; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D019938:Cyclin D1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000099162:Endothelial PAS Domain-Containing Protein 1; C530104:CCND1 protein, human; C497442:HIF1A protein, human