Novel angiogenesis markers as long-term prognostic factors in renal cell cancer

Background

Angiopoetin-2 (Ang-2), vascular endothelial growth factor receptors (VEGFRs) and CD31, a member of immunoglobulin superfamily, regulate normal vascular development and remodeling, as well as pathological neovascularization in cancer. The aim of this study was to investigate Ang-2 expression alone as single prognostic factor and in combination with other angiogenesis markers (VEGFR3 and CD31) and cell proliferation and survival markers (MIB-1 and BCL-2).

Methods

This study included 224 RCC patients whose nephrectomies were performed between 1985-1995 at Tampere University Hospital or Tampere Hospital. All tumor samples were re-evaluated and reclassified using Fuhrman grading system and Heidelberg classification. Two parallel multi tissue blocks were obtained fur further immunological analysis. Ang-2 expression was measured from digital images and positive area was expressed as the percentage of total tumor area. Ang-2 expression were categorized both by median into low (≤ 5.5) or high (>5.5) and by upper quartile into low (

Results

The median age of patients was 65 years at the time of diagnosis. Higher Ang-2 expression was associated with lower tumor stage and grade, positive VEGFR3 and high BCL-2 expression, and low MIB-1 expression (p = 0.042, p = 0.018, p = 0.005, p = 0.013 and p = 0.039, respectively). RCC patients with very high Ang-2 expression associated with better survival in Kaplan-Meier analysis. Multivariate analysis showed that RCC patients having low Ang-2 expression or high MIB-1 expression had poorer survival: HR 1.89; 95% CI 1.16-3.08, p = 0.010, HR 2.20; 95% CI 1.36-3.54, p = 0.001 compared with high Ang-2 and low MIB-1 expression. However tumor stage and grade were still powerful prognostic factors.

Conclusions

Very high Ang-2 expression was associated with better survival in RCC patients. Ang-2 expression was a significant prognostic factor in multivariate analysis together with known prognostic factors, tumor stage and grade.

Clinical trial identification

R94534

Legal entity responsible for the study

Juha Virman

Funding

Pirkanmaa Hospital District Science Center and the Academy of Finland Centre of Excellence Program.

Disclosure

P. Bono: Honoraria from Pfizer, novartis, Orion Pharma, BMS, MSD and research funding from Novartis. P-L. Kellokumpu-Lehtinen: Honoraria from Sanofi, Amgen, Bayer Eli Lilly and Researsch founding from Sanofi, Roche and Pfizer. All other authors have declared no conflicts of interest.