Angiogenesis in renal cell carcinoma: The role of tumor-associated macrophages

Objective: To explore vascularity and associated molecules in renal cell carcinoma (RCC) and to study their correlations to disease outcome. Methods: Tissue samples from 51 Japanese patients with renal cell carcinoma (RCC) were obtained between November 1997 and August 2000. Pyrimidine nucleoside phosphorylase and vascular endothelial growth factor (VEGF) levels of RCC and normal kidney tissue were determined by enzyme-linked immunosorbent assay. Microvessel density (MVD) was measured by immunohistochemistry using anti-factor-VIII-related antigen and CD34. The number of infiltrating tumor-associated macrophages (TAM) was measured by immunohistochemistry using anti-CD68 antibody. Results: Pyrimidine nucleoside phosphorylase and VEGF levels were significantly higher in RCC than in normal kidney tissue. The VEGF level was higher in more progressive (high grade, larger or symptomatic) RCC. Although MVD as determined by the factor VIII level was higher in larger tumors, MVD determined by CD34 was higher in low-grade and low-stage tumors. Patients with symptoms, large tumor or high stage showed higher numbers of TAM. VEGF level and TAM were significantly higher in patients with recurrence than in those without recurrence. In univariate analysis, VEGF, TAM and CD34 tumor grade and stage were identified as prognostic factors. Moreover, TAM was the only independent prognostic factor by multivariate analysis. Among these parameters, only TAM and MVD as determined by factor VIII showed significant correlations. Conclusion: TAM and VEGF are substantially involved in tumor progression of RCC. As the TAM count is well correlated to the MVD, the main mechanism of tumor progression by TAM might be angiogenesis.