Correlation of vascular endothelial cell proliferation with microvessel density and expression of vascular endothelial growth factor and basic fibroblast growth factor in hepatocellular carcinoma.

Tumor-associated angiogenesis is essential for tumor growth or metastasis, and consists of multiple and sequential steps regulated by proangiogenic and antiangiogenic factors. Vascular endothelial cell proliferation is involved in this process. We investigated the correlation of vascular endothelial cell proliferation with microvessel density (MVD) and expression of major proangiogenic molecules, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in hepatocellular carcinoma (HCC). Formalin-fixed paraffin-embedded specimens of surgically resected HCC from 67 patients were used. Proliferating endothelial cells were detected by immunofluorescence double staining for CD34 and proliferating cell nuclear antigen (PCNA). The proliferation activity of endothelial cells was determined by the rate of PCNA-positive endothelial cells, and evaluated at the periphery and center of the tumors and adjacent non-neoplastic livers. MVD and the expression of VEGF and bFGF in the tumors were also examined immunohistochemically. The proliferation activity of endothelial cells at the periphery of the tumors was significantly higher than that at the center of the tumors (35.8% vs. 12.7%, P<0.0001). The rate of PCNA-positive endothelial cells in the tumors with higher bFGF expression was significantly higher than that in the tumors with lower bFGF expression (44.8% vs. 32.5%, P<0.005) at the periphery of the tumors. There was no significant correlation between the rate of PCNA-positive endothelial cells and clinicopathological findings or MVD. In HCC, the proliferation activity of vascular endothelial cells is suggested to be heterogeneous in the tumor and higher at the periphery of the tumor, and bFGF may play an important role in the positive regulation of tumor-associated vascular endothelial cell proliferation.