Expression of hypoxia-inducible factors is correlated with the presence of a fibrotic focus and angiogenesis in pancreatic ductal adenocarcinomas

Aims: To study the expression of hypoxia-regulated markers in pancreatic ductal adenocarcinomas (PA) in relationship to the presence of a fibrotic focus, angiogenesis quantification and clinical outcome. Methods and results: The expression of hypoxia-inducible factor (HIF)-1 alpha, HIF-2 alpha, carbonic anhydrase 9 (CA9) and vascular endothelial growth factor (VEGF) was inummohistochemically detected in 50 PA and correlated with tumour characteristics, microvascular density (MVD) and survival. HIF-1 alpha was expressed within tumour cells in 68%, HIF-2 alpha in 46%, CA9 in 78% and VEGF in 52% of the cases. Stromal expression was also noted for HIF-2 alpha and CA9 in, respectively, 42% and 48% of the cases. Tumour CA9 expression was associated with that of VEGF (P = 0.004) and that of stromal HIF-2 alpha (P = 0.013), with the presence of a fibrotic focus (P = 0.046) and with an increased MVD (P = 0.034). Tumour VEGF expression correlated with the presence of a fibrotic focus (P = 0.039) and a greater MVD (P = 0.047). Both the presence of a fibrotic focus (P = 0.0002) and high tumour CA9 expression (P = 0.029) were associated with reduced overall survival. Conclusion: The strong association of the presence of a fibrotic focus with CA9 expression and lower survival demonstrates that hypoxia-driven angiogenesis plays an important role in the progression of PA.